Xenobiotic metabolism: Difference between revisions

'''Xenobiotic metabolism''' (from the Greek [[xenos (Greek)|xenos]] "stranger" and biotic "related to living beings") is the set of [[metabolic pathway]]s that modify the chemical structure of [[xenobiotic]]s, which are compounds foreign to an organism's normal biochemistry, such as drugs and poisons. These pathways are a form of [[biotransformation]] present in all major groups of organisms, and are considered to be of ancient origin. These reactions often act to [[detoxification|detoxify]] poisonous compounds; however, in some cases such as in the metabolism of [[Alcohol (drug)|alcohol]], the intermediates in xenobiotic metabolism can themselves be the cause of toxic effects.

All organisms use [[cell membrane]]s as hydrophobic permeability barriers to control access to their internal environment. Polar compounds cannot diffuse across these [[cell membrane]]s, and the uptake of useful molecules is mediated through [[transport protein]]s that specifically select substrates from the extracellular mixture. This selective uptake means that most [[hydrophile|hydrophilic]] molecules cannot enter cells, since they are not recognised by any specific transporters.<ref>{{cite journal |authorvauthors=Mizuno N, Niwa T, Yotsumoto Y, Sugiyama Y |title=Impact of drug transporter studies on drug discovery and development |journal=Pharmacol. Rev. |volume=55 |issue=3 |pages=425–61 |year=2003 |pmid=12869659 |url=http://pharmrev.aspetjournals.org/cgi/content/full/55/3/425#C.%20Role%20of%20Transporters%20in%20Drug%20AbsorptionA |doi=10.1124/pr.55.3.1}}</ref> In contrast, the diffusion of [[hydrophobe|hydrophobic]] compounds across these barriers cannot be controlled, and organisms, therefore, cannot exclude [[lipid]]-soluble xenobiotics using membrane barriers.

The detoxification of the reactive by-products of normal metabolism cannot be achieved by the systems outlined above, because these species are derived from normal cellular constituents and usually share their polar characteristics. However, since these compounds are few in number, specific enzymes can recognize and remove them. Examples of these specific detoxification systems are the [[glyoxalase system]], which removes the reactive [[aldehyde]] methylglyoxal,<ref>{{cite journal |authorvauthors=Thornalley PJ |title=The glyoxalase system: new developments towards functional characterization of a metabolic pathway fundamental to biological life |journal=Biochem. J. |volume=269 |issue=1 |pages=1–11 |date=1 January 1990|doi=10.1042/bj2690001 |pmid=2198020 |pmc=1131522 }}</ref> and the various antioxidant systems that eliminate reactive oxygen species.<ref name=Sies>{{cite journal |authorvauthors=Sies H |title=Oxidative stress: oxidants and antioxidants |url=http://ep.physoc.org/cgi/reprint/82/2/291.pdf |journal=Exp Physiol |volume=82 |issue=2 |pages=291–5 |year=1997 |doi=10.1113/expphysiol.1997.sp004024 |pmid=9129943}}</ref>

In phase I, a variety of enzymes acts to introduce reactive and polar groups into their substrates. One of the most common modifications is hydroxylation catalysed by the [[cytochrome P450|cytochrome P-450-dependent mixed-function oxidase system]]. These enzyme complexes act to incorporate an atom of oxygen into nonactivated hydrocarbons, which can result in either the introduction of hydroxyl groups or N-, O- and S-dealkylation of substrates.<ref>{{cite journal |authorvauthors=Guengerich FP |title=Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity |journal=Chem. Res. Toxicol. |volume=14 |issue=6 |pages=611–50 |year=2001 |pmid=11409933 |doi=10.1021/tx0002583}}</ref> The reaction mechanism of the P-450 oxidases proceeds through the reduction of cytochrome-bound oxygen and the generation of a highly-reactive oxyferryl species, according to the following scheme:<ref>{{cite journal |authorvauthors=Schlichting I, Berendzen J, Chu K, ''|display-authors=et al.'' |title=The catalytic pathway of cytochrome p450cam at atomic resolution |journal=Science |volume=287 |issue=5458 |pages=1615–22 |year=2000 |pmid=10698731 |doi=10.1126/science.287.5458.1615|bibcode=2000Sci...287.1615S }}</ref>

