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OBJECTIVES
After studying this chapter, you should be able to:
Discuss how drugs and other xenobiotics are metabolized in the body.
Describe the two general phases of xenobiotic metabolism, the first involving mainly hydroxylation reactions catalyzed by cytochrome P450 species and the second conjugation reactions catalyzed by various enzymes.
Describe the metabolic importance of glutathione.
Appreciate that xenobiotics can cause pharmacologic, toxic, immunologic, and carcinogenic effects.
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BIOMEDICAL IMPORTANCE
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We are exposed to a wide variety of foreign chemicals (xenobiotics), both naturally occurring compounds in plant foods, and synthetic compounds in medicines, food additives, and environmental pollutants. Knowledge of the metabolism of xenobiotics is essential for an understanding of pharmacology and therapeutics, toxicology, and the management of disease. All these areas involve either the administration of, or exposure to, xenobiotics. Many of the xenobiotics in plant foods have potentially beneficial effects (eg, acting as antioxidants, Chapter 45), and knowledge of their metabolism will permit extrapolation from in vitro measurement of antioxidant activity to in vivo protective action.
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Understanding the mechanisms involved in xenobiotic metabolism will permit the development of transgenic microorganisms and plants containing genes that encode enzymes for the metabolism of specific compounds that can be used to convert potentially hazardous pollutants to harmless compounds. Similarly, transgenic organisms may be used for biosynthesis of drugs and other chemicals.
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WE ENCOUNTER MANY XENOBIOTICS THAT MUST BE METABOLIZED BEFORE BEING EXCRETED
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A xenobiotic (Gk xenos “stranger”) is a compound that is foreign to the body. The principal classes of xenobiotics 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 xenobiotics 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.
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The metabolism of xenobiotics is generally considered in two phases. In phase 1, the major reaction involved is hydroxylation, catalyzed 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.
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Phase 1 metabolism renders compounds more ...