Singh, J Clinic Toxicol 2011, S:4

Clinical Toxicology http://dx.doi.org/10.4172/2161-0495.S4-001

Research Article
Review Article Open
OpenAccess
Access

Clinical Biochemistry of Hepatotoxicity

Anita Singh1, Tej K Bhat2 and Om P Sharma2*
1
CSK Himachal Pradesh, Krishi Vishva Vidyalaya, Palampur (HP) 176 062, India
2
Biochemistry Laboratory, Indian Veterinary Research Institute, Regional Station, Palampur (HP) 176 061, India

Abstract
Liver plays a central role in the metabolism and excretion of xenobiotics which makes it highly susceptible
to their adverse and toxic effects. Liver injury caused by various toxic chemicals or their reactive metabolites
[hepatotoxicants) is known as hepatotoxicity. The present review describes the biotransformation of hepatotoxicants
and various models used to study hepatotoxicity. It provides an overview of pathological and biochemical mechanism
involved during hepatotoxicity together with alteration of clinical biochemistry during liver injury. The review has been
supported by a list of important hepatotoxicants as well as common hepatoprotective herbs.

Keywords: Hepatotoxicity; Hepatotoxicant; In Vivo models; In Vitro production of bile thus leading to the body’s inability to flush out the
models; Pathology; Alanine aminotransferase; Alkaline phosphatase; chemicals through waste. Smooth endoplasmic reticulum of the liver is
Bilirubin; Hepatoprotective the principal ‘metabolic clearing house’ for both endogenous chemicals
like cholesterol, steroid hormones, fatty acids and proteins, and
Introduction exogenous substances like drugs and alcohol. The central role played
by liver in the clearance and transformation of chemicals exposes it to
Hepatotoxicity refers to liver dysfunction or liver damage that is
toxic injury [4].
associated with an overload of drugs or xenobiotics [1]. The chemicals
that cause liver injury are called hepatotoxins or hepatotoxicants. Models to Study Hepatotoxicity
Hepatotoxicants are exogenous compounds of clinical relevance
and may include overdoses of certain medicinal drugs, industrial In vivo Systems
chemicals, natural chemicals like microcystins, herbal remedies and Animal models represent a major tool for the study of mechanisms
dietary supplements [2,3]. Certain drugs may cause liver injury when in virtually all of biomedical research [10]. They involve the complexity
introduced even within the therapeutic ranges. Hepatotoxicity may of the whole animal thus making the monitoring of in vivo systems
result not only from direct toxicity of the primary compound but also quite difficult. An in vivo system fully reflects the exposing profile and
from a reactive metabolite or from an immunologically-mediated the cellular function as the compounds are exposed in the successive
response affecting hepatocytes, biliary epithelial cells and/or liver manner through absorption from the first exposed site followed by
vasculature [4,5]. The hepatotoxic response elicited by a chemical metabolism, distribution and elimination. However, it should involve
agent depends on the concentration of the toxicant which may be basically the same mechanism as the reactions in humans and the
either parent compound or toxic metabolite, differential expression adverse effect must be clinically sufficiently high. Both small animals
of enzymes and concentration gradient of cofactors in blood across like rats, mice, rabbits and guinea pigs as well as large animals like
the acinus [6]. Hepatotoxic response is expressed in the form of pigs, cattle, sheep and monkeys are useful and reliable for studying
characteristic patterns of cytolethality in specific zones of the acinus. the hepatotoxicant effects, distribution and clearance. They may be
Hepatotoxicity related symptoms may include a jaundice or icterus used to elucidate basic mechanism of xenobiotic activities which will
appearance causing yellowing of the skin, eyes and mucous membranes be useful in understanding their impact on human health. However,
due to high level of bilirubin in the extracellular fluid, pruritus, the relevance of the findings of in vivo studies using different animal
severe abdominal pain, nausea or vomiting, weakness, severe fatigue, models to humans may vary due to differences in drug metabolism
continuous bleeding, skin rashes, generalized itching, swelling of the and pathobiology in various species. Due to the lack of sufficient data
feet and/or legs, abnormal and rapid weight gain in a short period of to reliably assess the value of preclinical animal studies to predict
time, dark urine and light colored stool [7,8]. hepatotoxicity in humans, the preclinical animal toxicity studies
may not be sufficient as the only modelling systems used to predict
Liver- The Target Organ hepatotoxicity [11,12]. Further, in order to reduce the use of animal in
Liver is the largest organ of the human body weighing toxicity studies, there is a need for a long-term in vitro system.
approximately 1500 g, and is located in the upper right corner of
the abdomen on top of the stomach, right kidney and intestines
and beneath the diaphragm. The liver performs more than 500 vital *Corresponding author: Om P Sharma, Biochemistry Laboratory, Indian
metabolic functions [9]. It is involved in the synthesis of products like Veterinary Research Institute, Regional Station, Palampur [HP) 176 061, India,
Tel: +91 1894 230526; Fax: +91 1894 233063; E-mail: [email protected]
glucose derived from glycogenesis, plasma proteins, clotting factors
and urea that are released into the bloodstream. It regulates blood Received November 09, 2011; Accepted December 19, 2011; Published
December 22, 2011
levels of amino acids. Liver parenchyma serves as a storage organ for
several products like glycogen, fat and fat soluble vitamins. It is also Citation: Singh A, Bhat TK, Sharma OP (2011) Clinical Biochemistry of
involved in the production of a substance called bile that is excreted Hepatotoxicity. J Clinic Toxicol S4:001. doi:10.4172/2161-0495.S4-001
to the intestinal tract. Bile aids in the removal of toxic substances Copyright: © 2011 Singh A, et al. This is an open-access article distributed under
and serves as a filter that separates out harmful substances from the the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
bloodstream and excretes them [4]. An excess of chemicals hinders the source are credited.

J Clinic Toxicol Clinical Pharmacology: Research & Trials ISSN: 2161-0495 JCT, an open access journal
Citation: Singh A, Bhat TK, Sharma OP (2011) Clinical Biochemistry of Hepatotoxicity. J Clinic Toxicol S4:001. doi:10.4172/2161-0495.S4-001

Page 2 of 19

In vitro Systems Certain substances may share the same cytochrome P450 specificity,
thus competitively block their biotransformation activity and lead to
They are much easier to control and manage than the intact
accumulation of drugs metabolized by the enzyme. Genetic variations
organism. The data of in vitro studies can be utilized for deciding
appropriate doses for in vivo studies. In an in vitro system, compounds or polymorphisms in cytochrome P450 metabolism may also be
affect the cells directly and continuously until the removal of compound- responsible for unusual sensitivity or resistance to drug effects at
containing medium [13]. These models contribute to the ‘3R’ concept normal doses among different individuals [27]. Hepatotoxicity may
[refinement, reduction and replacement] of animal experimentation also arise from an adaptive immune response to proteins bound to
which leads to reduction of animal utilization for research purposes the hepatotoxicant or its metabolites [28,29]. Random exposure to
[14]. This system is quite useful for safety evaluation in the early stage lipopolysaccharides (LPS) or other inflammatory conditions could
of drug discovery as they are helpful in generating sufficient results at potentiate hepatotoxicity by involving a combination of fibrin deposit-
a low cost and high speed, and with less use of animals [15]. Several in induced hypoxia and neutrophil-mediated cell damage [30].
vitro human and animal liver models are available ranging from short-
term to long-term cell or tissue culture systems. Generally, chemical The differences in enzyme expression and substrate specificity
hepatotoxicity can be studied using six in vitro experimental systems, in species, strain or gender can produce qualitative differences or
namely, isolated perfused liver preparations, liver slices, isolated quantitative differences in the metabolic pathways involved in the
hepatocytes in suspension, isolated hepatocytes culture and co-culture, bioactivation or detoxification of hepatotoxicants. Hepatotoxic effect of
cell lines and subcellular fractions [6,12,14,16,17]. acetaminophen differs in different species. For instance, hamsters and
mice are sensitive to the hepatotoxic effects of acetaminophen whereas
Biotransformation of Hepatotoxicants rats and humans appear to be resistant. This is mainly due to differences
Liver plays a central role in biotransformation and disposition of in the rate of production of toxic metabolite of acetaminophen,
xenobiotics [18]. The close association of liver with the small intestine N-acetyl-p-benzoquinoneimine (NABQI). However, isolated
and the systemic circulation enables it to maximize the processing of hepatocytes from all the four species are equally susceptible to the toxic
absorbed nutrients and minimize exposure of the body to toxins and effects of NABQI [31]. Male rats are sensitive to the hepatoxic effect of
foreign chemicals. The liver may be exposed to large concentrations of senecionine, a pyrrolizidone alkaloid while female rats are resistant to
exogenous substances and their metabolites. Metabolism of exogenous its hepatotoxicity. This is due to the absence of isoform of cytochrome
compounds can modulate the properties of hepatotoxicant by either P450 involved in the bioactivation of senecionine in female rats [32].
increasing its toxicity (toxication or metabolic activation) or decreasing Further, the rate-controlling step in biotransformation reactions
its toxicity (detoxification) [6]. Most of the foreign substances are is cofactor supply [33]. Changes in the concentration of cofactors
lipophilic thus enabling them to cross the membranes of intestinal like NADPH and glutathione can markedly alter the sensitivity of
cells. They are rendered more hydrophilic by biochemical processes
animals to hepatotoxicants. The nutritional status of animals also
in the hepatocyte, yielding water-soluble products that are exported
plays a role in the hepatic concentrations of these cofactors. Fed rats
into plasma or bile by transport proteins located on the hepatocyte
are relatively resistant to the hepatotoxic effects of bromobenzene and
membrane and subsequently excreted by the kidney or gastrointestinal
acetaminophen whereas an overnight fasting makes them extremely
tract [19] (Figure 1).
susceptible to these hepatotoxicants [34].
The hepatic biotransformation involves Phase I and Phase II
reactions. Phase I involves oxidative, reductive, hydroxylation and
demethylation pathways, primarily by way of the cytochrome P-450
enzyme system located in the endoplasmic reticulum, which is the
most important family of metabolizing enzymes in the liver. The
endoplasmic reticulum also contains a NADPH-dependent mixed
function oxidase system, the flavin-containing monooxygenases,
which oxidizes amines and sulphur compounds. Phase I reactions often
produce toxic intermediates which are rendered non-toxic by phase
II reactions. Phase II reactions involve the conjugation of chemicals
with hydrophilic moieties such as glucuronide, sulfate or amino acids
and lead to the formation of more water-soluble metabolite which can
be excreted easily [6]. Another Phase II reaction involves glutathione
which can covalently bind to toxic intermediates by glutathione-S-
transferase [20]. As a result, these reactions are usually considered
detoxification pathways. However, this phase can also lead to the
formation of unstable precursors to reactive species that can cause
hepatotoxicity [21,22].
The activities of enzymes are influenced by various endogenous
factors and exogenous drugs or chemicals [23]. Many substances
can influence the cytochrome P450 enzyme mechanism [24]. Such
substances can serve either as inhibitors or inducers. Enzyme
inhibitors act immediately by blocking the metabolic activity of one
or several cytochrome P450 enzymes [25]. Enzyme inducers act slowly
and increase cytochrome P450 activity by increasing its synthesis [26].

J Clinic Toxicol Clinical Pharmacology: Research & Trials ISSN: 2161-0495 JCT, an open access journal
Citation: Singh A, Bhat TK, Sharma OP (2011) Clinical Biochemistry of Hepatotoxicity. J Clinic Toxicol S4:001. doi:10.4172/2161-0495.S4-001

Page 3 of 19

Mechanism of Hepatotoxicity hepatitis. Non-nucleoside reverse transcriptase inhibitors, especially

viramune [nevirapine] are also associated with hepatitis and hepatic
Pathology necrosis [46,47].
Liver pathology serves as an important tool for identifying and Cholestasis: This type of liver injury leads to impairment of bile flow,
characterizing liver injury whether or not clinicobiochemical changes itching and jaundice. Kaplowitz [43] reported angiotensin-converting
are also identified. Main patterns of liver injury during hepatotoxicity enzyme [ACE] inhibitors, amoxicillin, chlorpromazine, erythromycins
may include zonal necrosis, hepatitis, cholestasis, steatosis, granuloma, and sulindac to be associated with etiology of cholestasis. It may be
vascular lesions, neoplasm and veno-occlusive diseases (Figure 2). inflammatory, bland or ductal. Inflammatory cholestasis may be caused
Zonal necrosis: This type of injury may be caused by exogenous by allopurinol, co-amoxiclav or carbamazepine. Bland cholestasis
substances like paracetamol [35] and carbon tetrachloride [36,37]. without any parenchymal inflammation may be caused by anabolic
Amatoxins cause necrosis of liver as a consequence of the cessation of steroids and androgens [4], while ductal cholestasis showing progressive
protein synthesis due to the inhibition of RNA synthesis [38]. Herbal destruction of small bile ducts may be caused by chlorpromazine and
plants like Atractylis gummifera and Callilepsis laureola [39], Larrea flucloxacillin [48].
trdentata [40] and Teucrium polium [41] also cause necrosis. Such Steatosis: This type of liver injury may manifest as triglyceride
injury is largely confined to a particular zone of the liver lobule. It may accumulation [4,49] which leads to either small droplet
manifest as a very high level of alanine aminotransferase and severe [microvesicular] or large droplet [macrovesicular] fatty liver. Aspirin,
disturbance of liver function leading to acute liver failure. ketoprofen, tetracycline, nucleoside reverse transcriptase inhibitors
Hepatitis: This type of liver injury shows hepatocellular necrosis and valproic acid [8,43] and Scutellaria sp. plant [50] may lead to
associated with infiltration of inflammatory cells. It may be further microvesicular steatosis while acetaminophen and methotrexate [51]
characterised into three categories, namely, viral, focal and chronic. may lead to macrovesicular steatosis. Amiodarone, chlorpheniramine
Viral hepatitis, where histological features are similar to acute viral and total parenteral nutrition may cause phospholipidosis [48] where
hepatitis, may be caused by halothane [42], isoniazid, acetaminophen, phospholipid accumulation leads to pattern similar to the diseases
bromfenac, nevirapine, ritonavir, troglitazone [43] and phenytoin [4]. with inherited phospholipid metabolism defects. Nucleoside reverse
Reports exist for acute hepatitis caused by Chelidonium majus [44]. transcriptase inhibitors, especially zerit [stavudine], videx [didanosine],
Focal hepatitis where scattered foci of cell necrosis may accompany and retrovir [zidovudine] are associated with a life threatening
lymphocytic infiltration may be caused by aspirin. Chronic hepatitis condition called lactic acidosis [46,47]. Tamoxifen also leads to non-
which is similar to autoimmune hepatitis clinically, serologically and alcoholic steatohepatitis [8,43].
histologically, may be caused by methyldopa, diclofenac, dantrolene, Granuloma: Hepatic granulomas are associated with granulomas
minocycline and nitrofurantoin [43]. Among herbal remedies, Larrea located in periportal or portal areas and show features of systemic
tridentata [40] and Lycopodium serratum [45] leads to chronic vasculitis and hypersensitivity. Drugs like allopurinol, sulfonamides,

J Clinic Toxicol Clinical Pharmacology: Research & Trials ISSN: 2161-0495 JCT, an open access journal
Citation: Singh A, Bhat TK, Sharma OP (2011) Clinical Biochemistry of Hepatotoxicity. J Clinic Toxicol S4:001. doi:10.4172/2161-0495.S4-001