In subsequent phase II reactions, these activated xenobiotic metabolites are conjugated with charged species such as [[glutathione]] (GSH), [[sulfate]], [[glycine]], or [[glucuronic acid]]. These reactions are catalysed by a large group of broad-specificity transferases, which in combination can metabolise almost any hydrophobic compound that contains nucleophilic or electrophilic groups.<ref name=Jakoby>{{cite journal |authorvauthors=Jakoby WB, Ziegler DM |title=The enzymes of detoxication |journal=J. Biol. Chem. |volume=265 |issue=34 |pages=20715–8 |date=5 December 1990 |doi=10.1016/S0021-9258(17)45272-0 |doi-access=free |pmid=2249981 |url=http://www.jbc.org/cgi/reprint/265/34/20715 }}</ref> One of the most important of these groups are the [[glutathione S-transferase]]s (GSTs). The addition of large anionic groups (such as GSH) detoxifies reactive [[electrophile]]s and produces more polar metabolites that cannot diffuse across membranes, and may, therefore, be actively transported.

After phase II reactions, the xenobiotic conjugates may be further metabolised. A common example is the processing of glutathione conjugates to [[acetylcysteine]] ([[mercapturic acid]]) conjugates.<ref>{{cite journalbook |authorvauthors=Boyland E, Chasseaud LF |titlechapter=The roleRole of glutathioneGlutathione and glutathioneGlutathione S-transferasesTransferases in mercapturicMercapturic acidAcid biosynthesisBiosynthesis |title=Advances in Enzymology and Related Areas of Molecular Biology |journal=Adv. Enzymol. Relat. Areas Mol. Biol. |series=Advances in Enzymology - and Related Areas of Molecular Biology |volume=32 |issue= |pages=173–219 |year=1969 |pmid=4892500 |doi=10.1002/9780470122778.ch5|isbn=978-0-470-64961-9 }}</ref> Here, the [[glutamic acid|γ-glutamate]] and [[glycine]] residues in the glutathione molecule are removed by [[Gamma-glutamyl transpeptidase]] and [[dipeptidase]]s. In the final step, the [[cystine]] residue in the conjugate is [[acetylated]].

Conjugates and their metabolites can be excreted from cells in phase III of their metabolism, with the anionic groups acting as affinity tags for a variety of membrane transporters of the [[P-glycoprotein|multidrug resistance protein]] (MRP) family.<ref>{{cite journal |authorvauthors=Homolya L, Váradi A, Sarkadi B |title=Multidrug resistance-associated proteins: Export pumps for conjugates with glutathione, glucuronate or sulfate |journal=Biofactors |volume=17 |issue=1-41–4 |pages=103–14 |year=2003 |pmid=12897433 |doi=10.1002/biof.5520170111}}</ref> These proteins are members of the family of [[ATP-binding cassette transporter]]s and can catalyse the ATP-dependent transport of a huge variety of hydrophobic anions,<ref>{{cite journal |authorvauthors=König J, Nies AT, Cui Y, Leier I, Keppler D |title=Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance |journal=Biochim. Biophys. Acta |volume=1461 |issue=2 |pages=377–94 |year=1999 |pmid=10581368 |doi=10.1016/S0005-2736(99)00169-8|doi-access=free }}</ref> and thus act to remove phase II products to the extracellular medium, where they may be further metabolised or excreted.<ref>{{cite journal |authorvauthors=Commandeur JN, Stijntjes GJ, Vermeulen NP |title=Enzymes and transport systems involved in the formation and disposition of glutathione S-conjugates. Role in bioactivation and detoxication mechanisms of xenobiotics |journal=Pharmacol. Rev. |volume=47 |issue=2 |pages=271–330 |year=1995 |pmid=7568330}}</ref>

Studies on how people transform the substances that they ingest began in the mid-nineteenth century, with chemists discovering that organic chemicals such as [[benzaldehyde]] could be oxidized and conjugated to amino acids in the human body.<ref name="pmid11353742">{{cite journal | author vauthors= Murphy PJ | title = Xenobiotic metabolism: a look from the past to the future | journal = Drug Metab. Dispos. | volume = 29 | issue = 6 | pages = 779–80 |date=1 year =June 2001 | month = June | pmid = 11353742 | doi = | url = http://dmd.aspetjournals.org/cgi/content/full/29/6/779 }}</ref> During the remainder of the nineteenth century, several other basic detoxification reactions were discovered, such as [[methylation]], [[acetylation]], and [[sulfonic acid|sulfonation]].

