Drug Metabolism Reviews

ISSN: 0360-2532 (Print) 1097-9883 (Online) Journal homepage: https://www.tandfonline.com/loi/idmr20

Ethanol and its metabolites: update on toxicity,

benefits, and focus on immunomodulatory effects

Brendan Le Daré, Vincent Lagente & Thomas Gicquel

To cite this article: Brendan Le Daré, Vincent Lagente & Thomas Gicquel (2019): Ethanol and its
metabolites: update on toxicity, benefits, and focus on immunomodulatory effects, Drug Metabolism
Reviews, DOI: 10.1080/03602532.2019.1679169

To link to this article: https://doi.org/10.1080/03602532.2019.1679169

Published online: 24 Oct 2019.

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DRUG METABOLISM REVIEWS
https://doi.org/10.1080/03602532.2019.1679169

REVIEW ARTICLE

Ethanol and its metabolites: update on toxicity, benefits, and focus on

immunomodulatory effects

a,b,c
Brendan Le Dare , Vincent Lagentea and Thomas Gicquela,c
a
Univ Rennes, INSERM, INRA, Institut NuMeCan (Nutrition, Metabolisms and Cancer), Rennes, France; bPharmacy Unit, Pontchaillou
University Hospital, Rennes, France; cForensic and Toxicology Laboratory, Pontchaillou University Hospital, Rennes, France

ABSTRACT ARTICLE HISTORY

This article summarizes recent experimental and epidemiological data on the toxic and beneficial Received 14 August 2019
effects of ethanol and its metabolites (acetaldehyde), and focuses on their immunomodulatory Accepted 7 October 2019
effects. The section dealing with the toxic effects of alcohol focuses on its chronic toxicity (liver
KEYWORDS
disorders, carcinogenic effects, cardiovascular disorders, neuropsychic disorders, addiction and
Ethanol; alcohol;
withdrawal syndrome, hematologic disorders, reprotoxicity, osteoporosis) although acute toxicity acetaldehyde; metabolism;
is considered. The role of oxidative metabolism of ethanol by alcohol dehydrogenase, cyto- toxicity; immunomodulation
chrome P450 2E1, and aldehyde dehydrogenase, as well as the impact of genetic polymorphism
in its physiopathology are also highlighted. The section dealing with the beneficial effects of low
to moderate alcohol consumption (on cardiovascular system, diabetes, the nervous system and
sensory organs, autoimmune diseases, and rheumatology) highlights the importance of anti-
inflammatory and immunomodulatory effects in these observations. This knowledge, enriched by
a focus on the immunomodulatory effects of ethanol and its metabolites, in particular on the
NLRP3 inflammasome pathway, might facilitate the development of treatments that can reduce
ethanol’s harmful effects or accentuate its beneficial effects.

1. The origin of alcoholic beverages problems. In his 1849 book Alcoholismus Chronicus, the
Swedish physician Magnus Huss introduced the term
It is not known when humans discovered alcohol and its
‘alcoholism’ and described a number of alcohol-related
effects. One can nevertheless assume that as is often the
visceral or mental illnesses. The first temperance soci-
case for the evolution of lifestyle factors, this was not a
eties were founded in the following decades, on the
chance discovery. Given that ethanol can be produced
basis of scientific publications and literary depictions of
by the fermentation of sugars contained in fruits, our
alcoholism (such as those by the novelists Zola in
ancestors may have consumed alcohol involuntarily by
France and Dickens in the UK). The first centers for
eating rotten (and thus fermented) fruits. In Neolithic treating and recovering from alcoholism were also
times, the simultaneous appearance of agriculture and founded at around this time (Porter 1987).
pottery may have markedly facilitated the exploitation of Specialist in-hospital care of alcoholic patients
this natural phenomenon. Thus, the first traces of fer- appeared in the 1920s; for example, Sainte-Anne psy-
mented beverages based on rice, honey and fruits (dis- chiatric hospital (Paris, France) opened a ward in 1922.
covered in Henan Province, China) date back to the The first pharmacologic treatment (apomorphine, with
seventh millennium BC (McGovern et al. 2004). its emetic effects) was introduced in the 1930s.
In the eighteenth century, the development of new Disulfiram (discovered in 1948) is still prescribed today
agricultural and distillation techniques led to the wide in out-patient treatment (Porter 1987). A large body of
availability of spirits as consumer products. During the scientific research has now shed light on the patho-
industrial revolution, the poor increasingly resorted to physiological mechanisms underlying acute and chronic
alcohol as a means of enduring their harsh working or alcoholism. However, there is also a growing body of
living conditions. It was not until the end of the eight- evidences in favor of ethanol’s beneficial effects in gen-
eenth century that alcohol addiction and alcohol abuse eral and its anti-inflammatory and immunomodulatory
began to be perceived as physical and mental health effects in particular. These diverging characteristics

CONTACT Brendan Le Dar
e [email protected] Univ Rennes, INSERM, INRA, Institut NuMeCan (Nutrition, Metabolisms and Cancer),
Rennes F-35000, France.
ß 2019 Informa UK Limited, trading as Taylor & Francis Group
2 B. LE DAR
E ET AL.

mean that ethanol has a ‘Jekyll and Hyde’ profile. Here, Cytosolic alcohol dehydrogenase (ADH) is the major
we review the current state of knowledge about etha- enzyme responsible for the phase I oxidative metabol-
nol and its harmful and beneficial effects (notably its ism of ethanol, producing acetaldehyde and reduced
immunomodulatory properties). nicotinamide adenine dinucleotide (NADH) (Cederbaum
2012). The enzyme is predominantly expressed by hep-
atocytes but is also found in the gastrointestinal tract,
2. Search strategy lung and kidneys (Crabb 1995; Edenberg 2000). In
MEDLINE and PubMed databases were searched for humans, seven genes (ADH1 to ADH7) code, respect-
ively, for ADH’s different subunits (a, b1, b2, b3, c1, c2,
relevant papers published in English in peer-reviewed
p, v, r, and l) (Cederbaum 2012). These subunits bind
journals between 1979 and 2019. Studies providing
together in pairs to form isoenzymes classified into five
information about association between drinking and
classes (ADH class I to ADH class V), depending on their
selected diseases or benefits, or mechanic explanation
enzymatic proprieties (Crabb 1995). Class I ADH (formed
for the association were included for review.
from subunits encoded by ADH1, ADH2, and ADH3) has
a crucial role in alcohol metabolism. Even though poly-
3. The metabolism of ethanol morphisms in ADH isoenzyme have been described,
they do not appear to be linked to a particular alcohol-
Given that ethanol’s biological effects are closely related disease or change in alcohol metabolism.
related to its metabolism, knowledge of the latter is However, some researchers have reported that alcohol
essential for understanding the associated pathophysio- is eliminated more slowly in the fasted state than in the
logical mechanisms (Figure 1). In the first part of this fed state because of decreased ADH levels
section, we consider the metabolism of ethanol to acet- (Cederbaum 2012).
aldehyde. In the second part, we look at the production The microsomal pathway (involving the cytochrome
of acetate from acetaldehyde. P450 (CYP) family) is responsible for about 10% of the

