Xenobiotic metabolism is the set of
metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organism's normal biochemistry, such as drugs and poisons. These pathways are a form of biotransformationpresent in all major groups of organisms, and are considered to be of ancient origin. These reactions often act to detoxify poisonous compounds; however, in some cases, the intermediates in xenobiotic metabolism can themselves be the cause of toxic effects.
Xenobiotic metabolism is divided into three phases. In phase I, enzymes such as
cytochrome P450 oxidases introduce reactive or polar groups into xenobiotics. These modified compounds are then conjugated to polar compounds in phase II reactions. These reactions are catalysed by transferaseenzymes such as glutathione S-transferases. Finally, in phase III, the conjugated xenobiotics may be further processed, before being recognised by efflux transporters and pumped out of cells.
The reactions in these pathways are of particular interest in
medicineas part of drug metabolismand as a factor contributing to multidrug resistancein infectious diseases and cancer chemotherapy. The actions of some drugs as substrates or inhibitors of enzymes involved in xenobiotic metabolism are a common reason for hazardous drug interactions. These pathways are also important in environmental science, with the xenobiotic metabolism of microorganisms determining whether a pollutant will be broken down during bioremediation, or persist in the environment.
Permeability barriers and detoxification
That the exact compounds an organism is exposed to will be largely unpredictable, and may differ widely over time, is a major characteristic of xenobiotic toxic stress. The major challenge faced by xenobiotic detoxification systems is that they must be able to remove the almost-limitless number of xenobiotic compounds from the complex mixture of chemicals involved in normal
metabolism. The solution that has evolved to address this problem is an elegant combination of physical barriers and low-specificity enzymatic systems.
All organisms use
cell membranes as hydrophobic permeability barriers to control access to their internal environment. Polar compounds cannot diffuse across these cell membranes, and the uptake of useful molecules is mediated through transport proteins that specifically select substrates from the extracellular mixture. This selective uptake means that most hydrophilic molecules cannot enter cells, since they are not recognised by any specific transporters. [cite journal |author=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] In contrast, the diffusion of hydrophobic compounds across these barriers cannot be controlled, and organisms, therefore, cannot exclude lipid-soluble xenobiotics using membrane barriers.
However, the existence of a permeability barrier means that organisms were able to evolve detoxification systems that exploit the hydrophobicity common to membrane-permeable xenobiotics. These systems therefore solve the specificity problem by possessing such broad substrate specificities that they metabolise almost any non-polar compound. Useful metabolites are excluded since they are polar, and in general contain one or more charged groups.
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
aldehydemethylglyoxal, [cite journal |author=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 |year=1990 |pmid=2198020 |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=2198020] and the various antioxidant systems that eliminate reactive oxygen species.cite journal |author=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 |pmid=9129943]
Phases of detoxification
The metabolism of xenobiotics is often divided into three phases: modification, conjugation, and excretion. These reactions act in concert to detoxify xenobiotics and remove them from cells.
Phase I - modification
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 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. [cite journal |author=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] 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: [cite journal |author=Schlichting I, Berendzen J, Chu K, "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]
Phase II - conjugation
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.cite journal |author=Jakoby WB, Ziegler DM |title=The enzymes of detoxication |journal=J. Biol. Chem. |volume=265 |issue=34 |pages=20715–8 |year=1990 |pmid=2249981 |url=http://www.jbc.org/cgi/reprint/265/34/20715] One of the most important of these groups are the glutathione S-transferases (GSTs). The addition of large anionic groups (such as GSH) detoxifies reactive electrophiles and produces more polar metabolites that cannot diffuse across membranes, and may, therefore, be actively transported.