Page 4 of 19

pyrazinamide, phenytoin, isoniazid, penicillin and quinidine have been for conjugation can lead to the depletion of glutathione thus rendering
found to cause such injury [4,8]. cells more susceptible to the toxic effects of chemicals [64]. The reactive
metabolites may also alter liver proteins leading to an immune response
Vascular lesions: Such condition is caused by injury to the vascular
and immune-mediated injury.
endothelium and may be caused by chemotherapeutic agents [52],
bush tea [Crotalaria spp.] and anabolic steroids [53]. Lipid peroxidation and redox cycling: These are involved in
hepatotoxicity leading to cell death due to oxidative stress which is
Neoplasm: Prolonged exposure to some medications and toxins
caused by an alteration in the intracellular prooxidant to antioxidant
like vinyl chloride, anabolic steroids, arsenic and thorotrast may cause
ratio in favor of prooxidants [65]. Lipid peroxy radicals lead to increased
neoplasms like hepatocellular carcinoma, angiosarcoma and liver
adenomas [48]. cell membrane permeability, decreased cell membrane fluidity,
inactivation of membrane proteins and loss of polarity of mitochondrial
Veno-occlusive: The hepatic vein becomes clogged, blocking off membranes. Metal ions like iron and copper participate in redox
the blood supply to the liver. It is a non-thrombotic obliteration of cycling while cycling of oxidised and reduced forms of a toxicant leads
small intrahepatic veins by subendothelial fibrin [54] associated with to the formation of reactive oxygen free radicals which can deplete
congestion and potentially fatal necrosis of centrilobular hepatocytes. glutathione through oxidation or oxidize critical protein sulfhydryl
The pyrrolizidine alkaloids have been associated with this type of severe groups involved in cellular or enzymatic regulation or can initiate lipid
liver disorder [55]. Busulfan and cyclophosphamide also cause veno- peroxidation. Excessive consumption of ethanol contributes to free
occlusive disease [43,52]. radical generation, lipid peroxidation and glutathione depletion [4].
Histological findings like liver biopsy or autopsy can support Severe α-amanitin hepatotoxicity is also contributed by a peroxidative
the diagnosis of hepatotoxicity [56] (Benichou, 1990). Liver injury process [66]. Halogentaed hydrocarbons, hydroperoxides, acrylonitrile,
caused by hepatotoxicity can also be determined with X-rays, cadmium, iodoacetamide, chloroacetamide and sodium vanadate are
computerized tomography [CT] scan and endoscopic retrograde also reported to exhibit hepatotoxicity due to lipid peroxidation.
cholangiopancreatography (ERCP). Ultrastructural pathology can Disruption of calcium homeostasis: Calcium is involved in a wide
provide evidence for enzyme induction, mitochondrial changes, drug variety of critical physiological functions. Calcium homeostasis is very
accumulation and early indications of histopathological symptoms. precisely regulated in the cell. Cytosolic free calcium is maintained at
Biochemical Mechanism relatively lower concentration. The calcium concentration gradient
between the inside of the cell [10-7M] and the extracellular fluid
The hepatotoxic effects of chemical agents may involve different [10-3M] is maintained by an active membrane-associated calcium
mechanisms of cytolethality [6,43] (Figure 2). These mechanisms may and magnesium effluxing adenosine triphosphatase [ATPase]
have either direct effect on organelles like mitochondria, endoplasmic enzyme system which is an important potential target for toxicants.
reticulum, the cytoskeleton, microtubules and nucleus or indirect Chemically induced hepatotoxicity may lead to the disruption of
effect on cellular organelles through the activation and inhibition of calcium homeostasis [67,68]. Non-specific increases in permeability
signalling kinases, transcription factors and gene-expression profiles. of the plasma membrane, mitochondrial membrane and membranes
The resultant intracellular stress may lead to cell death caused by either of smooth endoplasmic reticulum lead to disruption of calcium
cell shrinkage and nuclear disassembly [apoptosis] or swelling and lysis homeostasis by increasing intracellular calcium. Decline in available
[necrosis]. Main mechanisms involved are listed below: NADPH, a cofactor required by calcium pump may also disrupt
Direct effect of toxicant upon critical cellular systems: calcium homeostasis. Disruption of calcium homeostasis may
Hepatotoxicants can attack directly certain critical cellular targets like result in the activation of many membrane damaging enzymes like
plasma membrane, mitochondria, endoplasmic reticulum, nucleus and ATPases, phospholipases, proteases and endonucleases, disruption
lysosomes thus disrupting their activity. Various chemicals and metal of mitochondrial metabolism and ATP synthesis and damage of
ions bind to mitochondrial membranes and enzymes, disrupting energy microfilaments used to support cell structure. Quinines, peroxides,
metabolism and cellular respiration [6]. Many hepatotoxicants act as acetaminophen, iron and cadmium are some of the hepatotoxicants
direct inhibitors and uncouplers of mitochondrial electron transport showing this mechanism.
[25]. Covalent binding of the drug to intracellular proteins cause a
Biochemical Markers
decrease in ATP levels leading to actin disruption and rupture of the
membrane. The mushroom toxin, phalloidin also causes increase in The hepatotoxins produce a wide variety of clinical and
plasma membrane permeability by binding to actin and disrupting the histopathological indicators of hepatic injury. Liver injury can be
cell cytoskeleton [57]. Toxicants like chlorpromazine, phenothiazines, diagnosed by certain biochemical markers like alanine aminotransferase
erythromycin salts and chenodeoxycholate have direct surfactant [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP]
effects on the hepatocyte plasma membrane [58]. NAPQI forms a and bilirubin. Elevations in serum enzyme levels are taken as the
covalent adduct with mitochondrial proteins having thiol groups and relevant indicators of liver toxicity whereas increases in both total and
plasma membrane proteins involved in calcium homeostasis. conjugated bilirubin levels are measures of overall liver function. An
elevation in transaminase levels in conjunction with a rise in bilirubin
Formation of reactive metabolites: Many hepatotoxicants like
level to more than double its normal upper level, is considered as an
carbon tetrachloride [59], amodiaquine [60], acetaminophen [61],
ominous marker for hepatotoxicity [69]. Macroscopic and in particular
halothane [42], isoniazid [62,63] allyl alcohol and bromobenzene are
histopathological observations and investigation of additional clinical
metabolically activated to chemically reactive toxic metabolites which
biochemistry parameters allows confirmation of hepatotoxicity.
can covalently bind to crucial cellular macromolecules thus inactivating
critical cellular functions [6]. Glutathione provides an efficient Hepatotoxicity can be characterized into two main groups, each
detoxification pathway for most electrophilic reactive metabolites. with a different mechanism of injury: hepatocellular and cholestatic
However, many alkylating agents, oxidative stress and excess substrates [1]. Hepatocellular or cytolytic injury involves predominantly initial

J Clinic Toxicol Clinical Pharmacology: Research & Trials ISSN: 2161-0495 JCT, an open access journal
Citation: Singh A, Bhat TK, Sharma OP (2011) Clinical Biochemistry of Hepatotoxicity. J Clinic Toxicol S4:001. doi:10.4172/2161-0495.S4-001

Page 5 of 19

serum aminotransferase level elevations, usually preceding increases and to metabolize drugs or xenobiotics. Several enzymes that trigger
in total bilirubin levels and modest increases in alkaline phosphatase important chemical reactions in the body are produced in the liver and
levels. Such injury is attributable to drugs like acetaminophen, are normally found within the cells of the liver. However, if the liver
allopurinol, amiodarone, diclofenac, isoniazid, ketoconazole, is damaged or injured, the liver enzymes spill into the blood, causing
methotrexate, nevirapine, nonsteroidal antiinflammatory drugs, elevated liver enzyme levels. The liver enzymes like transaminases,
pyrazinamide, rifampicin, retonavir, statins, tetracyclines, trazodone, alkaline phosphatase, γ-glutamyl transpeptidase, sorbitol
troglitazone and valproic acid [1,8]. Cholestatic injury is characterized dehydrogenase, glutamate dehydrogenase and lactate dehydrogenase
by predominantly initial alkaline phosphatase level elevations that in the blood can be measured to know the normal functioning of
precede or are relatively more prominent than increases in the levels liver. These enzymes help in detecting injury to hepatocytes. In case
of serum aminotransferases. Such injury is associated with amoxicillin- of patients showing hepatotoxicity with elevated liver enzymes
clavulanic acid, anabolic steroids, chlorpromazine, erythromycins, due to certain hepatotoxicant, the enzymes levels usually return to
estrogens, phenothiazines or tricyclics [1,8]. Generally mixed type of normal within weeks or months after stopping the exposure to the
injuries, involving both hepatocellular and cholestatic mechanisms, hepatotoxicant which is suspected of causing the problem. Another
occurs [70]. Azathioprine, captopril, clindamycin, ibuprofen, measurable liver function is reflected in the albumin concentration,
nitrofurantoin, phenobarbital, phenytoin, sulfonamides and verapamil total protein and the prothrombin time which are the markers of liver
are associated with causing mixed pattern liver injury [1,8,43]. The biosynthetic capacity. Biochemical markers involved in hepatotoxicity
ratio ALT: ALP plays an important role in deciding the type of liver in blood plasma and serum are listed in Table 1.
damage by hepatotoxins. The ratio is greater than or equal to five
Alanine aminotransferases- the standard clinical biomarker
during hepatocellular damage while the ratio is less than or equal
to two during cholestatic liver damage. During mixed type of liver
of hepatotoxicity
damage, the ratio ranges between two and five. ALT and AST or in Alanine aminotransferase or serum glutamic pyruvic transaminase
combination with total bilirubin are primarily recommended for the [SGPT] activity is the most frequently relied biomarker of
assessment of hepatocellular injury in rodents and non-rodents in hepatotoxicity. It is a liver enzyme that plays an important role in
non-clinical studies. ALT is considered a more specific and sensitive amino acid metabolism and gluconeogenesis. It catalyzes the reductive
indicator of hepatocellular injury than AST. transfer of an amino group from alanine to α-ketoglutarate to yield
glutamate and pyruvate. Normal levels are in the range of 5-50 U/L.
Clinical Biochemistry Elevated level of this enzyme is released during liver damage. The
The measurement of levels of substances that may be present in estimation of this enzyme is a more specific test for detecting liver
the blood helps in the initial detection of hepatotoxicity (Figure 3). abnormalities since it is primarily found in the liver [71,72,73].
The estimation of serum bilirubin, urine bilirubin and urobilinogen However, lower enzymatic activities are also found in skeletal muscles
helps in knowing the capacity of liver to transport organic anions and heart tissue. This enzyme detects hepatocellular necrosis.

J Clinic Toxicol Clinical Pharmacology: Research & Trials ISSN: 2161-0495 JCT, an open access journal
Citation: Singh A, Bhat TK, Sharma OP (2011) Clinical Biochemistry of Hepatotoxicity. J Clinic Toxicol S4:001. doi:10.4172/2161-0495.S4-001

Page 6 of 19

Biochemical
Tissue localization Cellular localization Histopathological lesion Reason of abnormality References
Parameter
Alanine
Primarily liver; trace amounts Cytoplasm and
aminotransferase Hepatocellular necrosis Leakage from damaged tissues [71,72,73]
in skeletal muscles and heart mitochondria
(EC 2.6.1.2)
Aspartate
Liver, heart, muscle, brain and Cytoplasm and
aminotransferase Hepatocellular necrosis Leakage from damaged tissues [71,72,75]
kidney mitochondria
(EC 2.6.1.1)
Alkaline phosphatase Liver, bile duct, bone, placenta, Hepatobiliary injury and
Cell membrane Overproduction and release in blood [4,76]
(EC 3.1.3.1) kidney and intestine cholestasis
γ-Glutamyl transferase Kidney, liver, bile duct, Hepatobiliary injury and
Cell membrane Overproduction and release in blood [79,80]
(EC 2.3.2.2) pancreas cholestasis
Direct (Liver, bile, small
intestine, large intestine) Hepatobiliary injury and
Total bilirubin Extracellular fluid Decreased hepatic clearance [4,75,81]
Indirect (Reticuloendothelial cholestasis
cells of spleen, serum)
Leakage of conjugated bilirubin out of the
Urine bilirubin Urine Hepatobiliary disease [82]
hepatocytes into urine
An increase in unconjugated bilirubin, due
to increased breakdown of RBCs, which
Urobilinogen Large intestine, urine Hepatocellular dysfunction [82]
undergoes conjugation, excretion in bile
and metabolism to urobilinogen
Produced in liver, stored in gall
Regurgitation into blood along with
Bile acids bladder and released into the Hepatobiliary disease [83,84]
conjugated bilirubin
intestine
Prothrombin time Hepatocellular dysfunction Decreased synthetic capacity [82]
Lactate
Liver peroxisomes, muscles, Mitochondria and
dehydrogenase Hepatocellular necrosis Leakage from damaged tissue [82]
kidney, heart sarcoplasmic reticulum
(EC 1.1.1.27)
Sorbitol
Liver, kidney, seminal vesicle, Cytoplasm,
dehydrogenase Hepatocellular necrosis Leakage from damaged tissue [75]
intestine mitochondria
(EC 1.1.1.14)
Glutamate
dehydrogenase Liver, kidney Mitochondrial matrix Hepatocellular necrosis Leakage from damaged tissues [75,85]
(EC 1.4.1.2)
Albumin Produced in liver Blood plasma Hepatic dysfunction Decreased synthesis [82]
Produced in liver and immune
Total protein Blood plasma Hepatic dysfunction Decreased synthetic capacity [82]
system
Serum F protein Liver, kidney Primarily cytoplasm Hepatocellular necrosis Leakage from damaged tissue [87,88]
Glutathione-S- Cytoplasm,
Early hepatocyte injury; Readily released from hepatocytes in
transferase Liver, kidney mitochondrial, 75,91
Hepatocellular necrosis response to injury
(EC 2.5.1.18) centrolobular cells
Arginase I
Liver Cytoplasm Hepatocellular necrosis Release from injured hepatocytes [75,93,94]
(EC 3.5.3.1)
Malate dehydrogenase Cytoplasm,
Liver, heart, muscle, brain Hepatocellular necrosis Leakage from damaged tissues [75,97,99]
(EC 1.1.1.37) mitochondria
Cytoplasm of
Purine nucleoside
endothelial cells, Released into hepatic sinusoids with
phosphorylase Liver, muscle, heart Hepatocellular necrosis [75]
kupferr cells, necrosis
(EC 2.4.2.1)
hepatocytes
Paraoxonase 1 Cytoplasm, microsomal, Not a leakage enzyme; reduced hepatic
Liver, kidney, brain, lung Hepatocellular necrosis [75,102]
(EC 3.1.8.1) endoplasmic reticulum synthesis and secretion
Table 1: Biochemical markers of hepatotoxicity in blood plasma and serum.

Aspartate aminotransferases Alkaline phosphatase- An additional conventional biomarker

Aspartate aminotransferases or serum glutamic oxaloacetate supplementing ALT activity
transaminase [SGOT] is another liver enzyme that aids in producing Alkaline phosphatase is a hydrolase enzyme that is eliminated in the
proteins. It catalyzes the reductive transfer of an amino group from bile. It hydrolyzes monophosphates at an alkaline pH. It is particularly
aspartate to α-ketoglutarate to yield oxaloacetate and glutamate. present in the cells which line the biliary ducts of the liver. It is also
Besides liver, it is also found in other organs like heart, muscle, brain found in other organs including bone, placenta, kidney and intestine.
and kidney. Injury to any of these tissues can cause an elevated blood Several isozymes have been identified in humans and preclinical
level [74]. Normal levels are in the range of 7-40 U/L. It also helps species. Normal levels are in the range of 20-120U/L. It may be elevated
in detecting hepatocellular necrosis but is considered a less specific if bile excretion is inhibited by liver damage. Hepatotoxicity leads to
biomarker enzyme for hepatocellular injury [75] as it can also signify elevation of the normal values due to the body’s inability to excrete it
abnormalities in heart, muscle, brain or kidney [71,72]. The ratio of through bile due to the congestion or obstruction of the biliary tract,
serum AST to ALT can be used to differentiate liver damage from other which may occur within the liver, the ducts leading from the liver to
organ damage [74]. the gallbladder, or the duct leading from the gallbladder through the

J Clinic Toxicol Clinical Pharmacology: Research & Trials ISSN: 2161-0495 JCT, an open access journal
Citation: Singh A, Bhat TK, Sharma OP (2011) Clinical Biochemistry of Hepatotoxicity. J Clinic Toxicol S4:001. doi:10.4172/2161-0495.S4-001