Figure 1. Oxidative and non-oxidative ethanol metabolic pathways in the hepatocyte. ADH: alcohol dehydrogenase; ALDH: alde-
hyde dehydrogenase; CYP: cytochrome P450; EtOH: ethanol; FAE: fatty acid ester; FAEE: fatty acid ethyl ester; SULT: sulfotransfer-
ase; UGT: uridine diphosphate glucuronyltransferase.
 DRUG METABOLISM REVIEWS 3

body’s ethanol metabolism (Hamitouche et al. 2006). and constitutes a risk factor in the development of alco-
Even though CYP1A2 and CYP3A4 are known to be holism (Agarwal and Goedde 1989). Indeed, the effects
involved, CYP2E1 is considered to be the main CYP in of ethanol intolerance (such as nausea, dysphagia,
the first phase of ethanol metabolism (Kunitoh et al. headache, and the vasodilation responsible for facial
1996; Cederbaum 2012). This oxidative metabolic path- flush in particular) have been attributed to the concen-
way takes place in the endoplasmic reticulum of hepa- tration of acetaldehyde. The accumulation of this
tocytes. Using NADPH and oxygen, CYP2E1 converts metabolite in individuals with inactive or poorly active
ethanol into acetaldehyde and then acetaldehyde into ALDH isoenzymes may explain the cultural barriers to
acetate. The conversion of ethanol into acetaldehyde drinking large amounts of alcohol seen in some soci-
produces reactive oxygen species (ROS), which notably eties, which thus protect against alcoholism. This is par-
contribute to alcohol’s toxicity (Ekstro€m and Ingelman- ticularly the case in eastern Asia, where 15–40% of the
Sundberg 1989). Furthermore, ethanol upregulates its population has inactive ALDH2 isoenzymes and thus
own metabolism by protecting CYP2E1 from ubiquitina- acetaldehyde levels that are 5–20 times higher than in
tion and degradation by the proteasome complex individuals with active isoenzyme (Cederbaum 2012).
(Zhukov and Ingelman-Sundberg 1999; Lu and
Cederbaum 2008). This mechanism results in elevated
4. The toxicity of ethanol
levels of CYP2E1 in hepatocytes, and is considered to
have a major role in the ethanol tolerance seen in According to the World Health Organization, alcohol
chronic alcohol users (Cederbaum 2012). consumption is a causal factor in more than 60 major
Catalase (an enzyme found in peroxisomes) is also types of diseases and injuries, and results in approxi-
known to metabolize alcohol. However, hepatic catalase mately 2.5 million deaths each year (World Health
does not have a significant role in ethanol metabolism. Organization 2011). Thus, approximately 4.5% of the
In contrast, brain catalase appears to be involved in global burden of disease and injury is attributable to
alcohol tolerance and positive reinforcement alcohol. Furthermore, this morbidity and mortality
(Cederbaum 2012). caused by alcohol consumption has socioeconomic
Other minor phase II non-oxidative metabolic path- impacts, including the medical costs borne by govern-
ways for ethanol include glucuronidation (giving rise to ments, and the financial and psychological burden to
ethylglucuronide) and sulfation (giving rise to ethylsul- families (World Health Organization 2011). By conven-
fate). Phosphatidylethanol and fatty acid ethyl esters tion, ethanol’s toxicity is subdivided into acute toxicity
(respectively, produced by phospholipase D and fatty and chronic toxicity. Here, we review the main acute
acid ethyl ester synthase) also contribute to the non- and chronic outcomes of ethanol consumption, and
oxidative metabolism of ethanol (Pichini et al. 2009; describe the relationship between dose and over-
Cederbaum 2012; Schro €ck et al. 2018). all mortality.
The acetaldehyde generated by these metabolic path-
ways is then oxidized by aldehyde dehydrogenase
4.1. Overall mortality as a function of dose
(ALDH) to form acetate. In humans, the ALDH superfam-
ily of NADþ-dependent enzymes is encoded by 16 Many researchers have reported that low levels of alco-
genes. The cytosolic ALDH1 and mitochondrial ALDH2 hol intake are associated with a lower risk of mortality
isoenzymes are those primarily involved in ethanol (Keller 2016). Jayasekara et al.’s (2014) meta-analysis of
metabolism (Vasiliou and Pappa 2000). In contrast to 62,950 study participants found that ethanol’s protect-
ADH, polymorphisms appear to have a greater influence ive effect is observed for intakes of 1–29 g/day (corre-
on ALDH activity. The ALDH21 allele (known to code for sponding to zero to three standard units of alcohol per
a highly active variant) is considered to protect against day), with a relative risk (RR) [95% confidence interval
liver disease in alcoholism, whereas the enzyme encoded (CI)] of 0.90 [0.81, 0.99]. Conversely, alcohol consump-
by ALDH22 allele is an inactive enzyme (Cederbaum tions of between 30 and 59 g/day and over 60 g/day
2012). Furthermore, chronic ethanol consumption lowers were associated with RR [95%CI] of mortality of 1.19
ALDH and increases the acetaldehyde level (Lin et al. [0.89, 1.58] and 1.52 [0.78, 2.98], respectively
1984). Acetate is not the final metabolite in this pathway (Jayasekara et al. 2014). In a study of 380,395 people,
because it be converted into CO2, fatty acids, ketones, Bergmann et al. (2013) found that limiting alcohol con-
cholesterol or steroids (Cederbaum 2012). sumption to below five alcoholic units per day was
The activity of the various isoforms of ADH and associated with a lower risk of death (mainly due to less
ALDH regulates acetaldehyde concentrations, cardiovascular disease), whereas the consumption of
4 B. LE DAR
E ET AL.