Phase III - further modification and excretion
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. [cite journal |author=Boyland E, Chasseaud LF |title=The role of glutathione and glutathione S-transferases in mercapturic acid biosynthesis |journal=Adv. Enzymol. Relat. Areas Mol. Biol. |volume=32 |issue= |pages=173–219 |year=1969 |pmid=4892500 |doi=10.1002/9780470122778.ch5] Here, the γ-glutamate and glycineresidues in the glutathione molecule are removed by Gamma-glutamyl transpeptidaseand dipeptidases. In the final step, the cystineresidue 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 multidrug resistance protein (MRP) family. [cite journal |author=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=1-4 |pages=103–14 |year=2003 |pmid=12897433] These proteins are members of the family of
ATP-binding cassette transporters and can catalyse the ATP-dependent transport of a huge variety of hydrophobic anions, [cite journal |author=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] and thus act to remove phase II products to the extracellular medium, where they may be further metabolised or excreted. [cite journal |author=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]
The detoxification of endogenous reactive metabolites such as
peroxides and reactive aldehydes often cannot be achieved by the system described above. This is the result of these species' being derived from normal cellular constituents and usually sharing their polar characteristics. However, since these compounds are few in number, it is possible for enzymatic systems to utilize specific molecular recognition to recognize and remove them. The similarity of these molecules to useful metabolites therefore means that different detoxification enzymes are usually required for the metabolism of each group of endogenous toxins. Examples of these specific detoxification systems are the glyoxalase system, which acts to dispose of the reactive aldehyde methylglyoxal, and the various antioxidantsystems that remove reactive oxygen species.
Studies on how people transform the substances that they ingest began in the mid-nineteenth century, with chemists discovering that organic chemicals such as
benzaldehydecould be oxidized and conjugated to amino acids in the human body. [cite journal |author=Murphy PJ |title=Xenobiotic metabolism: a look from the past to the future |journal=Drug Metab. Dispos. |volume=29 |issue=6 |pages=779–80 |year=2001 |pmid=11353742 |url=http://dmd.aspetjournals.org/cgi/content/full/29/6/779] During the remainder of the nineteenth century, several other basic detoxification reactions were discovered, such as methylation, acetylation, and 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 Williams of the book "Detoxication mechanisms" in 1947. [ [http://links.jstor.org/sici?sici=0080-4606(198211)28%3C685%3ARTW2F1%3E2.0.CO%3B2-P Richard Tecwyn Williams. 20 February 1909-29 December 1979] A. Neuberger, R. L. Smith Biographical Memoirs of Fellows of the Royal Society, Vol. 28, Nov., 1982 (Nov., 1982), pp. 685-717] This modern biochemical research resulted in the identification of glutathione "S"-transferases in 1961, [cite journal |author=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 |year=1961 |pmid=16748905 |url=http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16748905] followed by the discovery of cytochrome P450s in 1962, [cite journal |author=Omura T, Sato R |title=A new cytochrome in liver microsomes |journal=J. Biol. Chem. |volume=237 |issue= |pages=1375–6 |year=1962 |pmid=14482007 |url=http://www.jbc.org/cgi/reprint/237/4/PC1375] and the realization of their central role in xenobiotic metabolism in 1963. [cite journal |author=Estabrook RW |title=A passion for P450s (rememberances of the early history of research on cytochrome P450) |journal=Drug Metab. Dispos. |volume=31 |issue=12 |pages=1461–73 |year=2003 |pmid=14625342 |url=http://dmd.aspetjournals.org/cgi/content/full/31/12/1461 |doi=10.1124/dmd.31.12.1461] [cite journal |author=Estabrook, R. W., Cooper, D. Y., and Rosenthal, O. |title=The light reversible carbon monoxide inhibition of steroid C-21 hydroxylase system in adrenal cortex. |journal=Biochem. Z. |volume=338 |pages=741–55 |year=1963]
* [http://www.drugmetabolism.co.uk/Default.aspx Drug metabolism database]
* [http://www.icgeb.org/~p450srv/ Directory of P450-containing Systems]
* [http://umbbd.msi.umn.edu/ University of Minnesota Biocatalysis/Biodegradation Database]
* [http://www.ionsource.com/tutorial/metabolism/drug_metabolism.htm Small Molecule Drug Metabolism]
* [http://www.cytochrome.net/ Drug metabolism portal]
* [http://www.horizonpress.com/gateway/biodegradation.html Microbial Biodegradation, Bioremediation and Biotransformation]
* [http://web.archive.org/web/20070713035439/http://www.issx.org/hisintro.html History of Xenobiotic Metabolism]
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