Page 7 of 19

pancreas that empty into the duodenum [small intestine]. Increase in product of hemoglobin breakdown. It is produced in the intestinal
alkaline phosphatase and/or bilirubin with little or no increase in ALT tract as a result of the action of bacteria on bilirubin. Almost half of the
is primarily a biomarker of hepatobiliary effects and cholestasis [4,76]. urobilinogen produced recirculates through the liver and then returns
In humans, increased ALP levels have been associated with drug- to the intestines through the bile duct. Urobilinogen is then excreted
induced cholestasis [77]. in the faeces where it is converted to urobilin. As the urobilinogen
circulates in the blood to the liver, a portion of it bypasses the liver
γ-Glutamyl transferase- A specific biomarker of hepatobiliary and is diverted to the kidneys and appears as urinary urobilinogen.
injury Normal urobilinogen level in urine is <1 mg/dl. Increased breakdown
γ-Glutamyl transferase [GGT] or transpeptidase [GGTP] is an of red blood cells may lead to an increase in unconjugated bilirubin
enzyme which is found in liver, kidney and pancreatic tissues, the which undergoes conjugation, excretion in bile and metabolism to
enzyme concentration being low in liver as compared to kidney [75]. urobilinogen in intestines. More urobilinogen is reabsorbed and
It catalyzes transfer of γ-glutamyl groups to amino acids and short passed to the liver and urine thus resulting in higher level of urine
peptides. It is more useful clinically when compared to ALP. ALP is urobilinogen. Low level of urine urobilinogen may be observed during
more sensitive but much less specific than GGT. The comparison of obstruction of bilirubin passage into the gut or failure of urobilinogen
the two enzymes helps in determining the occurrence of bone or liver production in the gut. Comparing the urinary bilirubin result with the
injury. Normal GGT level with an elevated ALP level is suggestive of urobilinogen result may assist in distinguishing between red blood
bone disease as GGT is not found in bone [78] while an elevated level cell hemolysis, hepatic disease, and biliary obstruction. Urobilinogen
of both the enzymes is suggestive of liver or bile duct disease. Normal is increased in hemolytic disease and urine bilirubin is negative.
levels are in the range of 0-51 U/L. GGT is a specific biomarker of Urobilinogen is increased in hepatic disease, and urine bilirubin may
hepatobiliary injury, especially cholestasis and biliary effects [79]. It be positive or negative. Urobilinogen is low with biliary obstruction,
was reported as a specific indicator of bile duct lesions in the rat liver and urine bilirubin is positive.
[80]. Bile acids
Total bilirubin levels- Another biomarker of hepatobiliary Bile acids are involved in many functions. They aid in the catabolism
injury and elimination of cholesterol, regulate pancreatic secretions and
contribute to the digestion and absorption of fat in the small intestine.
Bilirubin is an endogenous anion derived from the regular
Serum bile acid levels can be influenced by diet and fasting. Bile acids
degradation of haemoglobin from the red blood cells and excreted
are produced from cholesterol in the liver and are stored in the gall
from the liver in the bile. It is a chemical normally present in the
bladder. Gall bladder contraction with feeding releases bile acids
blood in small amounts and used by the liver to produce bile. Normal
into the intestine. They are absorbed in the intestine and taken up
bilirubin levels in the blood range between 0.2 to 1.2 mg/dL. When
by hepatocytes for re-excretion into bile. Measurement of bile acid
the liver cells are damaged, they may not be able to excrete bilirubin
concentrations is a good indicator of hepatobiliary function. The bile
in the normal way, causing a build-up of bilirubin in the blood and
acids are elevated with liver injury [83,84].
extracellular [outside the cells] fluid. Serum bilirubin could be
elevated if the serum albumin increases and the bilirubin shifts from Prothrombin time
tissue sites to circulation. Increased levels of bilirubin may also result
The prothrombin time or protime [PT] is also used to differentiate
due to decreased hepatic clearance and lead to jaundice and other
between a normal and damaged liver as it evaluates the functioning
hepatotoxicity symptoms [4]. Increase in bilirubin with little or no
of blood clotting factors that are proteins made by the liver. During
increase in ALT indicates cholestasis. In acute human hepatic injury,
hepatotoxicity, the blood clotting factors are not produced normally
total bilirubin can be a better indicator of disease severity compared
due to liver cell damage or bile flow obstruction and prolongation of
to ALT [81].
more than 2 seconds is considered abnormal [82]. The normal range of
Bilirubin is measured as total bilirubin and direct bilirubin. Total PT is 9 to 11 seconds.
bilirubin is a measurement of all the bilirubin in the blood while direct
bilirubin is a measurement of a water-soluble conjugated form of Lactate dehydrogenase
bilirubin made in the liver and its normal range is 0-0.3 mg/dl. Indirect Lactate dehydrogenase [LDH] assists in energy production. It
bilirubin is calculated by the difference of the total and direct bilirubin catalyzes the interconversion of pyruvate and lactate with concomitant
and is a measure of unconjugated fraction of bilirubin. interconversion of NADH and NAD+. Normal levels are in the range of
100-220U/L. Elevated levels of this enzyme is released from damaged
Urine bilirubin level cells in many areas of the body, including the liver. It also helps in
Bilirubin itself is not soluble in water and is tightly bound to albumin detecting hepatocellular necrosis [82].
and thus does not appear in urine. Under normal circumstances, a tiny
Sorbitol dehydrogenase
amount of bilirubin is excreted in the urine. If the liver’s function is
impaired or when biliary drainage is blocked, some of the conjugated Sorbitiol dehydrogenase [SDH] catalyzes the reversible oxidation-
bilirubin leaks out of the hepatocytes and appears in the urine, turning reduction of sorbitol, fructose and NADH. It is primarily found in the
it dark amber. The presence of urine bilirubin indicates hepatobiliary cytoplasm and mitochondria of liver, kidney and seminal vesicles. It
disease [82]. is a specific marker of acute hepatocellular injury [75] that functions
across preclinical species like rodents, rhesus monkey and beagle dogs.
Urobilinogen level Normal levels in the plasma are in the range of 1-3 U/L.
Hepatotoxicity may lead to an increase in the urobilinogen in
Glutamate dehydrogenase
urine. Increased urobilinogen has been observed during alcoholic
liver damage, viral hepatitis and hemolysis [82]. Urobilinogen is a by- Glutamate dehydrogenase [GLDH] is an enzyme that is involved

J Clinic Toxicol Clinical Pharmacology: Research & Trials ISSN: 2161-0495 JCT, an open access journal
Citation: Singh A, Bhat TK, Sharma OP (2011) Clinical Biochemistry of Hepatotoxicity. J Clinic Toxicol S4:001. doi:10.4172/2161-0495.S4-001

Page 8 of 19

in oxidative deamination of glutamate. It is present primarily in liver Arginase I

with lesser amount in kidney. GLDH activity is more liver specific
than transaminases and is not substantially affected by skeletal muscle Arginase is a hydrolase that catalyzes the catabolism of arginine to
damage [75]. Normal range of GLDH activity is reported to be 7-11 urea and ornithine. There are two isoforms of arginase, cytoplasmic
U/L in men and 5-6.4 U/L in women. Its activity increases with arginase I and mitochondrial arginase II, encoded by two different
hepatocellular damage [85]. In rats, the elevations of GLDH activity genes. Arginase I is highly liver specific compared to the other liver
reported were of much greater magnitude and persisted longer after enzymes [93,94]. Normal value of arginase I in plasma of healthy
treatment with different hepatotoxicants as compared to that of ALT humans is 1.8 to 30 ng/ml which increase approximately ten-folds
[85]. during liver injury. Arginase I showed the earliest and the greatest
increase in serum levels as compared to ALT and AST activities in
Albumin thioacetamide [TAA]-induced acute and chronic histopathological
It is the main protein in blood and is made by the liver. injury in rats [95]. Arginase I was evaluated as a more specific test of
Hepatotoxicity leads to decrease in albumin production [82]. Its liver function compared to traditional serum markers in humans after
normal range is 3.4-5.4 g/dl. It can be used as a supplementary test for liver transplantation [94].
hepatic biosynthetic functions.
Malate dehydrogenase
Total protein Malate dehydrogenase [MDH] is an enzyme in the citric acid cycle
The estimation of total proteins in the body is helpful in that catalyzes the reversible conversion of malate into oxaloacetate
differentiating between a normal and damaged liver function as the utilizing NAD+. The absolute activity in the cytoplasm is greatest
majority of plasma proteins like albumins and globulins are produced in liver followed by heart, skeletal muscle and brain [96]. MDH is
in the liver [82]. Normal range of total protein is 6.0 to 8.3 g/dl. Total also a periportal enzyme that is released into the serum indicating
protein is often reduced slightly but the albumin to globulin ratio tissue damage. Normal value of MDH in healthy human plasma is
shows a sharp decline during hepatocellular injury. 23.5-47.7 U/L. MDH activity was utilized as a biochemical index of
acetaminophen induced liver injury that coincided with histological
Serum F protein or 4-hydroxyphenylpyruvate dioxygenase evidence of necrosis in rats [97]. Elevations in MDH activity was
Serum F protein or 4-hydroxyphenylpyruvate dioxygenase [HPD] found to correlate with morphological changes after dosing with
is a key enzyme involved in tyrosine catabolism [86]. It is produced in thioacetamide, dimethylonitrosamine and diethanolamine [98]. The
large amounts in liver and small amounts in kidney while circulating at measurements of MDH activity were reported to be more useful in
low serum concentrations [0.08±0.03 U/L] in normal human subjects. estimating the severity of liver injury than similar AST measurements
There are reports showing elevations in the serum F protein of patients [99]. Ozer et al. [75] suggested that MDH can be utilized as a novel
with hepatocellular damage [87]. They reported that the serum F enzymatic serum liver biomarker.
protein concentration was a more sensitive and specific marker of liver
damage than conventional liver function tests involving AST, ALP and Purine nucleoside phosphorylase
GGT activities and showed a close correlation with the histological Purine nucleoside phosphorylase [PNP] is a key enzyme involved in
assessment of liver damage. Serum F protein is suggested as an indicator the purine salvage pathway that reversibly catalyzes the phosphorolysis
of hepatocellular dysfunction associated with anticonvulsant therapy of nucleosides to their respective bases and corresponding 1-[deoxy]-
[88]. Serum F protein is produced across a wide variety of mammalian ribose phosphate. Mammalian PNP enzyme is found in a number of
species [89]. The correlation between elevated serum F protein and tissues including liver, muscle and heart. Maximum PNP activity has
liver histopathological alterations has not yet been fully elucidated in been reported in rat liver with very less activity in heart and muscle
preclinical animal models [90]. [100]. The enzyme is reported to be released into hepatic sinusoids
Glutathione-S-transferase alpha during necrosis [75]. Elevations in serum PNP activity were observed
in rats after dosing with galactosamine [101]. Cellular necrosis and
Glutathione-S-transferase [GST] is an inducible phase II endothelial cell damage in hepatic sinusoids also showed increase in
detoxification enzymes that catalyze the conjugation of glutathione
serum PNP activity. Ozer et al. [75] suggested that PNP can also be
with reactive metabolites formed during phase I of metabolism [75].
utilized as a novel enzymatic serum liver biomarker. Normal level of
Induction of GST synthesis is a protective mechanism that occurs in
PNP in healthy human plasma is 3.2±1.4 U/L.
response to xenobiotic exposure. It is released quickly and in large
quantities into the bloodstream during hepatocellular injury and the Paraoxonase 1
elevations in its activity are more rapid than AST or ALT. Four isozymes
of GST, namely, alpha, pi, mu and theta, are expressed in human and Paraoxonase 1 [PON1] is a calcium dependent esterase that
other mammals [75]. GSTα expression is restricted to liver and kidney. is associated with high-density lipoprotein. It is involved in the
Muscle necrosis is not associated with changes in serum GSTα levels detoxification of organophosphates in the liver. PON1 is recognized
indicating that this marker may be useful in differentiating liver injury as an antioxidant enzyme and protects low-density lipoproteins from
from muscle injury [75]. Normal level of GSTα in human plasma is < oxidative modifications. It is not a leakage enzyme and is released into
4.0 µg/L. Marked hepatotoxicity and GSTα elevations corresponding to normal circulation. PON1 is produced primarily in the liver. It also
liver histopathological findings were induced in rats by a single dose of shows activity in other tissues like kidney, brain and lungs. Normal
α-napthylisothiocynate, bromobenzene and thioacetamide [91]. Much serum PON1 level in healthy candidates is 53-186 kU/L. Decreases
greater fold increases of GSTα were observed for each compound in serum PON1 activity are indicative of tissue damage in liver which
than either serum ALT or AST activities. However, the elevation was may be due to a reduction in PON1 synthesis and secretion by the
less than those observed with GLDH, SDH or total bilirubin and bile liver [102]. PON1 activity does not appear to show high specificity
acids. GSTα elevations preceded histopathological necrosis in a study for liver damage as it is linked to a number of disease conditions like
monitoring valproic acid induced hepatotoxicity in rats [92]. atherosclerosis, vasculitis and chronic hepatic damage. However, Ozer

J Clinic Toxicol Clinical Pharmacology: Research & Trials ISSN: 2161-0495 JCT, an open access journal
Citation: Singh A, Bhat TK, Sharma OP (2011) Clinical Biochemistry of Hepatotoxicity. J Clinic Toxicol S4:001. doi:10.4172/2161-0495.S4-001

Page 9 of 19

et al. [75] recommended its evaluation as a down regulated marker in overdose, a large amount of the toxic metabolite is generated which
hepatic injury. overwhelms the detoxification process and leads to liver cell death and
hepatocellular necrosis. Administration of acetylcysteine, a precursor
Hepatotoxicants of glutathione, can limit the severity of the liver damage by capturing
Hepatotoxicity can be caused by a wide variety of pharmaceutical the toxic metabolite [109]. Hydroalcoholic extract of Aerva lanata has
agents, natural products, chemicals or environmental pollutants been reported to possess hepatoprotective activity against paracetamol
and dietary constituents (Table 2 data included as supplementary). induced hepatotoxicity in rats [110].
Exposure to these hepatotoxic agents is usually accidental, through Aniline antibiotics [Sulfonamides]: Sulfonamides are aromatic
contaminated food, water or air or from unanticipated side effects amines associated with a wide range of adverse reactions including
of therapeutic agents. Toxic liver diseases caused by such agents are hepatotoxicity. Higher incidence of hepatotoxicity was observed in
often recognized late because their hepatotoxic potency is considered patients with advanced HIV infection which was probably caused
to be minimal or non-existent. Hepatotoxicity is reversible at early by increasing the oxidation to toxic metabolites by the P 450 system
stages upon cessation of exposure to the toxicant. However, severe
[1,111]. Similar symptoms were observed in dogs and humans [112].
intoxication with hepatotoxic agents can lead to liver necrosis and
Larger breeds especially Dobermans, were at higher risk than small
death of the organism if left untreated.
breeds. But the ethical and practical issues involved in experimentation
Drugs with large-dog breeds, limit the practical usefulness of this animal
model.
Drug-induced hepatotoxicity is the most important cause of
acute liver failure in many countries [5,43,63]. Almost all drugs are Anticoagulants: Oral anticoagulants like warfarin, ximelagatran,
identified as foreign substances by the body which subjects them enoxaparin, acenocoumarin, phenprocoumon and heparin are being
to various biochemical transformations involving reduction of fat used for prevention of stroke and venous thromboembolism [113].
solubility and change of biological activity, to make them suitable for Anticoagulants induced hepatotoxicity has been found to be associated
elimination [19]. Adverse drug reactions [ADRs] can be considered as with asymptomatic elevation of serum transaminases, clinically
Type A reactions [predictable or high incidence or pharmacological] significant hepatitis and fatal liver failure. Elevation of alkaline
or Type B reactions [unpredictable or low incidence or idiosyncratic; phosphatase was reported with dabigatran, ximelagatran and warfarin.
IADRs]. Type A reactions are dose-dependent and occur in a Jaundice was reported only with ximelagatran and warfarin [113].
relatively consistent time-frame. All individuals are susceptible to Heparin hepatotoxicity involved direct toxicity, hepatocyte membrane
Type A reactions which are generally a result of direct liver toxicity modification and immune-mediated hypersensitivity reaction [114].
of the parent drug or its metabolites [103] eg acetaminophen-induced Phenprocoumon hepatotoxicity caused direct damage of hepatocytes
hepatotoxicity [104] or phenytoin-induced hepatotoxicity [105]. Type by reactive metabolites which resulted in augmented antigenicity and
B reactions are unrelated to the pharmacological action of the drug consequent immunoallergic reaction. It also involved high energy
[106]. They occur in a minority of individuals and occur at doses that reactions involving cytochrome P-450 enzymes, causing decline of
do not cause toxicity in most individuals. They have variable latency adenosine triphosphate levels, loss of ionic gradients, cell swelling and
period. Further, they have not been reproducible in animal models rupture [115].
[5,43] eg troglitazone-induced hepatotoxicity [5] or isoniazid-induced Anticonvulsants or antiepileptic drugs: Some of the anticonvulsants
hepatotoxicity [10]. Some of the medications causing hepatotoxicity as may give rise to hepatotoxicity. Chloral hydrate, clonazepam,
a potential side effect are listed below: diazepam, primidone and sultiam are not considered to induce
Anaesthesia [Halothane]: Halothane causes idiosyncratic serious liver disease. Sodium valproate is an effective anticonvulsant
liver toxicity by forming a reactive trifluoroacetyl chloride reactive involving less risk of hepatotoxicity [116]. Valproate is transformed to
metabolite by cytochrome P450 and suggests an immune-mediated valproyl adenosine monophosphate and valproyl coenzyme A in the
reaction [42]. This unstable toxic metabolite binds to liver proteins mitochondrial matrix. The valproate induced depletion of coenzyme
causing cellular injury. Clinical investigations reveal elevated A affects the intramitochondrial pool of this cofactor and thus impairs
transaminases compatible with hepatitis. Patients are found to develop mitochondrial enzymes involved in β-oxidation of fatty acids [42].
autoantigens and antibodies against trifluoroacetylated protein. Patients who take phenytoin often have transaminase elevation up
An immune response to the oxidative metabolite of halothane can to three times the upper limit of normal [ULN] but liver biopsies do
be induced in guinea pigs but no clinical toxicity was observed. The not reveal significant pathology [117]. The usage of felbamate was
immune response did not escalate with repeated exposures suggesting markedly reduced because of its association with aplastic anemia and
the development of immune tolerance [107]. The toxicity induced in hepatotoxicity in some patients [5]. Phenobarbital is rarely known to
rats involves the formation of a free radical by a reductive pathway cause hepatic damage including hepatocellular and cholestatic liver
rather than trifluoroacetyl chloride by an oxidative pathway. It did not injury and also hypersensitivity reaction.
reveal the characteristics of an immune response similar to the liver
Anti-hyperlipidemic drugs: The pattern of injury from anti-
toxicity observed in humans [108].
hyperlipidemics is typically hepatocellular or mixed in nature with
Aniline analgesics [Acetaminophen]: Acetaminophen or rare instances of pure cholestatic hepatitis [118, 119]. Atorvastatin
paracetamol is usually well-tolerated in prescribed dose but overdose and lovastatin-related hepatotoxicity has been associated with a
is the most common cause of drug-induced hepatotoxicity worldwide. mixed pattern of liver injury typically occurring several months after
Damage to the liver is not due to the drug itself but to a toxic the initiation of the medication [120]. Simvastatin hepatotoxicity is
metabolite, NABQI, which is produced by cytochrome P-450 enzymes hypothesized to occur due to drug-drug interactions [121]. Provastatin
in the liver [61]. This metabolite is highly reactive and depletes has been reported to cause acute intrahepatic cholestasis [122].
glutathione. In normal circumstances, this metabolite is detoxified by Fenofibrate may very rarely instigate an autoimmune hepatitis type
conjugating with glutathione in phase II reaction. However, during reaction especially when taken in combination with statin medications