five or more alcoholic drinks per day was associated family of ligand-dependent transmembrane ion chan-
with a twofold to fivefold greater risk of death (mainly nels that enable rapid neuronal responses within the
due to alcohol-related cancer) (Bergmann et al. 2013). A mammalian central nervous system. Most GABA-A
meta-analysis linking moderate ethanol consumption to receptors are postsynaptic, although some subtypes are
lower all-cause mortality was consistent with these located outside the synapses (Davies 2003).
results (Gmel et al. 2003; Di Castelnuovo 2006). The GABA-A receptors are heteropentamers, and are
Despite the growing body of evidence for a protect- composed differently from among the 19 known subu-
ive effect of low to moderate alcohol consumption, the nits (a1-6, b1-4, c1-3, d, e, p, q1-2, and h) (Davies 2003).
results are subject to debate. For example, Goulden’s Most of the GABA-A receptors in the brain comprise two
(2016) study of 24,029 individuals over the age of a subunits, two b subunits and one c subunit; as such,
50 years did not reveal an association between all-cause they offer binding sites for many drugs, including as bar-
mortality and moderate alcohol consumption (Goulden biturates, benzodiazepines, and certain anesthetics.
2016). Likewise, a recent study of 28 million individuals Upon activation of the GABA-A receptor by an agonist,
found that all-cause mortality rose with increasing lev- the resulting influx of chlorine ions creates a hyperpola-
els of consumption; the researchers concluded that the rizing electrochemical gradient and decreases the action
level of alcohol consumption minimizing health loss is potential (Davies 2003). Gamma-aminobutyric acid is
zero (Griswold et al. 2018). classified as an inhibitory neurotransmitter because of its
Thus, the evidence is inconclusive as to whether receptor’s effects on the postsynaptic neuron. Thus, the
moderate alcohol consumption has a protective effect. binding of ethanol to the a-subunit of the GABA-A
However, all researchers agree that excessive alcohol receptor inhibits the postsynaptic neuron by allosteric
consumption increases all-cause mortality. The dose at modulation, and is thus responsible for cen-
which excess mortality is observed varies from one tral depression.
study to another but ranges from 30 to 40 g/day – cor- In addition to these effects on GABA-A receptors,
responding to three to four standard units of alcohol ethanol antagonizes N-methyl-D-aspartate receptors,
(Bergmann et al. 2013; Jayasekara et al. 2014). a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
receptors, and kainate receptors (Valenzuela et al. 1998;
L€ack et al. 2008). Since glutamate is an excitatory
4.2. Acute toxicity neurotransmitter, blockade of these receptors height-
The clinical manifestations of acute alcohol intoxication ens ethanol’s depressant action on the central nervous
are well known, and are closely related to those of alco- system (Hoffman et al. 1989). Lastly, ethanol has also
holism. The initial neuropsychic symptoms (intellectual been shown to interact with glycine receptors, neuronal
and psychic excitation) are followed by a cerebellar syn- nicotinic receptors, and serotonin type 3 receptors
drome accompanying marked drunkenness, and then (Davies 2003; Ding et al. 2015).
by a variably deep coma that may be life-threatening
(through paralysis of the respiratory centers) (Wimer 4.3. Chronic toxicity
et al. 1983; Girre et al. 1995).
In humans, the first symptoms (decreased motor Chronic ethanol exposure is toxic for many different
coordination, longer reaction time, and impaired judg- organs, and notably affects the digestive tract (steatosis,
ment) can be observed at a blood alcohol concentra- hepatic cirrhosis, chronic gastritis, and pancreatitis), the
tion of 0.2 g/L. These effects disappear quickly after the nervous system (polyneuritis, cerebellar atrophy, and
end of the exposure (Bismuth et al. 2000). Curiously, memory disorders) and the cardiovascular system.
the acute intoxicant effects of a given blood alcohol Ethanol also has chronic hematologic, carcinogenic and
reprotoxic effects. In the following section, we review
concentration are more intense when the level is rising
the pathophysiological effects of ethanol and its metab-
than when it is falling (the so-called ‘Mellanby effect’).
olites on these various organ systems.
By extension, this term is used to refer to the phenom-
enon of rapid ethanol tolerance because the neuropsy-
4.3.1. Liver disorders
chic effects are less intense when the concentration is
falling (Wang et al. 1993; Holland and Ferner 2017). In the early stages of ethanol-related liver disease, the
Ethanol’s depressant neuropsychic effects have been ROS generated by ethanol metabolism are responsible
well documented, and are related to the compound’s for a rapid increase in the fluidity of the hepatocyte cell
interaction with gamma-aminobutyric acid (GABA)-A membrane. In turn, this leads to elevated cytoplasmic
receptors (Davies 2003). These receptors belong to a levels of low-molecular-weight iron and thus even
 DRUG METABOLISM REVIEWS 5

greater ROS production. This phenomenon can then initial metabolite of ethanol can bind to proteins and
induce lipid peroxidation and apoptosis (Sergent alter their structures and functions – particularly for
et al. 2005). enzymes involved in DNA repair and glutathione (Garro
Liver injury due to ethanol can be divided into three et al. 1986). Furthermore, acetaldehyde can bind to
phases. The first phase (hepatic steatosis) involves the DNA and form adducts (Wang et al. 2000). Lastly, car-
accumulation of lipids in hepatocytes. It is relatively riers of an allele coding for inactive ALDH22 have an
benign, and usually reversible. The pathophysiology of increased risk of esophageal cancer, due to overexpos-
steatosis is closely related to the oxidative metabolism ure to this metabolite (Seitz and Stickel 2007).
of ethanol. By inducing lipolysis in adipocytes, chronic Thus, the mechanisms of ethanol-induced hepatocar-
alcohol consumption increases the fraction of free fatty cinogenesis are closely related to ethanol’s metabolic
acids captured by the liver (Wei et al. 2013; Osna et al. pathways; they involve the induction of hepatic cirrho-
2017). Furthermore, acetaldehyde increases the expres- sis, increased oxidative stress, and alterations in methy-
sion of sterol regulatory element-binding protein tran- lation. Lastly, retinoic acid (which is essential for
scription factor which upregulates lipogenesis genes proliferation and cell differentiation) is metabolized
(Osna et al. 2017). abnormally after CYP2E1 expression has been upregu-
In the second phase, steatohepatitis follows stea- lated by ethanol (Seitz and Stickel 2007).
tosis. The lipids accumulated in the hepatocytes In chronic alcohol users, a meta-analysis found that
undergo peroxidation and oxidative damage. Complex the risk of breast cancer increase with a dose-response
interactions involving the effects of acetaldehyde, ROS, relation giving a relative risk of 1.11 (CI ¼ 1.07–1.16),
intestinal lipopolysaccharide-mediated lesions and 1.24 (CI ¼ 1.15–1.34), and 1.38 (CI ¼ 1.23–1.55) with the
endoplasmic reticulum stress are responsible for infiltra- consumption of one, two or three drinks a day, respect-
tion of the liver by immune system cells (such as neu- ively (Longnecker 1994). This risk is linked to the etha-
trophils) and activation of Kupffer cells (the liver’s nol-induced increase in estradiol levels. Since steroid
resident macrophages) (Osna et al. 2017). The resulting hormones, including estrogens are metabolized by ADH
massive release of pro-inflammatory cytokines is dir- (McEvily et al. 1988), the effect might be due to compe-
ectly responsible for hepatocyte death and the main- tition between estrogen and ethanol, resulting in
tenance of alcoholic hepatitis (Duddempudi 2012). impaired metabolism of estrogens (Seitz and Stickel
The third phase reflects the fibrotic progression of 2007; Al-Sader et al. 2009). These data are supported by
inflammatory steatohepatitis. The regeneration of hepa- Hines et al. (2000) findings, showing a positive correl-
tocytes is severely compromised, and hepatic lesions ation between alcohol consumption and bioavailable
lead to the activation of hepatic stellate cells – the estradiol in a prospective study involving 1086 individu-
main sources of extracellular matrix deposition that als (Hines et al. 2000). In addition, ethanol can stimulate
characterizes fibrosis. The progression of fibrosis during the transcriptional activity of estrogen receptor in
ethanol-induced chronic inflammation leads to the pro- human breast cancer cells which is related to increased
gressive replacement of the hepatic parenchyma by breast cancer risk (Fan et al. 2000).
scar tissue, which compromises the liver’s metabolic Furthermore, ethanol alters methyl group transfers.
and homeostatic functions (Osna et al. 2017). Gene methylation is crucial in the regulation of gene
Ultimately, severe complications develop, such as hepa- expression: hypermethylation tends to decrease gene
tocellular carcinoma – the second leading cause of can- expression, whereas hypomethylation increases it. Thus,
cer death – and portal hypertension (Grewal and the induction of oncogenes or the repression of tumor
Viswanathen 2012; Zhou et al. 2016). suppressor genes appear to be key steps in ethanol-
induced cancer. These mechanisms would be associ-
4.3.2. Carcinogenic effects
ated with frequent malnutrition of alcoholics, leading
According to Seitz and Stickel (2007), 3.6% of cancers to vitamins deficiencies (folate, vitamin B6), which are
worldwide are due to chronic alcohol consumption. cofactors of methyl group transfer. Conversely, an
This causal relationship is particularly strong for tumors excess of vitamin A has been associated with an
of the upper digestive tract (such as cancers of the increased risk of alcohol-associated tumors (Seitz and
mouth, pharynx, larynx, and esophagus), liver tumors, Stickel 2007).
colonic tumors, and breast tumors (Seitz and Stickel Lastly, the results of animal experiments have shown
2007; Zhou et al. 2016). that a large amount of acetaldehyde is produced by
Once again, acetaldehyde has been incriminated in colonic bacteria after alcohol consumption (Jokelainen
the pathophysiology of these cancers. Indeed, this et al. 1996). Furthermore, elevated colonic acetaldehyde
6 B. LE DAR
E ET AL.

