The effects of xenobiotics on metabolism

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Xenobiotic are foreign compounds that include not only drugs but also environmental pollutants, dietary supplements, and food additives. Human exposure to xenobiotic is pervasive; in a human lifetime, one might be exposed to 1-3 million xenobiotic. These compounds can be toxic or harmless, but nonetheless they are treated by the body as foreign. They are metabolized and ultimately eliminated through the urine, bile, and faeces. Xenobiotic can be eliminated unchanged, but the vast majority utilize endogenous mechanisms such as enzymatic functionalization and/or conjugation reactions that facilitate their elimination, and they use processes that are also involved in the metabolism and transport of endogenous compounds such as bilirubin, lipids, and steroids. Thus, it is important to have a comprehensive knowledge of in vivo xenobiotic metabolism so that potential problems such as the generation of reactive metabolites or bioavailability issues when co administering a drug can be ascertained. Metabolomics the unbiased global survey of low-molecular-weight molecules or metabolites in a bio fluid, cell, tissue, organ, or organism represents an ideal solution for understanding and measuring the impact of xenobiotic exposure on a biological system. The term metabolite was first used in 1998 and has been defined since as “the set of metabolites synthesized by a biological system”  it encompasses all the small metabolites present in a particular biofluid (urine, blood, sebum, cerebral spinal fluid, saliva), cell, or tissue. As metabolites are the ultimate downstream products of genomic, transcriptomic, and/or proteomic perturbations, changes in metabolite concentration and/or flux can reveal biologically relevant changes to the system. A xenobiotic is a compound that is foreign to the body. The principal classes of xenobiotic of medical relevance are drugs, chemical carcinogens, naturally occurring compounds in plant foods, and various compounds that have found their way into our environment by one route or another, such as polychlorinated biphenyls (PCBs), insecticides and other pesticides. More than 200,000 manufactured environmental chemicals exist. Most of these compounds are subject to metabolism, mainly in the liver. While the metabolism of xenobiotic is generally considered to be a process of detoxification, sometimes the metabolites of compounds that are themselves inert or harmless are biologically active. This may be desirable, as in the activation of a prodrug to the active compound, or it may be undesirable, as in the formation of a carcinogen or mutagen from an inert precursor.The metabolism of xenobiotic is generally considered in two phases. In phase 1, the major reaction involved is hydroxylation, catalysed mainly by members of a class of enzymes referred to as monooxygenases or cytochromes P450. Hydroxylation may terminate the action of a drug, though this is not always the case. In addition to hydroxylation, these enzymes catalyze a wide range of reactions, including those involving deamination, dehalogenation, desulfuration, epoxidation, peroxygenation, and reduction. Reactions involving hydrolysis (eg, catalyzed by esterases) and certain other non-P450-catalyzed reactions also occur in phase 1. In his book, Dr Williams proposed that foreign compounds were metabolized in two distinct phases: one including oxidations, reductions, and hydrolyses and the other comprised of conjugation reactions. Although these views were first published in 1959, the recognition and study of metabolic conjugates of parent xenobiotic occurred much earlier in the history of drug metabolism. In the mid- to late 1800’s, various conjugates of drugs and other chemicals were first discovered and characterized, including conjugates possessing sulfate, glucuronic acid, mercapturic acid, methyl, and acetylated moieties.

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John Mathews

Managing Editor

American Journal of Pharmacology and Pharmacotherapeutics