J Clinic Toxicol Clinical Pharmacology: Research & Trials ISSN: 2161-0495 JCT, an open access journal
Citation: Singh A, Bhat TK, Sharma OP (2011) Clinical Biochemistry of Hepatotoxicity. J Clinic Toxicol S4:001. doi:10.4172/2161-0495.S4-001

Page 10 of 19

[123]. Ezetimibe that lowers cholesterol by inhibiting its intestinal aspartate aminotransferase greater than three or five times of the ULN,
absorption at the brush border of the small intestine rarely causes with or without symptoms of hepatitis and/or jaundice, respectively
hepatotoxicity in the form of severe cholestatic hepatitis and acute [4]. Detoxification of drugs and metabolites are related to the activities
autoimmune hepatitis [124]. of liver enzymes. Polymorphism of these enzymes can cause variation
of hepatotoxicity by anti-tuberculosis drugs [8]. The exact mechanism
Antimalarial drugs: Antimalarial drugs like amodiaquine can
of ATDH is still unknown. Most anti-tuberculosis drugs are liposoluble
cause hepatotoxicity in humans by oxidation to a reactive metabolite,
and they are transformed into water soluble compounds by hepatic
iminoquinone, by liver microsomes and peroxidases [60]. The reactive
phase I and phase II biotransformation enzymes.
metabolites can irreversibly bind to proteins which lead to direct
toxicity by disrupting the cell function. Such patients were found to Isoniazid-induced hepatotoxicity is considered idiosyncratic i.e.
have antidrug IgG antibodies [125]. Amodiaquine can induce immune reactive toxic metabolites [hydrazine, mono acetylhydrazine] rather
response in rats analogous to that in humans but it is not sufficient to than the parent drug are responsible for hepatotoxicity [62,63].
result in clinical toxicity [126]. No animal model has been able to reproduce the characteristics of
isoniazid-induced hepatotoxicity in humans [10]. A much more rapid
Antiretroviral: There are reports regarding the hepatotoxic effects
onset of toxicity was observed in rabbits treated with isoniazid at
of three classes of antiretroviral drugs, namely, nucleoside reverse
3-hour intervals for 2 days [62]. Some of the animals showed increased
transcriptase inhibitors [NRTIs], non nucleoside reverse transcriptase
levels of transaminases that peaked at 36 hours as well as focal areas of
inhibitors [NNRTIs] and protease inhibitors [PIs] [48]. They may lead
liver necrosis. The mechanism of rifampicin-induced hepatotoxicity is
to hepatotoxicity by different mechanisms, namely, mitochondrial
unknown and there is no evidence for the presence of a toxic metabolite
damage by nucleoside analogs like didanosine and stavudine,
[131]. The combined use of rifampicin and isoniazid has been associated
hypersensitivity reactions by nevirapine, efavirenz, or abacavir, direct
with an increased risk of hepatotoxicity [132]. Rifampicin induces
liver injury byusing full doses of ritonavir and immune reconstitution
isoniazid hydrolase, increasing hydrazine production when rifampicin
phenomena, mainly in severely immunosuppressed patients with
is combined with isoniazid thus explaining the higher toxicity of the
underlying chronic hepatitis B virus [HBV]. Hypersensitivity reactions
combination. The mechanism of pyrazinamide-induced hepatotoxicity
are the most common with antiretroviral drugs [184]. Nucleoside
is also unknown. It is not clear whether hepatotoxicity is caused by
analogs [NRTIs], especially zerit [stavudine], videx [didanosine], and
pyrazinamide or its metabolites. In a rat study, pyrazinamide inhibited
retrovir [zidovudine], are associated with lactic acidosis and hepatic
the activity of several cytochrome P450 isoenzymes [133] but a study
steatosis [46]. Steatohepatitis accelerates the progression of liver
in human liver microsomes showed that it has no inhibitory effect on
fibrosis in patients with chronic hepatitis C virus [HCV] infection.
the cytochrome P450 isoenzymes [134]. A hepatoprotective effect of
NNRTIs, especially viramune [nevirapine] are associated with hepatitis
N-acetylcysteine [135] and silymarin [136] on ATDH has been shown
and hepatic necrosis. They cause liver damage by hypersensitivity
in rats.
reactions or by direct toxic effects. Nevirapine is more hepatotoxic
than efavirenz [127]. The presence of underlying chronic HCV Arthritis medications: It is not considered common but when it
infection enhances the risk of developing liver enzyme elevations. occurs it can be potentially serious. In patients treated for rheumatoid
Most protease inhibitors have been associated with episodes of liver arthritis with methotrexate, microscopic evidence of liver injury has
toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose been found for any transaminase elevation above the ULN [1,137].
ritonavir and nelfinavir being less hepatotoxic [128] and tipranavir/
Chemotherapy: Chemotherapy uses toxic chemicals or drugs like
low-dose ritonavir most hepatotoxic [129]. Low-dose ritonavir used
tyrosine kinase inhibitors, alkylating agents, antimetabolites, antitumor
as booster for other protease inhibitors does not cause hepatotoxicity.
antibiotics, platinums, biologic response modifiers and androgens to
Patients with chronic HCV infection have an increased risk of liver
destroy cancer cells [52,138]. But during treatment, if the toxins build
enzyme elevations following exposure to most antiretroviral drugs. The
up in the body faster than the liver can process them, hepatotoxicity
management of hepatotoxicity should be based on the knowledge of
may occur [139]. Chemotherapeutic agents alone or in combination
the mechanisms involved for each drug. Treatment of HCV infection
may cause hypersensitivity reactions or direct hepatic toxicity [52].
may reduce the chances for further development of liver toxicity in
these patients. Corticosteroids or glucocorticoids and anabolic androgenic
steroids: Glucocorticoids promote glycogen storage in the liver. An
Anti-tuberculosis drugs: Anti-tuberculosis drug-induced
enlarged liver is a rare side effect of long-term steroid use in children
hepatotoxicity [ATDH] is a serious problem and main cause of treatment
[140]. Steatosis may be observed both in adult and children upon
interruption and change in treatment regimen during tuberculosis
prolonged use [141]. Anabolic androgenic steroids being marketed as
treatment course [130]. ATDH causes substantial morbidity and
dietary supplements are a cause for serious hepatotoxicity [4,142].
mortality. Asymptomatic transaminase elevations are common during
anti-tuberculosis treatment but hepatotoxicity can be fatal when not Non-steroidal anti-inflammatory drugs [NSAIDs]: Hepatotoxic
recognized early and when therapy is not interrupted in time. Anti- effects of non-steroidal anti-inflammatory drugs like acetylsalicylic
tuberculosis drugs like isoniazid, rifampicin and pyrazinamide have acid range from asymptomatic elevations of serum transaminases and
been found to be potentially hepatotoxic [130]. There has been a alkaline phosphatase to acute cytolytic, cholestatic or mixed hepatitis.
report of ethambutol-induced liver cholestatic jaundice, with unclear Increases in serum transaminases and alkaline phosphatase are useful
circumstances. The risk of anti-tuberculosis drug induced hepatotoxicity parameters to monitor as early warning sign. In more severe cases,
has been found to increase by various factors like high alcohol intake, there may be accompanying signs and symptoms of anorexia, nausea,
older age, pre-existing chronic liver disease, chronic viral infection, vomiting, abdominal pain, weakness and jaundice besides increases
advanced TB, female sex, concominant administration of hepatotoxic in bilirubin and prothrombin time. Little is known about of the
drugs, inappropriate use of drugs and nutritional status [19, 130]. mechanism of NSAID-induced hepatotoxicity. Both dose-dependent
Anti-tuberculosis drug-induced hepatotoxicity has been defined as a and idiosyncratic reactions have been documented [143]. Two main
treatment-emergent increase in serum alanine aminotransferase or mechanisms are considered responsible for injury, hypersensitivity

J Clinic Toxicol Clinical Pharmacology: Research & Trials ISSN: 2161-0495 JCT, an open access journal
Citation: Singh A, Bhat TK, Sharma OP (2011) Clinical Biochemistry of Hepatotoxicity. J Clinic Toxicol S4:001. doi:10.4172/2161-0495.S4-001

Page 11 of 19

and metabolic aberration. Hypersensitivity reactions often have radical reactions] in hepatocytes might be contributing to the severe
significant anti-nuclear factor or anti-smooth muscle antibody titres, α-Amanitin hepatotoxicity. At present, the most effective clinical
lymphadenopathy and eosinophilia. Metabolic aberrations can occur antidote to acute Amanita phalloides mushroom poisoning is silybin,
as genetic polymorphisms and alter susceptibility to a wide range of an antioxidant possessing free radical scavenger activity and inhibiting
drugs [144]. Aspirin and phenylbutazone are associated with intrinsic lipid peroxidation, stabilizing membrane structure and protecting
hepatotoxicity. Ibuprofen, sulindac, phenylbutazone, piroxicam, enzymes under conditions of oxidative stress. The mushroom toxin,
diclofenac and indomethacin are associated with idiosyncratic reaction. phalloidin binds to actin thus disrupting the cell cytoskeleton, resulting
The clinical and biochemical features of diclofenac hepatotoxicity in increased plasma membrane permeability [57].
in humans and rats relates both to impairment of ATP synthesis by Likewise, aflatoxins, which are fungal toxins, cause both acute
mitochondria, and to production of active metabolites, particularly N,5- hepatotoxicity and liver carcinoma in exposed humans and animals
dihydroxydiclofenac, which causes direct cytotoxicity. Mitochondrial [29,154,155]. They are produced by the fungi, Aspergillus flavus and A.
permeability transition [MPT] has also been shown to be important parasiticus, which are common contaminants of grain foods. There have
in diclofenac-induced liver injury, resulting in generation of reactive been several reports of acute aflatoxicosis resulting in death in humans
oxygen species, mitochondrial swelling and oxidation of NADP and [154]. They have also reported that bacterial lipopolysaccharide [LPS]
protein thiols [144]. enhances the acute hepatotoxicity of aflatoxins in rats by a mechanism
Alcohol-induced hepatotoxicity that depends on tumour necrosis factor α (TNF α).

Excessive consumption of alcohol leads to hepatotoxicity which Toxic freshwater cyanobacteria are very common worldwide and
have been responsible for animal [156,157] and human intoxications
is a major health care problem worldwide [145]. Oxidative stress may
[158,159] due to the heptapeptide hepatotoxins called microcystins as
play a major role in the ethanol-mediated hepatotoxicity. It induces
well as pentapeptide hepatotoxins called nodularins. Cyanobacteria
cytochrome P450 which promotes metabolism of ethanol itself,
[Microcystis aeruginosa, Anabaena spp., Anabaenopsis spp., Nostoc
acetaminophen and others. Ethanol metabolism yields acetaldehyde
spp., Planktothrix spp., Hapalosiphon spp.] have been reported to
which contributes to glutathione depletion, protein conjugation,
commonly occur in natural lakes, reservoirs and large slow flowing
free radical generation and lipid peroxidation [4]. Findings have also
rivers. Aquatic animals like edible molluscs, fish and crayfish may be
demonstrated that ethanol feeding impairs several of the multiple
killed by microcystins but in many cases the toxicity is sub lethal and
steps in methionine metabolism that leads to progressive liver
so the animals can survive long enough to accumulate the toxins and
injury. Ethanol consumption has been reported to predominantly transfer them along the food chain and pose a risk for human health
inhibit the activity of a vital cellular enzyme, methionine synthase, [159]. These cyanobacterial toxins are reported to cause death by liver
involved in remethylating homocysteine. In some species, ethanol haemorrhage within a few hours of the acute doses in mouse bioassays
can also increase the activity of the enzyme, betaine homocysteine [160]. The mammalian toxicity of microcystins and nodularins is
methyltransferase which catalyzes an alternate pathway in methionine mediated through their strong binding to key cellular enzymes called
metabolism by utilizing hepatic betaine to remethylate homocysteine protein phosphatases [161,162]. Nagata et al. [163] have reported the
and form methionine and maintain levels of S-adenosylmethionine, protective effect of specific monoclonal antibodies on microcystin
the key methylating agent. Under extended periods of ethanol feeding, induced hepatotoxicity under both in vitro and in vivo conditions in
however, this alternate pathway cannot be maintained. This results in a mice.
decrease in the hepatocyte level of S-adenosylmethionine and increases
in two toxic metabolites, S-adenosyl homocysteine and homocysteine. Ecteinascidins [ETs] are marine natural products isolated from
Betaine has been reported to have a protective effect against the extracts of the tunicate, Ecteinascidia turbinata with potent cytotoxic
clinical problems caused by ethanol-induced vitamin A depletion activity [164,165]. The preclinical studies revealed hepatotoxicity in
and peroxidative injury in a variety of experimental models of liver rats, the females being more susceptible than the male rats [166]. The
disease [146,147,148]. Betaine, by virtue of aiding in the remethylation studies of Reid et al. [167] did not predict major gender-dependent
of homocysteine, removes both toxic metabolites [homocysteine differences in the toxicity of ET743 based on metabolism.
and S-adenosylhomocysteine], restores S-adenosylmethionine level, Fumonisins are a group of naturally occurring mycotoxins
reverses steatosis, prevents apoptosis and reduces both damaged produced primarily by fungi, Fusarium verticillioides, F. moniliform
protein accumulation and oxidative stress. and F. proliferatum, which frequently are found in corn. Experimental
administration of fumonisins cause dose-dependent hepatotoxicity in
Natural products
all species including cattle, pigs, horses, primates, sheep, rabbits, swine
There are two groups of toxicologically different compounds, and rats [168]. The backbone of the fumonisin molecule resembles that
amatoxins and phallotoxins in the hepatotoxic mushrooms of the of the sphingoid bases, sphinganine and sphingosine, two important
Amanita species, primarily of Amanita phalloides [149]. Reports precursors of sphingolipids. Sphingolipids are essential components of
exist for the toxicity cases of exposure to Amanita bisporigera [150]. cell membranes, and sphingoid bases play an important role in signal
They are cyclopeptides containing a tryptophan residue substituted transduction. Fumonisin B1 inhibits sphinganine [sphingosine]-N-
at position 2 of the indole ring by a sulfur atom which is critical for acyltransferase, a critical enzyme in the biosynthesis of sphingolipids
their toxicity [151]. α-Amanitin is a powerful natural hepatotoxin that and this fumonisin-induced alteration in sphingolipid biosynthesis in
belongs to the amatoxins isolated from deadly poisonous Amanita endothelial cells lead to increased permeability of the cell layer [169].
phalloides mushroom. The basic molecular mechanism of their toxicity He [170] reported that fumonisin B1 disrupts sphingolipid metabolism
was attributed to inhibition of RNA polymerase II of the eukaryotic by inhibiting ceramide synthase and induces expression of cytokines
cells [152]. Earlier, in vitro experiments demonstrated that α-Amanitin including TNFα in liver leading to perturbation of cell signaling.
could act either as an antioxidant or as a prooxidant depending Phomopsin is a hexapeptide mycotoxin produced by the fungus,
on the treatment conditions and toxin concentration [151,153]. Phomopsis leptostromiformis which grows on lupins after autumn rains
Zheleva et al. [66] have hypothesized that a peroxidative process [free [171,172]. The most affected animals are sheep, cattle, horses and pigs.