concentrations (due to the inhibition of ALDH) have functions, resulting in reduced synaptogenesis and
been linked to the induction of colonic carcinogenesis cell survival.
(Seitz et al. 1990). The diencephalon, cerebral cortex, hippocampus,
and white matter corresponding to myelin, are also tar-
4.3.3. Cardiovascular disorders gets for the toxicity of ethanol and its metabolites. This
toxicity results in atrophy of the brain, although the
High-dose ethanol consumption has been linked to
underlying mechanism is not yet fully understood (de
various cardiovascular disorders, such as hypertension,
la Monte 1988; Bu €hler and Mann 2011; Konrad et al.
atrial fibrillation, atherosclerosis, and alcoholic cardio-
2012). These various neurotoxic consequences are
myopathies (Girre et al. 1995; Bismuth et al. 2000; Zhou
aggravated by the thiamin (vitamin B1) deficiency
et al. 2016; Obad et al. 2018).
caused by ethanol’s inhibition of its absorption and
Although the mechanisms underlying this toxicity
physiological action (Vetreno et al. 2011).
are not fully understood, the metabolites of ethanol
Furthermore, there is growing evidence of a link
seem to be intricately involved. Indeed, myocardial
between the alcohol-induced loss of liver function and
damage appears to be associated with acetaldehyde
neurotoxicity. First, reduced ethanol metabolism in the
accumulation (Guo et al. 2012). The stress imposed on
liver is responsible for overexposure of the brain to this
myocytes by the increase in pro-inflammatory cyto-
toxic compound. Secondly, liver damage leads to the
kines, ROS, mitochondrial dysfunctions and endoplas-
production of metabolic and inflammatory mediators
mic reticulum stress are known to be involved in
that damage the brain. This relationship is most notable
myocyte hypertrophy, which in turn is responsible for
in the context of hepatic encephalopathy (De la Monte
altering the heart’s contractile performance
et al. 2009; Chen et al. 2012). Lastly, by jeopardizing the
(Machackova et al. 2006). The cardiovascular events
tight junctions of the intestinal mucosa, ethanol allows
associated with excessive alcohol consumption can
lipopolysaccharide (a Gram-negative bacterial endo-
therefore lead to cardiac arrest (Haddad et al. 2008).
toxin) to enter systemic circulation. As a result, lipopoly-
The pathophysiological mechanisms potentially
saccharide binds to TLR4 receptors on liver
involved in cardiovascular disease are summarized in
macrophages and promotes pro-inflammatory response
Table 1.
via cytokines, chemokines, proteases and ROS produc-
tion. These cytokines are known to cross the blood
4.3.4. Neuropsychic disorders
brain barrier and activate the brain’s resident macro-
The toxic effects of ethanol and its metabolites on brain phages (microglia), increasing neurotoxicity (Mayfield
tissue vary according to the region of the brain, age, et al. 2013).
the dose, and the duration of exposure. Both neurons In light of these effects, it is not surprising that
and glial cells are affected. The major complications chronic alcohol consumption is responsible for severe
include alteration of astrocyte and oligodendrocyte cognitive impairment, including dementia. The most

Table 1. Mechanisms potentially linking alcohol consumption with cardiovascular pathologies.

Cardiovascular diseases Potential mechanisms References
Heart failure Cardiac fibrosis Faris et al. (2003), Urbano-M
arquez and Fern
andez-
Vitamin deficiency and malnutrition Sola (2004), Fernandezsola et al. (2006), G€
urtl et al.
Decrease in contractile proteins, and myocyte loss (2009), and Laonigro et al. (2009)
Mitochondrial dysfunction
Impaired calcium homeostasis
Oxidative stress
Activation of neurohormonal systems
Coronary heart disease
Alcoholic cardiomyopathy Decrease in nNOS expression Machackova et al. (2006), Guo et al. (2012), Ji
Increased pro-inflammatory effects (2012), Panchenko et al. (2015), and Silva
Neurohormonal activation et al. (2015)
Metabolic changes
Acetaldehyde accumulation
Altered protein synthesis
Elevated of brain natriuretic peptide
Genetically related factors
Atrial fibrillation Increase in ROS Steinbigler et al. (2003)
Atherosclerosis Activation of the innate and adaptive immune systems Hansson et al. (2002)
Presence of mediators of inflammation (TNF, IFNɤ)
Hypertension Increased secretion of catecholamines Lopes da Silva et al. (2013) and Silva et al. (2015)
Decrease in nNOS expression
 DRUG METABOLISM REVIEWS 7

