Xenobiotic metabolism

Xenobiotic metabolism is the set of biotransformation present in all major groups of organisms, and are probably of ancient origin. These reactions often act to detoxify poisonous compounds, although in some cases the intermediates in xenobiotic metabolism can themselves be the cause of toxic effects.

Xenobiotic metabolism is commonly divided into three phases. In phase I, enzymes such as efflux transporters and pumped out of cells.

The reactions in these pathways are of particular interest in medicine as part of persist in the environment.

Permeability barriers and detoxification

A major characteristic of xenobiotic toxic stress is that which exact compounds an organism is exposed to will be largely unpredictable, and may differ widely over time.^[1] The major challenge faced by xenobiotic detoxification systems is that they must therefore be able to remove the almost limitless number of possible xenobiotic compounds from the complex mixture of chemicals involved in normal 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 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.^[1] 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 achieved by the systems outlined above. This is since 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,^[3] and the various antioxidant systems that eliminate reactive oxygen species.^[4]

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 act 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.^[5] 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:^[6]

$\mbox{NADPH} + \mbox{H}^+ + \mbox{RH} \rightarrow \mbox{NADP}^+ + \mbox{H}_2\mbox{O} +\mbox{ROH} \,$

Phase II - conjugation

In subsequent phase II reactions, these activated xenobiotic metabolites are conjugated with charged species such as 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 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 ATP-binding cassette transporters and can catalyse the ATP-dependent transport of a huge variety of hydrophobic anions,^[9] and thus act to remove phase II products to the extracellular medium, where they may be further metabolised or excreted.^[10]

Endogenous toxins

The detoxification of endogenous reactive metabolites such as reactive oxygen species.

History

Studies on how people transform the substances that they ingest began in the mid-nineteenth century, with chemists discovering that organic chemicals such as 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.^[12] This modern biochemical research resulted in the identification of glutathione S-transferases in 1961,^[13] followed by the discovery of cytochrome P450s in 1962,^[14] and the realization of their central role in xenobiotic metabolism in 1963.^[15]^[16]

References

^ ^a ^b ^c Jakoby WB, Ziegler DM (1990). "The enzymes of detoxication". J. Biol. Chem. 265 (34): 20715–8. PMID 2249981.
^ Mizuno N, Niwa T, Yotsumoto Y, Sugiyama Y (2003). "Impact of drug transporter studies on drug discovery and development". Pharmacol. Rev. 55 (3): 425–61. PMID 12869659.
^ Thornalley PJ (1990). "The glyoxalase system: new developments towards functional characterization of a metabolic pathway fundamental to biological life". Biochem. J. 269 (1): 1–11. PMID 2198020.
^ Sies H (1997). "Oxidative stress: oxidants and antioxidants". Exp Physiol 82 (2): 291-5. PMID 9129943.
^ Guengerich FP (2001). "Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity". Chem. Res. Toxicol. 14 (6): 611–50. PMID 11409933.
^ Schlichting I, Berendzen J, Chu K, et al (2000). "The catalytic pathway of cytochrome p450cam at atomic resolution". Science 287 (5458): 1615–22. PMID 10698731.
^ Boyland E, Chasseaud LF (1969). "The role of glutathione and glutathione S-transferases in mercapturic acid biosynthesis". Adv. Enzymol. Relat. Areas Mol. Biol. 32: 173–219. PMID 4892500.
^ Homolya L, Váradi A, Sarkadi B (2003). "Multidrug resistance-associated proteins: Export pumps for conjugates with glutathione, glucuronate or sulfate". Biofactors 17 (1-4): 103–14. PMID 12897433.
^ König J, Nies AT, Cui Y, Leier I, Keppler D (1999). "Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance". Biochim. Biophys. Acta 1461 (2): 377–94. PMID 10581368.
^ Commandeur JN, Stijntjes GJ, Vermeulen NP (1995). "Enzymes and transport systems involved in the formation and disposition of glutathione S-conjugates. Role in bioactivation and detoxication mechanisms of xenobiotics". Pharmacol. Rev. 47 (2): 271–330. PMID 7568330.
^ Murphy PJ (2001). "Xenobiotic metabolism: a look from the past to the future". Drug Metab. Dispos. 29 (6): 779–80. PMID 11353742.
^ 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
^ Booth J, Boyland E, Sims P (1961). "An enzyme from rat liver catalysing conjugations with glutathione". Biochem. J. 79 (3): 516–24. PMID 16748905.
^ Omura T, Sato R (1962). "A new cytochrome in liver microsomes". J. Biol. Chem. 237: 1375–6. PMID 14482007.
^ Estabrook RW (2003). "A passion for P450s (rememberances of the early history of research on cytochrome P450)". Drug Metab. Dispos. 31 (12): 1461–73. PMID 14625342.
^ Estabrook, R. W., Cooper, D. Y., and Rosenthal, O. (1963). "The light reversible carbon monoxide inhibition of steroid C-21 hydroxylase system in adrenal cortex.". Biochem. Z. 338: 741–55.