J Clinic Toxicol Clinical Pharmacology: Research & Trials ISSN: 2161-0495 JCT, an open access journal
Citation: Singh A, Bhat TK, Sharma OP (2011) Clinical Biochemistry of Hepatotoxicity. J Clinic Toxicol S4:001. doi:10.4172/2161-0495.S4-001

Page 12 of 19

Rubratoxin is a mycotoxin produced by the fungus, Penicillium phenylpropanoid compound found in various herbs and high-bran
rubrum and P. purpurogenum which is most commonly found on cereals has been reported to possess a protective role against arsenic
cereal grains. Symptoms vary depending on the degree of exposure and induced toxicity in rats [190].
hence extent of the liver damage or injury. Symptoms may be acute,
Carbon tetrachloride is said to induce hepatotoxicity in rats, rabbits
sub acute or chronic depending on the severity of the exposure. Factors
and humans after being metabolised to trichloromethyl free radical
such as age, race, gender, overall health and underlying liver problems
which causes peroxidative degradation in the adipose tissue resulting
may also influence a person’s risk of developing liver problems and the
in fatty infiltration of the hepatocytes [36,37,191]. Trichloromethyl free
severity of the symptoms. The hepatotoxic substance from the cultures
radicals elicit lipid peroxidation of membrane lipids in the presence
of P. rubrum produced toxic hepatitis and body hemorrhages in white
of oxygen generated by metabolic leakage from mitochondria. These
mice, guinea pigs, rabbits, and dogs [173,174]. Neubert and Merker
events lead to liver damage by loss of cell membrane integrity. Based on
[175] described several biochemical and histological observations in
the studies with isolated perfused rat liver, Masuda [59] suggested that
hepatic cells of rats injected with this material.
covalent binding of carbon tetrachloride metabolites rather than lipid
Pentacyclic triterpenoids are the focus of attention for drug research peroxidation has a significant role in the production of centrilobular
for anti-cancer, anti-AIDS, antiinflammatory and antimicrobial necrosis following carbon tetrachloride administration. The ethanol
activities. The toxic compounds of Lantana camara, lantadenes, extract of Spirulina laxissima West [Pseudanabaenaceae] has been
are also pentacyclic triterpenoids [176,177]. Both ruminants like found to have a protective effect against carbon tetrachloride-induced
cattle, buffaloes, sheep and goats, and non-ruminant animals like hepatotoxicities in rats [192]. Similarly, polyphenolic extracts from
rabbits, guinea pigs and female rats are susceptible to the hepatotoxic Ichnocarpus frutescense leaves have been found to have a protective
action of lantana toxins [178,179]. Likewise, a number of species of effect on experimental hepatotoxicity in rats by carbon tetrachloride
Eupatorium are toxic to grazing animals [180]. They are also reported [193]. Prakash et al. [194] have reported the hepatoprotective
to contain many bioactive constituents that can be exploited for drug activity of leaves of Rhododendron arboretum in carbon tetrachloride
discovery. Freeze-dried E. adenophorum powder is reported to cause induced hepatotoxicity in rats. They proposed that the flavonoids and
hepatic injury in mice [181]. Katoch et al. [182] reported that freeze- phenolic compounds present in the leaves may have the potential
dried E. adenophorum leaves caused hepatotoxicity and cholestasis hepatoprotective properties.
in rats as evident by their observations on elevated bilirubin level,
The hepatotoxicity of chloroform was reported to be due to
increase in the activities of plasma enzymes and hepatic lesions. The
phosphogene-mediated cellular glutathione depletion or increased
hepatotoxicant of E. adenophorum has been characterized as 9-oxo-
amounts of covalent binding to hepatocellular macromolecules
10,11-dehydroageraphorone [ODA], a cadinene sesquiterpene [183].
[195,196].
High tannin concentration in American cranesbill, bayberry, bilberry,
buckthorn, cola tree, lady’s mantle, oaks, poplar, walnut, wild iris, 1,1-Dichloroethylene is also reported as a remarkable hepatotoxin.
quercus and rosemary are also a potential hepatotoxicant [184]. It is more potent, faster acting and has a far more precipitous dose
threshold for liver injury in the fasted rat than carbon tetrachloride or
Industrial toxins 1,2-dichloroethylene [197,198]. Animals with diminished glutathione
The rapidly increasing levels of environmental chemicals, levels are more vulnerable to liver injury by 1,1-dichloroethylene [199].
especially heavy metals like mercury, lead and arsenic are matters of Various groups have have reported the hepatotoxicity of various olefins
increasing concern. Several natural, industrial and anthropogenic including vinyl chloride, trichloroethylene and 1,1-dichloroethylene
processes have been implicated for their higher environmental levels in [200,201]. 5-Nitro-o-toluidine is reported to cause hepatocellular
various parts of the world. Exposure to even low levels of these heavy carcinogenicity in rats [202]. The compound when taken orally as a
metals is known to have potential hazardous effect in animals as well as sweetener caused liver failure. Similarly, 4-nitro-2-aminotoluene, used
humans [185]. Mercury intoxication has been a public health problem as an artificial sweetener, has also shown liver toxicity. Hepatotoxic
for many decades [186]. Mercury has been one of the most dramatic effects of various polybrominated biphenyls in rats have also been
and best documented examples of bio-accumulation of toxins in the reported [203,204]. However, Schanbacher et al. [205] reported that
environment, particularly in the aquatic food chain. Ezeuko et al. [187] no hepatotoxicity was observed in cattle by polybrominated biphenyls.
showed that mercuric chloride is highly toxic to the liver functions in Deng et al. [206] reported the toxic effects of di- and tri-nitro toluenes
rats. They reported increase in bilirubin concentration thus indicating and amino-nitrotoluenes and proposed that the liver toxicity could be
that bile is not being excreted and/or that too much hemoglobin is being a secondary effect of primary hematological toxicities caused by these
destroyed and/or that the liver is not actively treating the hemoglobin, compounds. They found that hypoxia signalling could be an important
it is receiving and could therefore lead to jaundice. They also reported pathway affected by the compounds.
protective action of Zingiber officinalis on mercuric chloride induced
Herbal and alternative remedies or dietary supplements
hepatotoxicity. Toxicity of lead is closely related to its accumulation in
many tissues inside the body and its interference with the bioelements Since ancient times, many herbs are known to play an important
that will hamper several physiological and biochemical processes role in the treatment of various ailments. Now-a-days, the consumption
[188]. In vivo studies in lead exposed animals and workers showed the of herbal remedies in industrialised and developing countries is
generation of reactive oxygen species, stimulation of lipid peroxidation gaining popularity. These are generally recognised as safe and effective
and decreased antioxidant defense system [189]. Etlingera elatior has but some of these herbal remedies have been found to contain
been found to have a powerful antioxidant effect against lead-induced hepatotoxic constituents [39]. Very few herbal remedies have received
hepatotoxicity [185]. Likewise, environmental exposure to arsenic adequate medical and scientific evaluation. Further, they may be
also imposes a big health problem worldwide. Oxidative stress has contaminated with excessive amount of banned pesticides, microbial
been suggested as a contributory factor in the development of arsenic contaminants, heavy metals, chemical toxins adulteration with
induced hepatotoxicity. The metal chelating effect of sinapic acid, a synthetic drugs [207,208,209]. The liver injury from herbal remedies

J Clinic Toxicol Clinical Pharmacology: Research & Trials ISSN: 2161-0495 JCT, an open access journal
Citation: Singh A, Bhat TK, Sharma OP (2011) Clinical Biochemistry of Hepatotoxicity. J Clinic Toxicol S4:001. doi:10.4172/2161-0495.S4-001

Page 13 of 19

S. No. Plant Active component(s) Reference

Achillea millefolium (Gandana, Biranjasipha) Caffeic acid [226]
Andrographis paniculata (Kalmegh) Andrographolide [226,229]
Anoectochilus formosanus Kinsenoside [229]
Bacopa monniera (Bramhi) Bacoside A [229]
Cassia tora (Puvad, Chakvad) Ononitol monohydrate [226]
Cassia fistula (Amaltas) Ethanolic extract [226]
Cichorium intybus (Kasni, Chicory) Alcoholic extract, flavonoids [227]
Colchicum autumnale (Suranjan) Cochicine [229]
Curcuma longa (Haridra, turmeric) Curcumin [226]
Eclipta alba (Bhringaraj) Ethanolic extract [228,229]
Equisetum arvense (Horsetail) Onitine, Kaempferol-3-o-glucoside [226]
Foeniculum vulgare (Mishreya, Fennel) Essential oil [228]
Garcinia mangostana (Vrikshamla) Garcinone E [228]
Glycyrrhiza glabra (Yashti-madhu, Licorice) Glycyrrhzin [230]
Jatropha curcas (Ratanjyot Jangli erandi) Methanolic extract [228]
Phyllanthus amarus (Bhuiamala) Lignans, alkaloids, bioflavonoids [226,229,230]
Picrorhiza kuroa (Katuka) Irridoid glycoside mixture (Picroliv) [230]
Protium heptaphyllum (Almecega) α- And β- Amyrin [226]
Silybum marianum (Milk thistle) Flavonolignan (Silymarin) [227]
Solanum nigrum (Makoi) Aqueous extract [227]
T. catappa (Jangli badam) Punicalagin and punicalin [229]
Trigonella foenum graecum (Chandrika) Polyphenolic extract [228]
Wedelia calendulacea (Peela Bhangra) Alcoholic extract [227]
Table 3: Common medicinal plants having hepatoprotective activity.

has ranged from mild elevations of hepatic enzymes to fulminant Several reports of hepatotoxicity were made for Larrea tridentata
liver failure requiring liver transplantation. Complete absence of [Chapparal], proclaimed to be an aging retardant [212]. It has been
potential idiosyncratic reactions in any herbal therapy cannot be reported to cause jaundice, fulminant hepatitis, subacute hepatic
guaranteed. Intake of herbal supplements can cause adverse effect on necrosis, cholestatic hepatitis and acute liver failure [216,217]. It may
livers of people with normal functioning livers and no history of prior cause liver injury by inhibition of cyclooxygenase or cytochrome
liver disease. New patterns of liver injury continue to emerge among P450 activity or through an immune-mediated response. Acorus spp.
known herbal hepatotoxins. The varied manifestations of liver injury and Asarum spp. contain α-asarone, a volatile allylbenzene which
include steatosis, acute and chronic hepatitis, hepatic fibrosis, zonal can form a hepatotoxic epoxide metabolite when activated by hepatic
or diffuse hepatic necrosis, bile duct injury, veno-occlusive disease, microsomal enzymes [212]. Acute hepatitis was reported following
acute liver failure requiring liver transplantation and carcinogenesis. intake of greater celandine [Chelidonium majus], widely used to
Potential interactions between herbal medicines and conventional treat gallstone disease and dyspepsia [44,218]. The hepatotoxicity
drugs may also interfere with patient management [210,211]. caused by Kava [Piper methysticum rhizoma] is also well-documented
Pyrrolizidene alkaloids [PA] are found in many herbs belonging [70,219,220]. Cimicifugae racemosae rhizome [black cohosh, root]
to Asteracceae and Boraginaceae families and their toxicity is well- is also reported to be hepatotoxic [221]. Margosa oil is reported to
documented [212,213]. Any herb containing pyrrolizidine alkaloids induce microvesicular steatosis [42]. Marjuana [Cannabis sativa] and
is potentially hepatotoxic. Hepatotoxicity due to PA can result from hashish [Cannabis indica] commonly cause abnormalities of aspartate
either small amounts ingested over long periods of time or from large aminotransferase, alanine aminotransferase or alkaline phosphatase
amounts ingested over a short period of time. This hepatotoxicant but serious hepatotoxicity has not been reported [42]. Cocaine can also
has been found in approximately 350 different plant species. Some cause ischemic necrosis of the liver.
of the most toxic of these herbs containing PA are Tussilago farfara Many Chinese herbal remedies like Ma-huang, an alkaloid derived
[Coltsfoot], Borago officinalis [Borage], Symphytum spp. [Comfrey], from plants of the Ephedra species [222] and Sho-wu-pian have also
Eupatorium purpureum [Queen of the meadow], Petasites spp. been found to be hepatotoxic. Jin Bu Huan [Lycopodium serratum]
[Butterburr], Senecio spp. [Liferoot], Heliotropium and Crotalaria typically used as an herbal sedative, has been reported to cause acute
species. Pyrrolizidine poisoning is common in Africa and Jamaica, hepatitis [45]. It was reported to contain tetrahydropalmatine, an
two areas of the world where herbal teas containing this substance alkaloid that was used for alleviating pain and promoting sleep.
are consumed as folk remedies for a number of ailments. PAs have Dictamnus dasycarpus and D. baixianpi, one of the most commonly
been associated with a severe type of liver disorder known as veno- used Chinese herbs for treatment of eczema, was also found as a
occlusive disease. This can result in abdominal pain, vomiting, ascites, potential culprit in the liver toxicity cases in England [223]. The herb
hepatomegaly, edema, cirrhosis, liver failure, and even death due to has not shown up as a liver toxin in laboratory animal testing, and it
extensive liver damage. is not reported in the medical literature from other countries as being
All preparations containing germander [Teucrium chamaedrys], as suspected for causing adverse liver reactions.
a weight-loss remedy, were prohibited for human use in France and Treatment
Canada following the reports of several cases of hepatitis [214,215].
Furan-containing neoclerodane diterpenoids from germander have The treatment of hepatotoxicity is dependent upon the causative
been found to show hepatotoxicity in rat hepatocytes [215]. agent, the degree of liver dysfunction and the age and general health of

J Clinic Toxicol Clinical Pharmacology: Research & Trials ISSN: 2161-0495 JCT, an open access journal
Citation: Singh A, Bhat TK, Sharma OP (2011) Clinical Biochemistry of Hepatotoxicity. J Clinic Toxicol S4:001. doi:10.4172/2161-0495.S4-001

Page 14 of 19

the individual. There is no effective treatment other than stopping the Official ATS Statement: Hepatotoxicity of antituberculosis therapy. Am J Respir
Crit Care Med 174: 935-952.
causative medication or removal from the exposure to the causative
agent and providing general supportive care. The best way is to 5. Deng X, Luyendyk JP, Ganey PE, Roth RA (2009) Inflammatory stress and
discontinue the use of any medicinal drug that may put excess stress idiosyncratic hepatotoxicity: Hints from animal models. Pharmacol Rev 61: 262-
282.
on the liver and use an alternate medication that helps to diminish
or manage the side effects of hepatotoxicity. Alternatively the dosage 6. Kedderis GL (1996) Biochemical basis of hepatocellular injury. Toxicol Pathol
24: 77-83.
of current drug may be changed. Abstinence from alcohol use may
also reduce the risk of hepatotoxicity. Prompt use of N-acetylcysteine 7. Bleibel W, Kim S, D’Silva K, Lemmer ER (2007) Drug-induced liver injury:
after acetaminophen overdose [224] and intravenous carnitine for Review Article. Dig Dis Sci 52: 2463-2471.
valproate-induced hepatotoxicity [225] has been reported for the 8. Chang CY, Schaino TD (2007) Review article: Drug hepatotoxicity. Aliment
treatment of acute liver injury. Diuretics or water-pills like furosemide Pharmacol Ther 25: 1135-1151
and hydrochlorothiazide may also be prescribed as they work to 9. Naruse K, Tang W, Makuuchi M (2007) Artificial and bioartificial liver support: A
prevent or treat fluid accumulation in the body. Cholestyramine review of perfusion treatment for hepatic failure patients. World J Gastroenterol
and ursodeoxycholic acid may be used for alleviation of pruritus. 13: 1516-1521.
Nutrient supplements like taurine, methionine, S-adenosylmethionine, 10. Uetrecht J (2006) Role of animal models in the study of drug-induced
arginine, polyenylphosphatidylcholine, α-lipoic acid, vitamin B, hypersensitivity reactions. AAPS J 7: 914-921.
antioxidant vitamins [A,C,E] and methylsulfonylmethane that support 11. Olson H, Betton G, Robinson D, Thomas K, Monro A, et al. (2000) Concordance
phase I and phase II activities also serve as hepatoprotective agents. of the toxicology of pharmaceuticals in humans and animals. Regul Toxicol
There are many herbs and herbal drugs which are reported to have Pharmacol 32: 56-67.
hepatoprotective effect [226-229]. Some of them are listed in Table 12. Dambach DM, Andrews BA, Moulin F (2005) New technologies and screening
3. Only four plants have been elucidated scientifically following strategies for hepatotoxicity: use of in vitro models. Toxicol Pathol 33: 17-26.
internationally accepted standard protocols to develop evidence 13. Paillard F, Finot F, Mouche I, Prenez A, Vericat JA (1999) Use of primary
based alternative herbal hepatoprotective drugs [227]. Silymarin, a cultures of rat hepatocytes to predict toxicity in the early development of new
flavonolignan from Silybum marianum [milk thistle] is an effective chemical entities. Toxicol In Vitro13: 693-700.