common types of alcohol-related dementia are 4.3.6. Hematologic disorders

Wernicke-Korsakoff syndrome and Marchiafava-Bignami
Several hematological disorders are promoted or accen-
disease (Charness 1993; Victor 1994). Today, the frontal,
tuated by alcohol consumption: leukopenia, anemia,
cerebellar and/or temporal brain atrophy induced by
thrombocytopenia, myelodysplasia, and acute leukemia
ethanol consumption can be readily detected by med-
(Girre et al. 1995; Bismuth et al. 2000). Recently, Smith
ical imaging techniques (Matsui et al. 2012).
et al. (2015) hypothesized that an ALDH polymorphism
predisposes to these hematological disorders. Since the
4.3.5. Addiction and withdrawal syndrome
ALDH1A1 isoform protein is present in hematopoietic
In the field of addiction, ‘conventional’ products act on stem cells, overexposure to acetaldehyde may explain
a specific target: opiate receptors for heroin, cannabin- the increased risk of impaired hematopoiesis associated
oid CB1 receptors for cannabis, nicotinic receptors for with the inhibition of DNA repair (Smith et al. 2015).
tobacco, and monoamine transporters for cocaine
(Hamon 2014). In contrast, ethanol acts on many levels. 4.3.7. Reprotoxicity
As mentioned above, ethanol facilitates GABAergic
transmission via GABA-A receptors and decreases gluta- Ethanol consumption disrupts the menstrual cycle in
minergic neurotransmission (Hoffman et al. 1989; women and decreases male fertility, including testicular
Valenzuela et al. 1998; L€ack et al. 2008; Uusi-Oukari and atrophy, reduced libido, and decreased testosterone.
Korpi 2010). Furthermore, a decrease in the likelihood of a clinical
Like other addictogenic compounds, alcohol acti- pregnancy per cycle was observed from five units per
vates the reward circuit and thus the release of dopa- week upwards (Council of the Netherlands TH 2000;
mine into the mesocorticolimbic system. This system ANSES 2010).
consists of dopaminergic neurons whose cell bodies are During pregnancy, ethanol consumption is respon-
located in the ventral tegmental area and whose axons sible in a dose-dependent manner for multiple congeni-
project into the nucleus accumbens, amygdala, and tal anomalies, such as growth restriction, central
frontal cortex (Inserm 2012). Although dopamine has a nervous system impairments, and malformations. These
key role in the mechanism of dependence, other neuro- manifestations are referred to collectively as fetal alco-
transmitters (such as GABA, glutamate, serotonin, nor- hol syndrome (FAS), and give rise to a particular facies
epinephrine, and opioid peptides) are also involved with narrow palpebral fissures, a flat mid-face, a short
(Inserm 2012). nose, a smooth philtrum, a thin upper lip, epicanthus, a
The repeated intake of alcohol leads to tolerance flat nasal bridge, minor ear abnormalities, and micro-
and adaptive processes that decrease the effectiveness gnathia (Wattendorf and Muenke 2005).
of GABAergic neurotransmission and facilitate glutami- The pathogenesis of FAS is related to the pharmaco-
nergic neurotransmission. In turn, these processes lead kinetics and metabolism of ethanol. It is well known
to neuronal hyperexcitability – a characteristic of alco- that ethanol crosses the placenta, and distributes into
hol dependence (Hamon 2014). the fetal compartment. Furthermore, ethanol is elimi-
The respective roles of ethanol and its metabolites in nated slowly by the fetus, leading to greater exposure
the mechanism of alcohol addiction are still unclear but (Heller and Burd 2014). Furthermore, several character-
acetaldehyde has its own psychoactive effects and istics make the fetus more fragile to alterations in oxi-
rewarding proprieties (Brancato et al. 2017). dative metabolism. CYP2E1 protein is produced earlier
Chronic exposure to ethanol results in higher mem- than ADH during gestation (Hines and McCarver 2002;
brane levels of saturated fatty acids and cholesterol, Arfsten et al. 2004), and the induction of placental
which decrease the membrane’s fluidity (i.e. the oppos- CYP2E1 by ethanol (Rasheed et al. 1997) means that
ite of the fluidifying effects of acute ethanol consump- CYP becomes the major metabolic pathway for ethanol.
tion on the hepatocyte membrane described above). As Ethanol’s teratogenic effects are thought to be due to
a result, a sharp decrease in alcohol consumption ROS production (leading to mitochondrial damage,
causes temporary membrane hyper-rigidity and dis- brain lipid peroxidation, and a decrease in endogenous
rupts cellular homeostasis (Littleton 1998). In cases of antioxidant levels), apoptosis (leading to disrupted neu-
sudden alcohol withdrawal, clinical alcohol withdrawal ron-neuron adhesion), placenta vasoconstriction, and
syndrome is characterized by hypertension, tachycardia, inhibition of cofactors required for fetal growth and
hallucinations, agitation, fever, tremor, seizures, and development (Gupta et al. 2016).
hyperexcitation, and may progress to delirium tremens Acetaldehyde is also directly involved in the induc-
(Tetrault and O’Connor 2008). tion of FAS. It is now known that retinoic acid regulates
8 B. LE DAR
E ET AL.

various embryonic and differentiation processes in the pathophysiology underlying alcohol’s various
(Shabtai and Fainsod 2018). However, retinoic acid is toxic effects. The molecular and pathophysiological
obtained from retinaldehyde, which itself is obtained effects of acetaldehyde are summarized in Figure 2.
from vitamin A. Through competition with retinalde- Thus, acetaldehyde appears to have only harmful
hyde dehydrogenase, acetaldehyde inhibits the produc- effects, whereas ethanol’s effects are both beneficial
tion of retinoic acid and leads to characteristics and harmful.
developmental malformations (Shabtai and Fainsod
2018; Shabtai et al. 2018). Furthermore, the administra-
tion of acetaldehyde to pregnant mice had teratogenic 5. Benefits of ethanol
effects – suggesting that this metabolite of ethanol has Despite Burton and Sheron’s (2018) statement that ‘no
a direct role (O’Shea and Kaufman 1979). level of alcohol consumption improves health’ (Burton
Maternal consumption of 10–20 g of alcohol per day and Sheron 2018) and the many harmful effects of
(corresponding to one to two standard units) has been ethanol consumption, it nevertheless appears that light
shown to induce intellectual and behavioral delays – to moderate alcohol consumption does have benefi-
especially if the infant is breastfed (Bonnard et al. 2011). cial effects.

4.3.8. Osteoporosis
5.1. The cardiovascular system
It is well known that chronic high-level ethanol con-
sumption is associated with osteoporosis and osteopor- There is evidence of an inverse correlation between low
otic fractures (Diamond et al. 1989; Schapira 1990). The to moderate alcohol consumption (corresponding to
underlying mechanism has been linked to elevated p21 one to two units per day) and mortality from cardiovas-
expression, which suppresses osteoblast differentiation cular disease; this gives rise to the ‘French paradox’
and mineralization and disturbs remodeling (Maurel (Albert et al. 1999; Belleville 2002; Ronksley et al. 2011).
et al. 2012; Mikosch 2014). Furthermore, the observa- However, high alcohol consumption increases the risk
tion that protein-disrupting ALDH2 polymorphisms of mortality from other causes and wipes out the bene-
accentuate this toxicity suggests that acetaldehyde has ficial effects – giving results in a ‘J’ shaped curve for the
a direct role (Shimizu et al. 2011; Tsuchiya et al. 2013). relationship between mortality and alcohol consump-
It is now clear than acetaldehyde and oxidative tion (Klatsky et al. 1992). At present, there is no consen-
stress generated by ethanol metabolism have key roles sus on whether the protective cardiovascular effects of

Figure 2. Molecular and pathophysiological effects of acetaldehyde.