In the early twentieth century, work moved on to the investigation of the enzymes and pathways that were responsible for the production of these metabolites. This field became defined as a separate area of study with the publication by [[Richard Tecwyn Williams|Richard Williams]] of the book ''Detoxication mechanisms'' in 1947.<ref name="pmid6347595">{{cite journal | author url=https://www.jstor.org/stable/769915 Neuberger| A, Smith RLjstor=769915 | title = Richard Tecwyn Williams:. the20 man,February his1909-29 work,December his1979 impact| last1=Neuberger | journalfirst1=A. | last2=Smith Drug| Metabfirst2=R. RevL. | volume journal=Biographical 14Memoirs |of issueFellows =of 3the Royal Society | pages date= 559–6071982 | year volume= 198328 | pmid pages= 6347595685–717 | doi = 10.31091098/03602538308991399rsbm.1982.0026 }}</ref> This modern biochemical research resulted in the identification of glutathione ''S''-transferases in 1961,<ref name="pmid16748905">{{cite journal | author vauthors= Booth J, Boyland E, Sims P | title = An enzyme from rat liver catalysing conjugations with glutathione | journal = Biochem. J. | volume = 79 | issue = 3 | pages = 516–24 |date=1 year =June 1961 | month doi= June10.1042/bj0790516 | pmid = 16748905 | pmc = 1205680 | doi = }}</ref> followed by the discovery of cytochrome P450s in 1962,<ref name="pmid14482007">{{cite journal | author vauthors= OMURAOmura T, SATOSato R | title = A new cytochrome in liver microsomes | journal = J. Biol. Chem. | volume = 237 | issue = |4 |pages = 1375–6 |date=1 year =April 1962 |doi=10.1016/S0021-9258(18)60338-2 month |doi-access= Aprilfree | pmid = 14482007 | doi = | url = http://www.jbc.org/cgi/reprint/237/4/PC1375 }}</ref> and the realization of their central role in xenobiotic metabolism in 1963.<ref name="pmid14625342">{{cite journal | author vauthors= Estabrook RW | title = A passion for P450s (rememberancesremembrances of the early history of research on cytochrome P450) | journal = Drug Metab. Dispos. | volume = 31 | issue = 12 | pages = 1461–73 | year = 2003 | month pmid= December14625342 | pmid url= 14625342http://dmd.aspetjournals.org/cgi/content/full/31/12/1461 | doi = 10.1124/dmd.31.12.1461 }}</ref><ref name="pmid14087340">{{cite journal | author vauthors= Estabrook RW, Cooper DY, Rosenthal O | title = The light reversible carbon monoxide inhibition of steroid C-21 hydroxylase system in adrenal cortex. | journal = Biochem. Z. | volume = 338 | issue = | pages = 741–55 | year = 1963 | pmid = 14087340 | doi = }}</ref>

* {{cite book | author =C. ParvezIoannides H,|title=Enzyme ReissSystems CThat |Metabolise titleDrugs =and Molecular Responses toOther Xenobiotics | publisher=John =Wiley Elsevierand |Sons |year=2001 | isbn = 0-345471-4227789466-5 4}}

* {{cite book | author =M. Ioannides CRichardson | title = Enzyme Systems That Metabolise Drugs and OtherEnvironmental Xenobiotics | publisher=JohnTaylor Wiley& andFrancis SonsLtd | year = 20011996 | isbn = 0-4717484-894660399-4 X}}

* {{cite book | author =C. Richardson MIoannides | title =Cytochromes EnvironmentalP450: XenobioticsMetabolic and Toxicological Aspects | publisher =CRC TaylorPress & Francis LtdInc | year = 1996 | isbn = 0-74848493-03999224-X1}}

* {{cite book | author =Y.C. Ioannides CAwasthi | title =Toxicology Cytochromesof P450:Glutathionine Metabolic and Toxicological AspectsS-transferses | publisher = CRC Press Inc | year = 19962006 | isbn = 0-8493-92242983-1 3}}