herbal hepatoprotective agent which prevents damage to the liver by 14. Grosse-Siestrup C, Pfeffer J, Unger V, Nagel S, Witt C, et al. (2002) Isolated
antioxidative, anti lipid peroxidative, anti-inflammatory, membrane in Vitro hemoperfused slaughterhouse livers as a valid model to study
hepatotoxicity. Toxicol Pathol 30: 749-754.
stabilizing, immunomodulatory and liver regenerating mechanism
[230]. Glycyrrhiza glabra, Picrorhiza Kurroa and Phyllanthus amarus 15. Kikkawa R, Fujikawa M, Yamamoto T, Hamada Y, Yamada H, et al. (2006)
have also been proved scientifically to possess hepatoprotective effect In vivo hepatotoxicity study of rats in comparison with in vitro hepatotoxicity
screening system. J Toxicol Sci 31: 23-34.
[227]. Drugs like troglitazone, bromfenac, ticrynafen, benoxaprofen,
bromfenac, trovafloxacin, ebrotidine, nimesulide, nefazodone, 16. Groneberg DA, Grosse-Siestrup C, Fischer A (2002) In vitro models to study
hepatotoxicity. Toxicol Pathol 30: 394-399.
ximelagatran and pemoline have been withdrawn due to hepatotoxicity
[231,232,233]. Preclinical tests of various therapeutic agents should 17. Sahu SC, Tuschl G, Hrach J, Hewitt PG, Mueller SO (2008) Application of
hepatocyte cultures to predict toxicities. In: Hepatotoxicity: From genomics to in
be done scientifically. Public should be properly educated about the
vitro and in vivo models (ed.) John Wiley and Sons, England.
probability of various hepatotoxicants. Due emphasis should be given
on the possibility of drug interactions and sharing knowledge of newly 18. Miyai K, Meeks RG, Harrison SD, Bull RJ (1991) Structural organization of the
liver. In: Hepatotoxicology. CRC Press, Boca Raton, FL.
reported hepatotoxins. All the therapeutic agents should be properly
labelled and the dose standardized. Due importance should be given to 19. Tostmann A, Boeree MJ, Aarnoutse RE, de Lange WCM, van der Ven AJ,
et al. (2008) Antituberculosis drug-induced hepatotoxicity: Concise up-to-date
quality control. The individuals should adhere to recommended doses.
review. J Gastroenterol Hepatol 23: 192-202.
They should report unexpected liver symptoms. Regular monitoring of
liver function tests should be done. 20. Lee WM (1995) Medical progress: Drug-induced hepatotoxicity. N Engl J Med
333: 1118-1127.
Chaotic use of many herbal remedies is a growing medical, 21. Stogniew M, Fenselau C (1982) Electrophilic reactions of acyl linked
scientific and public health problem. The vast biodiversity of nature is glucuronides: Formation of clofibrate mercapturate in humans. Drug Metab
an abundant source of many bioactive compounds that may be useful Dispos 10: 609-613.
in the fight against chronic diseases. Many studies are being carried on 22. Anders MW, Lash L, Dekant W, Elfarra AA, Dohn DR (1988) Biosynthesis and
a vast number of herbs to evaluate their biological activity. The plant biotransformation of glutathione S-conjugates to toxic metabolites. Crit Rev
bioresource needs to be screened appropriately for various therapeutic Toxicol 18: 311-341.
activities for the discovery of new drugs. Such systematic studies are 23. Lee J, Boyer JL (2000) Molecular alterations in hepatocyte transport. Seminars
also needed so that the herbal remedies can be used with much more in Liver Disease 20: 373-384.
security. Because of the liver’s important role in biotransformation 24. Michalets EL (1998) Update: Clinically significant cytochrome P-450 drug
of drugs and toxins, drug-induced hepatotoxicity should be a major interactions. Pharmacotherapy 18: 84-112.
concern in drug development and chronic drug therapy. 25. Monshouwer M, Witkamp RF, Nijmeijer SM, Van Leengoed LA, Verheijden
JH, et al. (1995) Infection (Actinobacillus pleuropneumoniae)-mediated
References suppression of oxidative hepatic drug metabolism and cytochrome P450 3A
1. Navarro VJ, Senior JR (2006) Drug-related hepatotoxicity. N Engl J Med 354: mRNA levels in pigs. Drug Metab Dispos 23: 44-47.
731-739.
26. Lynch T, Price A (2007) The effect of cytochrome P450 metabolism on drug
2. Willett KL, Roth RA, Walker L (2004) Workshop overview: hepatotoxicity response, interactions, and adverse effects. Am Fam Physician 76: 391-396.
assessment for botanical dietary supplements. Toxicol Sci 79: 4-9.
27. Williams DP, Park BK (2003) Idiosyncratic toxicity: The role of toxicophores and
3. Papay JI, Clines D, Rafi R, Yuen N, Britt SD, et al. (2009) Drug-induced liver bioactivation. Drug Discov Today 8: 1044-1050.
injury following positive drug rechallenge. Regul Toxicol Pharmacol 54: 84-90.
28. Park BK, Naisbitt DJ, Gordon SF, Kitteringham NR, Pirmohamed M (2001)
4. Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, et al. (2006) An Metabolic activation in drug allergies. Toxicology 158: 11-23.

J Clinic Toxicol Clinical Pharmacology: Research & Trials ISSN: 2161-0495 JCT, an open access journal
Citation: Singh A, Bhat TK, Sharma OP (2011) Clinical Biochemistry of Hepatotoxicity. J Clinic Toxicol S4:001. doi:10.4172/2161-0495.S4-001

Page 15 of 19

29. Ju C, Uetrecht JP (2002) Mechanism of idiosyncratic drug reactions: Reactive antamanide: The biologically active components of poisonous Amanita
metabolite formation, protein binding and the regulation of the immune system. mushrooms. CRC Crit Rev Biochem 5: 185-260.
Curr Drug Metab 3: 367-377.
58. Seeman P (1972) The membrane actions of anesthetics and tranquilizers.
30. Luyendyk JP, Shaw PJ, Green CD, Maddox JF, Ganey PE, et al. (2005) Pharmacol Rev 24: 583-655.
Coagulation-mediated hypoxia and neutrophil-dependent hepatic injury in rats
given lipopolysaccharide and ranitidine. J Pharmacol Exp Ther 314: 1023-1031. 59. Masuda Y (2006) Learning toxicology from carbon tetrachloride-induced
hepatotoxicity. Yakugaku Zasshi 126: 885-899.
31. Tee LB, Davies DS, Seddon CE, Boobis AR (1987) Species differences in the
hepatotoxicity of paracetamol are due to differences in the rate of conversion to 60. Shimizu S, Atsami R, Itokawa K, Iwasaki M, Aoki T, et al. (2009) Metabolism-
its cytotoxic metabolite. Biochem Pharmacol 36: 1041-1052. dependent hepatotoxicity of amodiaquine in glutathione-depleted mice. Arch
Toxicol 83: 701-701.
32. Williams DE, Reed RL, Kedzierski B, Dannan GA, Guengerich FP, et al. (1989)
Bioactivation and detoxication of the pyrrolizidine alkaloid senecionine by 61. Wallace JL (2004) Acetaminophen hepatotoxicity: NO to the rescue. Br J
cytochrome P-450 enzymes in rat liver. Drug Metab Dispos 17: 387-392. Pharmacol 143: 1-2.

33. Thurman RG, Kauffman FC (1979) Factors regulating drug metabolism in intact 62. Sarich TC, Youssefi M, Zhou T, Adams SP, Wall RA, et al (1996) Role of
hepatocytes. Pharmacol Rev 31: 229-251. hydrazine in the mechanism of isoniazid hepatotoxicity in rabbits. Arch Toxicol
70: 835-840.
34. Pessayre D, Dolder A, Artigou JY, Wandscheer JC, Descatoire V, et al.
(1979) Effect of fasting on metabolite-mediated hepatotoxicity in the rat. 63. Lee WM (2003) Drug-induced hepatotoxicity. N Engl J Med 349: 474-485.
Gastroenterology 77: 264-271.
64. Meister A (1988) Glutathione metabolism and its selective modification. J Biol
35. Boyd EH, Bereczky GM (1966) Liver necrosis from paracetamol. Br J Pharmacol Chem 263: 17205-17208.
Chemother 26: 606-614.
65. Sies H (1985) Oxidative Stress: Introductory Remarks. In: Oxidative Stress.
36. Parkinson A, Klaassen CD (2001) Biotransformation of xenobiotics. In: Casarett Academic Press, London.
and Doull’s Toxicology. (6th edn) McGraw-Hill, New York.
66. Zheleva a, Tolekova a, Zhelev M, Uzunova V, Platikanova M, et al. (2007) Free
37. Mochizuki M, Shimizu S, Urasoko Y, Umeshita K, Kamata T, et al. (2009) radical reactions might contribute to severe alpha amanitin hepatotoxicity- A
Carbon tetrachloride-induced hepatotoxicity in pregnant and lactating rats. J hypothesis. Med hypotheses 69: 361-367.
Toxicol Sci 34: 175-181.
67. Pounds JG, Rosen JF (1988) Cellular Ca2+ homeostasis and Ca2+ mediated cell
38. Vetter J (1998) Toxins of Amanita phalloides. Toxicon 36: 13-24. processes as critical targets for toxicant action: Conceptual and methodological
pitfalls. Toxicol Appl Pharmacol 94: 331-341.
39. Larrey D (1997) Hepatotoxicity of herbal remedies. J Hepatol 26: 47-51.
68. Nicotera P, Bellomo G, Orrenius S (1990) The role of Ca2+ in cell killing. Chem
40. Lee AU, Farrell GC (1997) Drug-induced liver disease. Curr Opin Gastroenterol Res Toxicol 3: 484-494.
13: 199-205.
69. Reuben A (2004) Hy’s law. Hepatol 39: 574-578.
41. Mattéi A, Rucay P, Samuel D, Feray C, Reynes M, et al. (1995) Liver
transplantation for acute liver failure after herbal medicine (Teucrium polium) 70. Teschke R (2009) Hepatotoxicity by drugs and dietary supplements: safety
administration. J Hepatol 22: 597. perspectives on clinical and regulatory issues. Ann Hepatol 8: 184-195.

42. Murray KF, Hadzic N, Wirth S, Bassett M, Kelly D (2008) Drug-related 71. Dufour DR, Lott JA, Nolte FS, Gretch DR, Koff RS, et al. (2000) Diagnosis and
hepatotoxicity and acute liver failure. J Pediatr Gastroenterol Nutr 47: 395-405. monitoring of hepatic injury: I. Performance characteristics of laboratory tests.
Clin Chem 46: 2027-2049.
43. Kaplowitz N (2004) Drug-induced liver injury. Clin Infect Dis 38: S44-S48.
72. Dufour DR, Lott JA, Nolte FS, Gretch DR, Koff RS, et al. (2000) Diagnosis and
44. Benninger J, Schneider HT, Schuppan D, Kirchner T, Hahn EG (1999) Acute monitoring of hepatic injury: II. Recommendations for use of laboratory tests in
hepatitis induced by Greater Celandine (Chelidonium majus). Gastroenterology screening, diagnosis and monitoring. Clin Chem 46: 2050-2068.
117: 1234-1237.
73. Amacher DE (2002) A toxicologist’s guide to biomarkers of hepatic response.
45. Picciotti A, Campo N, Brizzolara R, Giusto R, Guido G, et al. (1998) Chronic Hum Exp Toxicol 21: 253-262.
hepatitis induced by Jin Bu Huan. J Hepatol 28: 165-167.
74. Nathwani RA, Pais S, Reynolds TB, Kaplowitz N (2005) Serum alanine
46. Piroth L (2005) Liver steatosis in HIV-infected patients. AIDS Rev 7: 197-209. aminotransferase in skeletal muscle diseases. Hepatology 41: 380-382.
47. Patel V, Hedayati SS (2006) Lactic acidosis in an HIV-infected patient receiving 75. Ozer J, Ratner M, Shaw M, Bailey W, Schomaker S, et al. (2008) The current
highly active antiretroviral therapy. Nat Clin Pract Nephrol 2: 109-114. state of serum biomarkers of hepatotoxicity. Toxicology 245: 194-205.
48. Brind AM (2007) Drugs that damage the liver. Medicine 35: 26-30. 76. Ramaiah SK (2007) A toxicologist guide to the diagnostic interpretation of
hepatic biochemical parameters. Food Chem Toxicol 45: 1551-1557.
49. Yu AS, Keeffe EB (2002) Nonalcoholic fatty liver disease. Rev Gastroenterol
Disord 2: 11-19. 77. Wright TM, Vandenberg AM (2007) Risperidone- and quetiapine-induced
50. Itoh S, Marutani K, Nishijima T, Matsuo S, Itabashi M (1995) Liver injuries cholestasis. Ann Pharmacother 41: 1518-1523.
induced by herbal medicine, syo-saiko-to (xiao-chai-hutang). Dig Dis Sci 40: 78. Daniel SP, Marshall MK (1999) Evaluation of the liver: Laboratory tests. Schiff’s
1845-1848. diseases of the liver (8th edn). JB Lippincott publications USA 205-239.
51. Langman G, Hall PM, Todd G (2001) Role of non-alcoholic steatohepatitis in 79. Sheehan M, Haythorn P (1979) Predictive values of various liver function tests
methotrexate-induced liver injury. J Gastroenterol Hepatol 16: 1395-1401. with respect to the diagnosis of liver disease. Clin Biochem 12: 262-263.
52. King PD, Perry MC (2001) Hepatotoxicity of chemotherapy. The Oncologist 6: 80. Leonard TB, Neptun DA, Popp JA (1984) Serum gamma glutamyltransferase
162-176. as a specific indicator of bile duct lesions in the rat liver. Am J Pathol 116:
53. Ishak KG, Zimmerman HJ (1995) Morphologic spectrums of drug-induced 262-269.
hepatic disease. Gastroenterol Clin North Am 24: 759-786. 81. Dufour DR, Lott JA, Nolte FS, Gretch DR, Koff RS, et al. (2001) Diagnosis and
54. Rollins BJ (1986) Hepatic veno-occlusive disease. Am J Med 81: 297-306. monitoring of hepatic injury. II. Recommendations for use of laboratory tests in
screening, diagnosis and monitoring. Clin Chem 47: 1133-1135.
55. Farrell GC (1994) Drug-Induced Liver Disease. Churchill Livingstone, New
York. 82. Thapa BR, Walia A (2007) Liver function tests and their interpretation. Indian J
Pediatr 74: 663-671.
56. Benichou C (1990) Criteria for drug-induced liver disorder: report of an
international consensus meeting. J Hepatol 11: 272-276. 83. Geuken E, Visser D, Kuipers F, Blokzijl H, Leuvenink HG, et al. (2004) Rapid
increase of bile salt secretion is associated with bile duct injury after human
57. Wieland T, Faulstich H (1978) Amatoxins, phallotoxins, phallolysin and liver transplantation. J Hepatol 41: 1017-1025.