 DRUG METABOLISM REVIEWS 9

ethanol are restricted to one or more types of alcoholic sensitivity in moderate alcohol consumers (Kawamoto
beverage drink (i.e. wine, beer or spirits) (Bau et al. et al. 2009; Schrieks et al. 2015; Zhou et al. 2016) and
2007). However, many studies have found that wine an increase of estradiol in women (Rohwer et al. 2015).
had a greater beneficial effect on cardiovascular events. Furthermore, alcohol consumption appears to have
Rodrigues et al. (Rodrigues et al. 2018) found that wine beneficial effects on lipid metabolism by raising levels of
consumption was associated with less harmful findings HDL and apolipoproteins A1 and A2 (Fragopoulou et al.
in cardiac structure. Wine’s particular protective effect is 2018). However, these findings must be considered with
linked to the anti-inflammatory, antioxidant and hypo- caution since detailed mechanisms are still poorly under-
tensive properties of polyphenols (Das et al. 2007; stood (Polsky and Akturk 2017). Moreover, alcohol con-
Arranz et al. 2012). In parallel, ethanol per se has been sumption, even moderate, is associated with impaired
linked to elevated high-density lipoprotein (HDL) chol- self-care behavior including glucose self-monitoring and
esterol levels, reduced low-density lipoprotein (LDL) exercise (Howard et al. 2004; Engler et al. 2013). Lastly,
cholesterol levels, and reduced blood coagulation interactions are well known between alcohol and dia-
(Agarwal 2002). Moderate long-term alcohol consump- betes medications such as sulfonylureas for which the
tion was also found to be associated with low blood tri- risk of hypoglycemia is increased (Shai et al. 2004).
glyceride levels and elevated lipoprotein lipase activity
(Kov
ar and Zem
ankov
a 2015). A review of wine’s meta-
5.3. The nervous system and sensory organs
bolic effects has been published (Markoski et al. 2016).
Gil-Bernabe et al. (2011) found that moderate alcohol 5.3.1. Neuroprotection and dementia
consumption reduces atherosclerosis by regulating
Interestingly, ethanol appears to have a neuroprotec-
fibroblasts’ production of CXCL12 (stromal cell-derived
tive effect. For example, Tizabi et al.’s (2018) studies in
factor-1). Furthermore, Nurmi et al.’s (2013) work on the
in vitro models of Parkinson’s and Alzheimer disease
underlying pathophysiological mechanisms prompted
evidenced a protective effect of low ethanol consump-
the suggestion that the NLRP3 inflammasome is a key
tion (Tizabi et al. 2018). The underlying mechanisms
player in the protective cardiovascular effect of moder-
were related to low levels of pro-inflammatory cyto-
ate alcohol consumption. Indeed, acute exposure to
kines (TNF-a and IL-1b) and elevated levels of brain-
ethanol was found to inhibit the NLRP3 inflammasome
derived neurotrophic factor and the anti-inflammatory
in macrophages, leading to an anti-inflammatory effect
cytokine IL-10 – resulting in greater neuroplasticity and
(Nurmi et al. 2013). These results were confirmed by
neuroprotection. Furthermore, preclinical studies in an
Hoyt et al. (2016).
animal model have shown that a low blood ethanol
The procyanidin compounds in wine have also been
concentration has an antidepressant effect (Mu €ller
found to inhibit the NLRP3 inflammasome; this sug-
et al. 2017).
gests that wine has a stronger anti-inflammatory effect
In a broader context, a recent prospective study of
than other beverages. Given the presence of many
9087 participants aged between 35 and 55 at baseline
pharmacologically active compounds other than etha-
found that moderate alcohol consumption was associ-
nol in alcoholic beverages, it is hard to predict the
ated with a lower risk of dementia. Over the 23-year
effects of these mixtures (Liu et al. 2017).
study, teetotalers and those who consumed more than
14 units of alcohol per week had a higher risk of
5.2. Diabetes dementia (hazard ratio [95%CI] ¼ 1.47 [1.15; 1.89]).
People consuming between one and 14 units of alcohol
The positive impact of moderate alcohol consumption
per week were therefore protected against this risk
on the cardiovascular system appears to be coupled
(Yasar 2018). These results were supported by those of
with beneficial effects on diabetes mellitus. In Knott
Peters et al. (2008).
et al.’s (2015) meta-analysis of 1,902,605 participants,
Consistently, Paganini-Hill et al. (2016) found that
consumption of less than 63 g of alcohol per day in
moderate drinkers participating in the 90þ Study pre-
women and in non-Asian populations was associated
sented a decreased risk of dementia.
with a decrease in the risk of developing type 2 dia-
betes mellitus (Knott et al. 2015). The risk of diabetes
5.3.2. Chronic pain
increased for alcohol consumption levels above this
threshold. In mechanistic terms, some researchers have On the same lines, Scott et al.’s (2018) study of 2583
attributed these observations to a decrease in fasting patients with chronic pain found that moderate alcohol
insulin concentrations, an increase in the insulin consumption was associated with lower pain levels,
10 B. LE DAR
E ET AL.

fewer painful body areas, and less intense somatic and stopping the progression of collagen-induced arthritis
mood symptoms (Scott et al. 2018). Physical function (Jonsson et al. 2007).
also appeared to be improved by moderate alcohol
consumption (Scott et al. 2018). 5.4.2. Systemic lupus erythematosus
Two studies have reported that alcohol has beneficial
5.3.3. Anxiolytic effects
effects in patients with systemic lupus erythematosus;
As mentioned above, ethanol depresses the central the consumption of no more than 30 units per week
nervous system by interacting with GABA and N- was inversely correlated with the development of this
methyl-D-aspartate receptors. This depressant effect disease (Nagata et al. 1995; Hardy et al. 1998).
triggers an anxiolytic effect and behavioral disinhibition
at ethanol blood concentrations between 5 and 10 mM, 5.4.3. Thyroid disorders
with an effect on the hippocampus and the amygdala
Alcohol consumption was found to protect against the
in particular (Harrison et al. 2017). Interestingly, etha-
development of autoimmune hypothyroidism, inde-
nol’s anxiolytic effects (i.e. making people more likely to
pendently of sex or the type of alcoholic beverage
start a conversation) have been linked to language abil-
(Carle et al. 2012). Interestingly, Carl
e et al. (2013) also
ities. Indeed, consumption of a small amount of ethanol
reported that moderate alcohol consumption is associ-
was found to have beneficial effects on the pronunci-
ated with a dose-dependent reduction in the risk of
ation of a recently learned foreign language (Renner
developing of Grave’s hyperthyroidism.
et al. 2018).
Ethanol’s beneficial action on the symptoms of these
autoimmune diseases highlights an interesting spectrum
5.4. Autoimmune diseases of immune effects. However, alcohol does not appears
to be of value in all immune diseases, for example,
Of all ethanol’s beneficial effects, those affecting the
Skaaby et al. (2018) did not observe a causal relationship
immune system are the least well understood, and
between alcohol consumption and the prevalence of
there is no consensus on the pathophysiologic mecha-
asthma or allergic disease (Skaaby et al. 2018).
nisms. The following section summarizes the literature
data in this field.
5.5. Rheumatology
5.4.1. Rheumatoid arthritis
Over the last few decades, several studies have
In Di Giuseppe et al.’s (2012) study of 34,141 women described beneficial effects of ethanol on bone mineral
(197 of whom presented with rheumatoid arthritis), the density in general and in the trochanteric region of the
consumption of at least three units of alcohol per week proximal femur in particular (Angus et al. 1988;
halved the incidence of the disease (relative to tee- Holbrook and Barrett-Connor 1993). Furthermore,
totalers) (Di Giuseppe et al. 2012). Consistently, a 2014 Felson et al. found that at least 7 oz/week (approxi-
meta-analysis found that low to moderate alcohol con- mately 200 mL/week) of alcohol was associated with
sumption in women prevents the onset of rheumatoid high bone density in postmenopausal women. The
arthritis in a time-, dose-dependent, and sex-dependent researchers concluded that these results might be
manner (Jin et al. 2014). Even after the development of related to the elevated endogenous estrogen levels
rheumatoid arthritis, the effects of alcohol consumption induced by ethanol, and ruled out a direct effect of
should still be considered – especially for the avoidance alcohol (Felson et al. 1995). Consistent with these
of drug interactions. According to the results of a study results, Ganry et al.’s analysis of the ‘Epid
emiologie de
published in 2008, alcohol consumption does not l’Ost
eoporose’ (EPIDOS) study found that trochanteric
increase the hepatic toxicity of methotrexate and leflu- bone mineral density was higher in elderly women with
nomide – both of which are widely prescribed to moderate alcohol consumption (one to three glasses of
patients with rheumatoid arthritis. Hence, the British wine per day) than in teetotalers (Ganry et al. 2000).
Society for Rheumatology guidelines suggests that alco-
hol consumption well within national limits is appropri-
5.6. Cancer
ate (Rajakulendran et al. 2008).
Furthermore, the frequent consumption of low Although alcohol is known to be a carcinogenic agent
amounts of alcohol was found to interact with the in humans (see above), moderate wine consumption
innate immune response by delaying the onset and may decrease the risk of several cancers (including
 DRUG METABOLISM REVIEWS 11

colon, lung, ovarian and prostate cancer, basal cell car- effects of ethanol on the immune system found that
cinoma, and esophageal adenocarcinoma) (Bianchini ethanol had dose-dependent effects on adaptive
and Vainio 2003; Schoonen et al. 2005; Anderson et al. immune responses; moderate alcohol consumption
2009; Klarich et al. 2015; Zhou et al. 2016). These propri- increased T and B lymphocyte counts, whereas chronic
eties are mostly related to resveratrol, an antioxidant heavy consumption was associated with a falls in cell
agent that inhibits the metabolic activation of carcino- counts (Barr et al. 2016). In addition, McClintick et al.
gens, decreases cell proliferation, induces apoptosis (2019) showed that ethanol exposure on lymphoblas-
and exerts anti-inflammatory effects. The mechanisms toid cells induce a robust immune response after 24 h
underlying the beneficial effects of ethanol are sum- exposure (including neuroinflammation and KFjB path-
marized in Table 2. way, IL-6, IL-2, and IL-8 activation), but decreased in
intensity after 48 h exposure (partially explained by a
reversal of interferon signaling) (McClintick et al. 2019).
6. The immunomodulatory effects of ethanol
Furthermore, some researchers have reported that
Alcohol has contrasting effects on the body. Most of moderate alcohol consumption is associated with lower
alcohol’s toxic effects are linked to acetaldehyde (the levels of immunoglobulins G, M and A (Gonzalez-
first oxidative metabolite of ethanol), whereas most of Quintela et al. 2007; Romeo et al. 2007). These findings
its beneficial effects appear to be related to the proper- may explain the above-mentioned beneficial effect of
ties of ethanol per se. Thus, ethanol can be likened to low to moderate alcohol consumption on autoimmune
Robert Louis Stevenson’s literary character Dr Jekyll, diseases such as rheumatoid arthritis, systemic lupus
with acetaldehyde as Mister Hyde. erythematosus, hyperthyroidism, and hypothyroidism.
Of all ethanol’s effects on the body, those on the In contrast, ethanol’s harmful and beneficial effects
immune system are particularly contrasting: the adverse on the cardiovascular system, nervous system, rheuma-
effects are associated with pro-inflammatory activities, tism, and cancer do not appear to interact with the
whereas the beneficial effects are associated with anti- adaptive immune response. One can therefore
inflammatory activities (in cardiovascular disease, can- hypothesize that the duality of ethanol’s effects (lead-
cer, and neuroprotection) and immune system modula- ing to anti-inflammatory and pro-inflammatory
tion (in rheumatoid arthritis, systemic lupus responses) particularly involves the innate immune
erythematosus, hyperthyroidism, and hypothyroidism). response. In the literature, a brief exposure to ethanol
The immune system is conventionally divided into was found to modulate the function of innate immune
innate and adaptive mechanisms, and alcohol is known cells (including monocytes) via the inhibition of NF-jB
to influence both. Barr et al.’s (2016) reviews of the and then a reduction in TNF-a, IL-6, and IL-1b