J Clinic Toxicol Clinical Pharmacology: Research & Trials ISSN: 2161-0495 JCT, an open access journal
Citation: Singh A, Bhat TK, Sharma OP (2011) Clinical Biochemistry of Hepatotoxicity. J Clinic Toxicol S4:001. doi:10.4172/2161-0495.S4-001

Page 16 of 19

84. Zollner G, Marschall HU, Wagner M, Trauner M (2006) Role of nuclear 106. Senior JR (2008) What is idiosyncratic hepatotoxicity? What is it not?
receptors in the adaptive response to bile acids and cholestasis: pathogenetic Hepatology 47: 1813-1815.
and therapeutic considerations. Mol Pharm 3: 231-251.
107. Furst SM, Luedke D, Gaw HH, Reich R, Gandolfi AJ (1997) Demonstration of
85. O’Brien PJ, Slaughter MR, Polley SR, Kramer K (2002) Advantages of a cellular immune response in halothane-exposed guinea pigs. Toxicol Appl
glutamate dehydrogenase as a blood biomarker of acute hepatic injury in rats. Pharmacology 143: 245-255.
Lab Anim 36: 313-321.
108. McLain GE, Sipes IG, Brown BR (1979) An animal model of halothane
86. Neve S, Aarenstrup L, Tornehave D, Rahbek-Nielsen H, Corydon TJ, et al. hepatotoxicity: Roles of enzyme induction and hypoxia. Anesthesiology 51:
(2003) Tissue distribution, intracellular localization and proteolytic processing 321-326.
of rat 4-hydroxyphenylpyruvate dioxygenase. Cell Biol Int 27: 611-624.
109. Kozer E, Koren G (2001) Management of paracetamol overdose: Current
87. Foster GR, Goldin RD, Oliveira DB (1989) Serum F protein: a new sensitive controversies. Drug Safety 24: 503-512.
and specific test of hepatocellular damage. Clin Chim Acta 184: 85-92.
110. Manokaran S, Jaswanth A, Sengottuvelu S, Nandhakumar J, Duraisamy R et
88. Callaghan N, Majeed T, O’Connell A, Oliveira DB (1994) A comparative study al (2008) Hepatoprotective activity of Aerva lanata Linn. against paracetamol
of serum F protein and other liver function tests as an index of hepatocellular induced hepatotoxicity in rats. Research J Pharm and Tech 1: 398-400.
damage in epileptic patients. Acta Neurol Scand 89: 237-241. 111. Gordin FM, Simon GL, Wofsy CB, Mills J (1984) Adverse reactions to
89. Oliveira DB, Vindlacheruvu S (1987) The phylogenetic distribution of the liver trimethoprim-sulfamethoxazole in patients with the acquired immunodeficiency
protein F antigen. Comp Biochem Physiol 87: 87-90. syndrome. Ann Intern Med 100: 495-499.

90. Beckett GJ, Foster GR, Hussey AJ, Oliveira DB, Donovan JW, et al (1989) 112. Trepanier LA (2004) Idiosyncratic toxicity associated with potentiated
Plasma glutathione-S-transferase and F protein are more sensitive than alanine sulfonamides in the dog. J Vet Pharmacol Ther 27: 129-138.
aminotransferase as markers of paracetamol (acetaminophen)-induced liver 113. Arora N, Goldhaber SZ (2006) Anticoagulants and transaminase elevation.
damage. Clin Chem 35: 2186-2189. Circulation 113: 698-702.
91. Giffen PS, Pick CR, Price MA, Williams A, York MJ (2002) Alpha-glutathione- 114. Carlson MK, Gleason PP, Sen S (2001) Elevation of hepatic transaminases
S-transferase in the assessment of hepatotoxicity - Its diagnostic utility in after enoxaparin use: Case report and review of unfractionated and low
comparison with other recognized markers in the Wistar Han rat. Toxicol Pathol molecular weight heparin induced hepatotoxicity. Pharmacotherapy 21: 108-
30: 365-372. 113.
92. Tong V, Teng XW, Chang TK, Abbott FS (2005) Valproic acid II: Effects 115. Schimanski CC, Burg J, Mohler M, Hohler T, Kanzler S et al. (2004)
on oxidative stress, mitochondrial membrane potential and cytotoxicity in Phenprocoumon-induced liver disease ranges from mild acute hepatitis to
glutathione-depleted rat hepatocytes. Toxicol Sci 86: 436-443. (sub-) acute liver failure. J Hepatol 41: 67-74.
93. Ikemoto M, Tsunekawa S, Toda Y, Totani M (2001) Liver-type arginase is a 116. Green SH (1984) Sodium valproate and routine liver function tests. Arch Dis
highly sensitive marker for hepatocellular damage in rats. Clin Chem 47: 946- Child 59: 813-814.
948.
117. Amacher D (1998) Serum transaminase elevations as indicators of hepatic
94. Ashamiss F, Wierzbicki Z, Chrzanowska A, Scibior D, Pacholczyk M, et injury following the administration of drugs. Regul Toxicol Pharmacol 27: 119-
al. (2004) Clinical significance of arginase after liver transplantation. Ann 130.
Transplant 9: 58-60.
118. Chitturi S, George J (2002) Hepatotoxicity of commonly used drugs:
95. Murayama H, Ikemoto M, Fukuda Y, Tsunekawa S, Nagata A (2007) Advantage nonsteroidal anti-inflammatory drugs, antihipertensives, antidiabetic agents,
of serum type-I arginase and ornithine carbamoyltransferase in the evaluation psycotropic drugs. Semin Liver Dis 22: 195-206.
of acute and chronic liver damage induced by thioacetamide in rats. Clin Chim
Acta 375: 63-68. 119. Parra JL, Reddy KR (2003) Hepatotoxicity of hypolipidemic drugs. Clinics in
Liver Disease 7: 415-433.
96. Bergmeyer H, Gawehn K, Bergmeyer H (1974) Malate Dehydrogenase. In:
120. Bhardwaj SS, Chalasani N (2007) Lipid lowering agents that cause drug-
Methods of Enzymatic Analysis (Vol 2, 2nd edn) Academic Press, New York.
induced hepatotoxicity. Clin Liver Dis 11: 597.
97. Zieve L, Anderson W, Dozeman R, Draves K, Lyftogt C (1985) Acetaminophen
121. Ricaurte B, Guirguis A, Taylor HC, Zabriskie D (2006) Simvastatin-amiodarone
liver injury: Sequential changes in two biochemical indices of regeneration and
interaction resulting in rhabdomyolysis, azotemia, and possible hepatotoxicity.
their relationship to histologic alterations. J Lab Clin Med 105: 619-624.
Ann Pharmacother 40: 753-757.
98. Korsrud GO, Grice HC, McLaughlan JM (1972) Sensitivity of several serum
122. Hartleb M, Rymarczyk G, Januszewski K (1999) Acute cholestatic hepatitis
enzymes in detecting carbon tetrachloride-induced liver damage in rats. Toxicol
associated with provastatin. Am J Gastroenterol 94: 1388-1390.
App Pharmacol 22: 474-483.
123. Alsheikh-Ali AA, Kuvin JT, Karas RH (2004) Risk of adverse events with
99. Kawai M, Hosaki S (1990) Clinical usefulness of malate dehydrogenase and its fibrates. Am J Cardiol 94: 935-938.
mitochondrial isoenzyme in comparison with aspartate aminotransferase and
its mitochondrial isoenzyme in sera of patients with liver disease. Clin Biochem 124. Stolk MF, Becx MC, Kuypers KC, Seldenrijk CA (2006) Severe hepatic side
23: 327-334. effects of ezetimibe. Clin Gastroenterol Hepatol 4: 908-911.

100. Dwenger A, Ivar T, Bergmeyer H (1983) Purine-nucleoside phosphorylase. In: 125. Clarke JB, Neftel K, Kitteringham NR, Park BK (1991) Detection of antidrug
Methods of Enzymatic Analysis (Vol 3, 3rd edn) Academic Press, New York. IgG antibodies in patients with adverse drug reactions to amodiaquine. Int
Allergy Appl Immunol 95: 369-375.
101. Ohuchi T, Tada K, Akamatsu K (1995) Endogenous ET-1 contributes to liver
injury induced by galactosamine and endotoxin in isolated perfused rat liver. 126. Clarke JB, Maggs JL, Kitteringham NR, Park BK (1990) Immunogenicity of
Am J Physiol 268: 997-1003. amodiaquine in the rat. Int Arch Allergy Appl Immunol 91: 335-342.

102. Feingold K, Memon R, Moser A, Grunfeld C (1998) Paraoxonase activity in the 127. van Leth F, Phanuphak P, Ruxtrungham K, Baraldi E, Miller S, et al. (2004)
serum and hepatic mRNA levels decrease during the acute phase response. Comparison of first-line antiretroviral therapy with regimens including
Atherosclerosis 139: 307-315. nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a
randomised open-label trial, the 2NN Study. Lancet 363: 1253-1263.
103. Pham TV, Lu S, Kaplowitz N (1997) Acetaminophen hepatotoxicity. In:
Gastrointestinal Emergencies. 2nd ed. Taylor MB (ed.) Williams and Wilkins, 128. Sulkowski M, Mehta S, Chaisson R, Thomas D, Moore R (2004) Hepatotoxicity
Baltimore 371-88. associated with protease inhibitor-based antiretroviral regimens with or without
concurrent ritonavir. AIDS 18: 2277-2284.
104. Amar PJ, Schiff ER (2007) Acetaminophen safety and hepatotoxicity - Where
do we go from here? Expert Opin Drug Saf 6: 341-355. 129. Rockstroh J, Sulkowski M, Neubacher D, Mayers D, Stern J (2006) 24-week
efficacy of tipranavir boosted with ritonavir in hepatitis B or C coinfected
105. Shear N, Spielberg S (1988) Anticonvulsant hypersensitivity syndrome: In vitro patients. 45th Interscience Conference on Antimicrobial Agents and
assessment of risk. J Clin Invest 82: 1826-1832. Chemotherapy.

J Clinic Toxicol Clinical Pharmacology: Research & Trials ISSN: 2161-0495 JCT, an open access journal
Citation: Singh A, Bhat TK, Sharma OP (2011) Clinical Biochemistry of Hepatotoxicity. J Clinic Toxicol S4:001. doi:10.4172/2161-0495.S4-001

Page 17 of 19

130. Khalili H, Dashti-Khavidaki S, Rasoolinejad M, Rezaie L, Etminana M (2009) 154. Barton CC, Barton EX, Ganey PE, Kunkel SL, Roth RA (2001) Bacterial
Anti-tuberculosis drugs related hepatotoxicity: Incidence, risk factors, pattern lipopolysaccharide enhances aflatoxin B1 hepatotoxicity in rats by a mechanism
of changes in liver enzymes and outcome. DARU 17: 163-167. that depends on tumor necrosis factor α. Hepatology 33: 66-73.
131. Westphal JF, Vetter D, Brogard JM (1994) Hepatic side-effects of antibiotics. 155. Zhang L, Ye Y, An Y, Tian Y, Wang Y, et al. (2011) Systems responses of
J Antimicrob Chemother 33: 387-401. rats to aflatoxin B1 exposure revealed with metabonomic changes in multiple
biological matrices. J Proteome Res 10: 614-623.
132. Steele MA, Burk RF, DesPrez RM (1991) Toxic hepatitis with isoniazid and
rifampin. A meta-analysis. Chest 99: 465-471. 156. Watanabe MF, Oishi S (1980) Toxicities of Microcystis aeruginosa collected
from some lakes, reservoirs, ponds and moat in Tokyo and adjacent regions.
133. Maffei FR, Carini M (1980) The inhibitory effect of pyrazinamide on microsomal
Japanese Journal of Limnology 41: 5-9.
monooxygenase activities is related to the binding to reduced cytochrome
P-450. Pharmacol Res Commun 12: 523-537. 157. Scott WE (1991) Occurrence and significance of toxic cyanobacteria in
Southern Africa. Water Science and Technology 23: 175-180.
134. Nishimura Y, Kurata N, Sakurai E, Yasuhara H (2004) Inhibitory effect of
antituberculosis drugs on human cytochrome P450-mediated activities. J 158. Vasconcelos VM, Sivonen K, Evans WR, Carmichael WW, Namikoshi M
Pharmacol Sci 96: 293-300. (1996) Hepatotoxic microcystin diversity in cyanobacterial blooms collected in
135. Attri S, Rana SV, Vaiphei K, Sodhi CP, Katyal R, et al. (2000) Isoniazid- and Portuguese freshwaters. Water Research 30: 2377-2384.
rifampicin-induced oxidative hepatic injury- protection by N-acetylcysteine. 159. Vasconcelos VM (1999) Cyanobacterial toxins in Portugal: Effects on aquatic
Hum Exp Toxicol 19: 517-522. animals and risk for human health. Braz J Med Biol Res 32: 249-254.
136. Tasduq SA, Peerzada K, Koul S, Bhat R, Johri RK (2005) Biochemical 160. WHO (1999) Toxic cyanobacteria in water: A guide to their public health
manifestations of anti-tuberculosis drugs induced hepatotoxicity and the effect consequences, monitoring and management. Chorus I, Bartram J (ed).
of silymarin. Hepatol Res 31: 132-135.
161. Barford D, Keller J (1994) Co-crystallization of the catalytic subunit of the
137. Kremer JM, Lee RG, Tolman KG (1989) Liver histology in rheumatoid arthritis
serine/threonine specific protein phosphatase 1 from human in complex with
patients receiving long-term methotrexate therapy: A prospective study with
microcystin-LR. J Mol Biol 235: 763-766.
baseline and sequential biopsy samples. Arthritis Rheum 32: 121-127.
162. Goldberg J, Huang HB, Kwon YG, Greengard P, Nairn AC, et al. (1995)
138. Perry MC (1992) Chemotherapeutic agents and hepatotoxicity. Seminars in
Three-dimensional structure of the catalytic subunit of protein serine/threonine
Oncology 19: 551-565.
phosphatase-1. Nature 376: 745-753.
139. Lim AYL, Segarra I, Chakravarthi S, Akram S, Judson JP (2010) Histopathology
and biochemistry analysis of the interaction between sunitinib and paracetamol 163. Nagata S, Soutome H, Tsutsumi T, Hasegawa A, Sejikima M, et al. (1995)
in mice. BMC Pharmacol 10: 14-30. Novel monoclonal antibodies against microcystin and their protective activity
for hepatotoxicity. Nat Toxins 3: 78-86.
140. Iancu TC, Shiloh H, Dembo L (1986) Hepatomegaly following short-term high-
dose steroid therapy. Journal of Pediatr Gastroenterol Nutr 5: 41-46. 164. Wright AE, Forleo DA, Gunawardana GP, Gunasekera SP, Koehn FE, et al.
(1990) Antitumor tetrahydroisoquinoline alkaloids from the colonial ascidian
141. Alpers DH, Sabesin SM, Schiff L, Schiff ER (1982) Diseases of the liver. JB Ecteinascidia turbinata. J Org Chem 55: 4508-4512.
Lippincott, Philadelphia pp. 813-45.
165. Rinehart KL, Holt TG, Fregeau NL, Stroh JG, Keifer PA, et al. (1990)
142. Kafrouni MI, Anders RA, Verma S (2007) Hepatotoxicity associated with Ecteinascidins 729, 743, 745, 759A, 759B, and 770: Potent antitumor agents
dietary supplements containing anabolic steroids. Clinical Gastroenterol from the Caribbean tunicate Ecteinascidia turbinata. Journal of Organic
Hepatol 5: 809-812. Chemistry 55: 4512-4515.
143. Manov I, Motanis H, Frumin I, Iancu TC (2006) Hepatotoxicity of anti- 166. Mirsalis JC, Fairchild DG, Smith S, Duncan K, Donohue SJ, et al. (1997)
inflammatory and analgesic drugs: Ultrastructural aspects. Acta Pharmacol Toxicity of ecteinascidin 743 in female Fischer-344 rats administered i.v. in a
Sin 27: 259-272. multiple-dose regimen. Proceedings of the American Association for Cancer
Research 38: 309.
144. O’Connor N, Dargan PI, Jones AL (2003) Hepatocellular damage from non-
steroidal anti-inflammatory drugs. QJM 96: 787–791. 167. Reid JM, Kuffel MJ, Ruben SL, Morales JJ, Rinehart KL, et al. (2002) Rat
and human liver cytochrome P-450 isoform metabolism of Ecteinascidin 743
145. Lieber CS (1994) Metabolic consequences of ethanol. Endocrinologist 4: 127-
does not predict gender-dependent toxicity in humans. Clin Cancer Res 8:
139.
2952-2962.
146. Barak AJ, Beckenhauer HC, Mailliard ME, Kharbanda KK, Tuma DJ (2003)
Betaine lowers elevated S-adenosylhomocysteine levels in hepatocytes from 168. Mathur S, Constable PD, Eppley RM, Tumbleson ME, Smith GW, et al. (2001)
ethanol-fed rats. J Nutr 133: 2845-2848. Fumonisin B1 increases serum sphinganine concentration but does not alter
serum sphingosine concentration or induce cardiovascular changes in milk-
147. Kanbac G, Dokumacioglu A, Tektas A, Kartkaya K, Erden Inal M (2009) fed calves. Toxicol Sci 60: 379-384.
Betaine (trimethylglycine) as a nutritional agent prevents oxidative stress after
chronic ethanol consumption in pancreatic tissue of rats. Int J Vitam Nutr Res 169. Gumprecht LA, Beasley VR, Weigel RM, Parker HM, Tumbleson ME, et al.
79: 79-86. (1998) Development of fumonisin-induced hepatotoxicity and pulmonary
edema in orally dosed swine: morphological and biochemical alterations.
148. Kharbanda KK (2009) Alcoholic liver disease and methionine metabolism. Toxicol Pathol 26: 777-788.
Semin Liver Dis 29: 155-165.
170. He Q (2004) Modification of fumonisin B1 hepatotoxicity in mice: Implication of
149. Piqueras J (1989) Hepatotoxic mushroom poisoning: Diagnosis and free sphingoid base accumulation and cytokine signalling. PhD Dissertation
management. Mycopathologia 105: 99-110. submitted to the Graduate Faculty of the University of Georgia, Athens,
Georgia.
150. Madhok M, Scalzo AJ, Blume CM, Neuschwander-Tetri BA, Weber JA, et al.
(2006) Amanita bisporigera ingestion: Mistaken identity, dose-related toxicity 171. Peterson JE (1990) Biliary hyperplasia and carcinogenesis in chronic liver
and improvement despite severe hepatotoxicity. Pediatr Emerg Care 22: 177- damage induced in rats by phomopsin. Pathology 22: 213-222.
180.
172. Yu M, Than K, Colegate S, Shiell B, Michalski WP, et al. (2005) Peptide
151. Zheleva A, Michelot D, Zhelev Z, Carpenter B, Dobreva Z (1994) Reactivity of mimotopes of phomopsins: Identification, characterization and application in
the tryptathionin moiety of alpha-amanitin and implication in the toxic process. an immunoassay. Mol Divers 9: 233-240.
Toxicon 32: 410.
173. Hays AW, Wilson BJ (1968) Bioproduction and purification of rubratoxin B.
152. Seifart T, Sekeris CE (1969) Alpha-amanitin, a specific inhibitor of transcription Appl Microbiol 16: 1163-1167.
by mammalian RNA polymerase. Zeitschrift fur Naturforsch B 34: 1538-1542.
174. Moss MO, Robinson FV, Wood AB (1968) Rubratoxin B, a toxic metabolite of
153. Zhelev AM, Michelot D, Zhelev ZD (2000) Sensitivity of alpha-amanitin to Penicillium rubrum. Chem ind 18: 587-588.
oxidation by a lactoperoxidase–hydrogen peroxide system. Toxicon 38: 1055-
1063. 175. Neubert D, Merker HJ (1965) Some effects of toxins from microorganisms