Table 2. Diseases in which moderate alcohol consumption appears to have beneficial effects.
Disease Potential mechanisms References
Cardiovascular mortality Antioxidant and hypotensive responses Agarwal (2002), Das et al. (2007), Gil-Bernabe et al.
Elevated HDL cholesterol (2011), Arranz et al. (2012), Nurmi et al. (2013),
Low LDL cholesterol and reduced blood Kov
ar and Zem
ankov
a (2015), Hoyt et al. (2016),
coagulation Markoski et al. (2016), Liu et al. (2017), and
Inhibition of the NLRP3 inflammasome Rodrigues et al. (2018)
Type 2 diabetes Decrease in fasting insulin concentrations and Knott et al. (2015), Schrieks et al. (2015), and
lower insulin sensitivity Fragopoulou et al. (2018)
Neuroprotection Decrease in pro-inflammatory cytokine levels (TNF- M€uller et al. (2017)
a; IL-1b)
Elevated neurotrophic factors (BDNF)
Elevated anti-inflammatory cytokine levels (IL-10)
Dementia Mechanism unknown Peters et al. (2008), Paganini-Hill et al. (2016), and
Yasar (2018)
Chronic pain Central nervous system depressant effect Scott et al. (2018)
Meniere’s disease Mechanism unknown S
anchez-Sellero et al. (2018)
Rheumatoid arthritis Interaction with the innate immune response, Jonsson et al. (2007), Rajakulendran et al. (2008),
delaying the onset of collagen-induced arthritis Di Giuseppe et al. (2012), and Jin et al. (2014)
and stopping its progression
Systemic lupus erythematosus Mechanism unknown Nagata et al. (1995) and Hardy et al. (1998)
Hyperthyroidism Mechanism unknown Carl
e et al. (2013)
Hypothyroidism Mechanism unknown Carle et al. (2012)
Osteoporosis Elevated endogenous estrogen levels induced Angus et al. (1988),, Holbrook and Barrett-Connor
by ethanol (1993), Felson et al. (1995), and Ganry et al. (2000)
Cancers Resveratrol inhibits the metabolic activation of Bianchini and Vainio (2003), Schoonen et al.
carcinogens, decreases cell proliferation, induces (2005), Anderson et al. (2009), and Klarich
apoptosis and exerts anti-inflammatory activities et al. (2015)
12 B. LE DAR
E ET AL.

production (Muralidharan et al. 2014). Conversely, accentuate its toxicity. Furthermore, purinergic receptors
Sureshchandra et al. (2019a, 2019b) showed that (which are also able to activate the NLRP3 inflamma-
chronic alcohol drinking, regardless of dose alters resting some (Gicquel et al. 2017)) are affected by ethanol treat-
transcriptomes of peripherical blood mononuclear cells, ment. It was recently reported that 24 h of ethanol
with the largest impact seen in innate immune cells. exposure was enough to modulate purinergic receptor
Interestingly, the pro-inflammatory impact of drinking levels (including P2X7R upregulation in human macro-
was significant only with chronic heavy alcohol drinking. phages) and thus interleukin production – highlighting a
These transcriptional changes are being claimed to be new target for ethanol (Le Dar
e et al. 2018). Taken as a
partially explained by alterations in microRNA profiles whole, these results suggest that purinergic receptor
(Sureshchandra et al. 2019a). Furthermore, expansion of and NLRP3 inflammasome antagonists may be of value
granulocytic-myeloid-derived suppressor cells (one of in the treatment of ethanol-related disease.
the major components in the immune suppressive net-
work in both innate and adaptive immune responses) in 7. Conclusion
response to ethanol consumption has been highlighted
to play a protective role in acute alcoholic liver damage Alcohol consumption has both toxic and beneficial
(Li et al. 2018). Conversely, prolonged exposure to alco- effects; ethanol can be likened to Doctor Jekyll, whereas
hol in humans was associated with elevated blood levels acetaldehyde is Mister Hyde. The detrimental effects
of IL-6 and IL-1b (Pang et al. 2011). Lastly, it has been associated with high ethanol consumption are probably
reported that splenic macrophages from chronic heavy due to the high resulting concentrations of acetalde-
alcohol drinking animals generated a larger inflamma- hyde. Taken as a whole, the risk-benefit ratio of ethanol
tory response to lipopolysaccharide, both at protein and remains negative in terms of public health, particularly
gene expression levels. By increasing levels of H3K4me3 in view of the carcinogenic effects.
(a histone mark of active promoters), as well as chroma- Although a variety of mechanisms underlie the patho-
tin accessibility at promoters and intergenic regions that logic and beneficial effects of alcohol consumption, it
regulate inflammatory responses, alcohol is thought to appears that most of ethanol’s effects on the body relate
alter the immune fitness of tissue-resident macrophages to the immune system. Both innate and adaptive
via epigenetic mechanisms (Sureshchandra et al. 2019b). immune responses are affected by ethanol, leading to a
Recent studies have highlighted the NRLP3 inflamma- spectrum of clinical presentations. Modulation of adap-
some (a cytosolic complex of the innate immune system tive immunity might be associated with reductions in
mainly expressed by myeloid cells like monocytes and the incidence and severity of autoimmune diseases such
macrophages) as an important inhibitory target of etha- as rheumatoid arthritis, systemic lupus erythematosus,
nol (Nurmi et al. 2013). This inflammasome is a potent hyperthyroidism, and hypothyroidism. The inhibition of
means of immune defense, and triggers the production innate immunity by low to moderate alcohol consump-
tion has been linked to beneficial effects, whereas high
of IL-1b and IL-18 in response to danger and pathogen
consumption is associated with detrimental effects
signals. Activation of NRLP3 inflammasome requires the
(through pro-inflammatory activities). Although the spe-
assembly of three effectors: (i) NLRP3, (ii) the apoptosis-
cific mechanisms have yet to be characterized, the
associated speck-like protein containing a caspase
modulation of cytokine production via the NF-jB or
recruitment domain (ASC, an adaptor protein), and (iii)
NLRP3 pathways appears to be the cornerstone of etha-
procaspase 1 (Keyel 2014). Interestingly, ethanol was
nol’s immunomodulatory effects.
found to interact with the NRLP3 inflammasome by acti-
Further investigations are thus required in order to
vating the phosphorylation and thus inhibition of the
clarify the biological effects attributable to ethanol and
ASC adaptor protein (Hoyt et al. 2016). Hence, acute
acetaldehyde, and thus characterize the complex inter-
ethanol exposure has an anti-inflammatory effect.
actions between alcohol and the immune system. This
As described above, high levels of alcohol consump-
knowledge might facilitate the development of treat-
tion are responsible for many toxic effects. The oxidative
ments that can reduce ethanol’s harmful effects or
metabolic production of acetaldehyde is the cornerstone
accentuate its beneficial effects.
of this toxicity. Remarkably, oxidative stress and acetal-
dehyde were found to activate the NRLP3 inflamma-
some, which has a key role in the pro-inflammatory Acknowledgements
effect of chronic ethanol consumption (Hoyt et al. 2017). We wish to thank Doctor David Fraser for the English revi-
This sterile inflammation mechanism may override etha- sion; the kind support and enriching discussions provided by
nol’s beneficial effects on the immune system and Professor Isabelle Morel are also acknowledged.
 DRUG METABOLISM REVIEWS 13

Disclosure statement Bismuth C, Baud F, Conso F, Dally S, Frejaville JP, Garnier R.

2000. Toxicologie clinique. Paris: Me
decine-Sciences
No potential conflict of interest was reported by the authors. Flammarion.
Bonnard N, Falcy M, Jargot D, Pasquier E. 2011. Ethanol –
Fiche toxicologique n 48 [Internet]. Institut National de
ORCID Recherche et de S
ecurit
e [accessed 2018 Jul 3]. Available
Brendan Le Dar
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html?refINRS=FICHETOX_48&section=bibliographieAuteurs
Brancato A, Lavanco G, Cavallaro A, Plescia F, Cannizzaro C.
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