J Clinic Toxicol Clinical Pharmacology: Research & Trials ISSN: 2161-0495 JCT, an open access journal
Citation: Singh A, Bhat TK, Sharma OP (2011) Clinical Biochemistry of Hepatotoxicity. J Clinic Toxicol S4:001. doi:10.4172/2161-0495.S4-001

Page 18 of 19

on mammalian cellular metabolism and structure. In: Recent advances in the 1,1-dichloroethylene in rats: Comparison with carbon tetrachloride and
pharmacology of toxins. Raudonat HW (ed) Pergamon Press Limited, Oxford, 1,2-dichloroethylene. Toxicol Appl Pharmacol 23: 501-510.
England pp. 17-20.
198. Jaeger RJ, Trabulus MJ, Murphy SD (1973) Biochemical effects of
176. Sharma OP, Dawra RK, Makkar HPS (1988) Effect of polymorphic crystal 1, 1-dichloroethylene in rats: Dissociation of its hepatotoxicity from a
forms of lantana toxins on icterogenic action of guinea pigs. Toxicol Lett 42: lipoperoxidative mechanism. Toxicol Appl Pharmacol 24: 457-467.
29-37.
199. Reynolds ES, Moslen MT, Boor PJ, Jaeger RJ (1980) 1, 1-Dichloroethylene
177. Sharma S, Sharma OP (1999) Effect of lantadene A induced toxicity on hepatotoxicity: Time course of GSH changes and biochemical aberrations. Am
enzymes, associated with cholestasis in blood plasma of guinea pigs. Medical J Pathology 101: 331-344.
Science Research 27: 157-158.
200. Reynolds ES, Moslen MT, Szabo S, Jaeger RJ, Murphy SD (1975)
178. Singh A, Sharma, OP, Kurade NP, Ojha S (2001) Detoxification of lantana Hepatotoxicity of vinyl chloride and 1,1-dichloroethylene: Role of mixed
hepatotoxin, lantadene A using Alcaligenes faecalis. J Appl Toxicol 21: 225- function oxidase system. Am J Pathol 81: 219-236.
228
201. Reynolds ES, Moslen MT (1977) Damage to hepatic cellular membranes by
179. Sharma OP, Sharma S, Pattabhi V, Mahato SB, Sharma PD (2007) A review chlorinated olefins with emphasis on synergism and antagonism. Environ
of the hepatotoxic plant Lantana camara. Crit Rev in Toxicol 37: 313-352. Health Perspect 21: 137-147.
180. Sharma OP, Dawra RK, Kurade NP, Sharma PD (1998) A review of the 202. Shimizu H, Kumada T, Nakano S, Kiriyama S, Sone Y, et al. (2002) Liver
toxicosis and biological properties of the genus Eupatorium. Nat Toxins 6: dysfunction among workers handling 5-nitro-o-toluidine. Gut 50: 266-270.
1-14.
203. Lee KP, Herbert RR, Sherman H, Aftosmis JG, Waritz RS (1975) Bromine
181. Sani Y, Harper PAW, Cook RL, Seawright AA, Ng JC (1989) The toxicity of tissue residue and hepatotoxic effects of octabromobiphenyl in rats. Toxicol
Eupatorium adenophorum for the liver of mouse. In: Proceedings of the Third Appl Pharmacol 34: 115-127.
International Symposium on Poisonous Plants. 626-629.
204. Dent JG, Netter KJ, Gibson JE (1976) Effects of chronic administration
182. Katoch R, Sharma OP, Dawra RK, Kurade NP (2000) Hepatotoxicity of
of polybrominated biphenyls on parameters associated with hepatic drug
Eupatorium adenophorum to rats. Toxicon 38: 309-314.
metabolism. Res Commun Chem Pathol Pharmacol 13: 75-82.
183. Bhardwaj R, Singh A, Sharma OP, Dawra RK, Kurade NP, et al. (2001)
205. Schanbacher FL, Willett LB, Moorhead PD, Mercer HD (1978) Effects of PBBs
Hepatotoxicity and cholestasis in rats induced by the sesquiterpene, 9-oxo-
on Cattle. III. Target organ modification as shown by renal function and liver
10,11-dehydroageraphorone, isolated from Eupatorium adenophorum. J
biochemistry. Environ Health Perspect 23: 119-127.
Biochem Mol Toxicol 15: 279-286.
206. Deng Y, Meyer SA, Guan X, Escalon BL, Ai J, et al. (2011) Analysis of common
184. Fetrow CW, Avila JR (2004) Professional’s Handbook of Complementary and
and specific mechanisms of liver function affected by nitrotoluene compounds.
Alternative Medicines, 3rd edn Lippincott Williams and Wilkins, Philadelphia.
PLoS ONE 6: e14662
185. Haleagrahara N, Jackie T, Chakravarthi S, Rao M, Kulur A (2010) Protective
effect of Etlingera elatior (torch ginger) extract on lead acetate-induced 207. Bogusz MJ, Al Tufail M, Hassan H (2002) How natural are ‘natural herbal
hepatotoxicity in rats. J Toxicol Sci 35: 663-671. remedies’? A Saudi perspective. Adverse Drug React Toxicol Rev 21: 219-
229.
186. World Health Organization (1990) Methyl mercury. Environmental Health
Criteria 101: 144. 208. Chan K (2003) Some aspects of toxic contaminants in herbal medicines.
Chemosphere 52: 1361-1371.
187. Ezeuko VC, Nwokocha CR, Mounmbegna PE, Nriagu CC (2007) Effects of
Zingiber officinale on liver function of mercuric chloride-induced hepatotoxicity 209. Idodo-Umeh G, Ogbeibu AE (2010) Bioaccumulation of the heavy metals in
in adult Wistar rats. Electron J Biomed 3: 40-45. cassava tubers and plantain fruits grown in soils impacted with petroleum and
non-petroleum activities. Research Journal of Environmental Sciences 4: 33-
188. Berrehal AA, Nehdi A, Hajjaji N, Gharbi N, el-Fazaa S (2007) Antioxidant 41.
enzymes activities and bilirubin level in adult rat treated with lead. Comptes
Rendus Biologies 330: 581-588. 210. Miller LG (1998) Herbal medicinals. Selected clinical considerations focusing
on known or potential drug-herb interactions. Arch Intern Med 158: 2200-2210.
189. Sandhir R, Gill KD (1995) Effect of lead on lipid peroxidation in liver of rats. Biol
Trace Elem Res 48: 91-97. 211. Abebe W (2002) Herbal medication: Potential for adverse interactions with
analgesic drugs. J Clin Pharm Ther 27: 391-401.
190. Pari L, Jalaludeen AM (2011) Protective role of sinapic acid against arsenic-
induced toxicity in rats. Chem biol Interact 194: 40-47. 212. McGuffin M, Hobbs C, Upton R, Goldberg A (1997) American Herbal Products
Association’s Botanical Safety Handbook. Boca Raton, FL, CRC Press.
191. Boll M, Weber LWD, Becker LE, Stampfl A (2001) Mechanism of carbon
tetrachloride induced hepatotoxicity. Hepatocellular damage by reactive CCl4 213. Chitturi S, Farrell GC (2000) Herbal hepatotoxicity: An expanding but poorly
metabolites. Z Naturforsch C 56: 649-659. defined problem. J Gastroenterol Hepatol 15: 1093-1099.

192. Kuriakose GC, Kurup MG (2011) Antioxidant and antihepatotoxic effect of 214. Laliberte L, Villeneuve JP (1996) Hepatitis after the use of germander, a herbal
Spirulina laxissima against carbon tetrachloride induced hepatotoxicity in rats. remedy. CMAJ 154: 1689-1692.
Food Funct 2: 190-196.
215. Lekehal M, Pessayre D, Lereau JM, Moulis C, Fouraste, et al. (1996)
193. Kumarappan C, Vijayakumar M, Thilagam E, Balamurugan M, Thiagarajan Hepatotoxicity of the herbal medicine germander: metabolic activation of its
M, et al. (2011) Protective and curative effects of [polyphenolic extracts from furano diterpenoids by cytochrome P450 3A depletes cytoskeleton-associated
Ichnocarpus frutescense leaves on experimental hepatotoxicity by carbon protein thiols and forms plasma membrane blebs in rat hepatocytes.
tetrachloride and tamoxifen. Ann Hepatol 10: 63-72. Hepatology 24: 212-218.
194. Prakash T, Fadadu SD, Sharma UR, Surendra V, Goli D, et al. (2008) 216. Sheikh NM, Philen RM, Love LA (1997) Chaparral-associated hepatotoxicity.
Hepatoprotective activity of leaves of Rhododendron arboretum in CCL4 Arch Intern Med 157: 913-919.
induced hepatotoxicity in rats. J Med Plant Res 2: 315-320.
217. Seef LB, Lindsay KL, Bacon BR, Kresina TF, Hoofnagle JH (2001)
195. Purushothum KR, Lockard VG, Mehendale HM (1998) Amplification of Complementary and alternative medicine in chronic liver disease. Hepatology
chloroform hepatotoxicity and lethality by dietary chlordecone (Kepone) in 34: 595-603.
mice. Toxicol Pathol 16: 27-34.
218. Stickel F, Poschl G, Seitz HK, Waldherr R, Hahn EG, et al (2003) Acute
196. Burke AS, Redeker K, Kurten, RC, James LP, Hinson JA (2007) Mechanisms hepatitis induced by Greater Celandine (Chelidonium majus). Scand J
of chloroform-induced hepatotoxicity: Oxidative stress and mitochondrial Gastroenterol 38: 565-568.
permeability transition in freshly isolated mouse hepatocytes. J Toxicol
Environ Health 20: 1936-1945. 219. Schmidt M (2007) Quality criteria for kava. HerbalGram 73: 45-49.

197. Jenkins LJ Jr, Trabulus MJ, Murphy SD (1972) Biochemical effects of 220. Zhou P, Gross S, Liu JH, Yu BY, Feng LL, et al. (2010) Flavokawain B, the

J Clinic Toxicol Clinical Pharmacology: Research & Trials ISSN: 2161-0495 JCT, an open access journal
Citation: Singh A, Bhat TK, Sharma OP (2011) Clinical Biochemistry of Hepatotoxicity. J Clinic Toxicol S4:001. doi:10.4172/2161-0495.S4-001

Page 19 of 19

hepatotoxic constituent from kava root, induces GSH-sensitive oxidative stress Mahesh Kumar K, et al. (2010) Hepatoprotective Herbs – A Review. Int J Res
through modulation of IKK/NF-κB and MAPK signaling pathways. FASEB J 24: Pharm Sci 1: 1-5.
4722-4732.
228. Vishnu Priya V, Niveda S, Pratiksha G, Gayathri R (2010) A review of
221. Teschke R, Schwarzenboeck A (2008) Suspected hepatotoxicity by hepatoprotective natural products. Recent Research in Science and
Cimicifugae racemosa rhizoma (black cohosh, root): critical analysis and Technology 2: 49-52.
structured casuality assessment. Phytomedicine 16: 72-84.
229. Deshwal N, Sharma AK, Sharma Piush (2011) Review on hepatoprotective
222. Nadir A, Agarwal S, King PD, Marshall JB (1996) Acute hepatitis associated plants. International Journal of Pharmaceutical Sciences Review and
with the use of a chinese herbal product, Ma-huang. Am J Gastroenterol 91: Research 7: 15-26.
1436-1438.
230. Pradhan SC and Girish C (2006) Hepatoprotective herbal drug, silymarin from
223. McRae CA, Agarwal K, Mutimer D, Bassendine MF (2002) Hepatitis associated experimental pharmacology to clinical medicine. Indian J Med Res 124: 491-
with Chinese herbs. Eur J Gastroenterol Hepatol 14: 559-562. 504.

224. Polson J, Lee WM. (2005) AASLD position paper: the management of acute 231. Xu JJ, Diaz D, O’Brien PJ (2004) Applications of cytotoxicity assays and pre-
liver failure. Hepatology 41: 1179-1197. lethal mechanistic assays for assessment of human hepatotoxicity potential.
Chemico-Biol Interact 150: 115-128.
225. Bohan TP, Helton E, McDonald I, Konig S, Gazitt S, et al. (2001) Effect of
L-carnitine treatment for valproate-induced hepatotoxicity. Neurology 41: 232. CDER (2005) Report to the Nation: Improving Public health through Human
1405-1409. Drugs. Food and Drug Administration, Centre for Drug Evaluation and
Research, US Department of Health and Human Services.
226. Bhragual DD, Kumar N, Garg VK, Sharma PK (2010) Review on plants having
hepatoprotective activity. J Pharm Res 3: 2077-2082. 233. Goldkind L, Laine L (2006) A systematic review of NSAIDS withdrawn from the
market due to hepatotoxicity: Lessons learned from the bromfenac experience.
227. Mohamed Saleem TS, Madhusudhana Chetty C, Ramkanth S, Rajan VST, Pharmacoepidemiol Drug Saf 15: 213-220.

Submit your next manuscript and get advantages of OMICS

Group submissions
Unique features:

• User friendly/feasible website-translation of your paper to 50 world’s leading languages

• Audio Version of published paper
• Digital articles to share and explore
Special features:

• 200 Open Access Journals

• 15,000 editorial team
• 21 days rapid review process
• Quality and quick editorial, review and publication processing
• Indexing at PubMed (partial), Scopus, DOAJ, EBSCO, Index Copernicus and Google Scholar etc
• Sharing Option: Social Networking Enabled
This article was originally published in a special issue, Clinical Pharmacology: • Authors, Reviewers and Editors rewarded with online Scientific Credits
Research & Trials handled by Editor(s). Dr. Jennifer Helen Martin, University • Better discount for your subsequent articles
of Queensland, Australia Submit your manuscript at: www.omicsonline.org/submission/

J Clinic Toxicol Clinical Pharmacology: Research & Trials ISSN: 2161-0495 JCT, an open access journal