Overview

The enzymes of drug metabolism mainly act to protect the cell from insult by foreign agents, such as drugs, industrial chemicals, and environmental pollutants. However, these versatile proteins also overlap with normal cellular function by participating in the anabolism and catabolism of a variety of endogenous compounds, including steroids, bile salts, vitamins, and products of the arachidonic acid cascade, to name but a few.1

In terms of their xenobiotic function, the drug-metabolizing enzymes can create or unmask hydrophilic moieties in such xenobiotics in order to facilitate their renal clearance (e.g., cytochrome P450 (P450), flavin-containing monooxygenase (FMO), esterases, glucuronyltransferases, sulfotransferases), or they can detoxify electrophilic species that may be damaging to the cell (e.g., epoxide hydrolase, carbonyl reductases and glutathione (GSH) transferases). This enzymatic division is not a strict one, as certain oxidative P450 reactions and conjugation reactions, for example, can be viewed as bioactivation processes that convert a relatively benign compound into a more reactive species.2 Regardless, these diverse proteins can be divided operationally into three main categories: (1) redox enzymes, that catalyze oxidation and reduction reactions; (2) hydrolases, that catalyze reaction of water with esters, amides, and epoxides; and (3) transferases, that conjugate xenobiotics with relatively small polar molecules.

With regard to the metabolism of therapeutic agents, a survey of the top 200 prescribed drugs from 2002 indicated that more than two-thirds were cleared by metabolic processes, and that of this number about 75% owed their clearance mainly to metabolism by redox enzymes (mostly P450s), up to 15% were cleared by transferases (mostly UDP-glucuronyltransferases (UGTs)), and some 10% were cleared by hydrolase enzymes (mostly esterases).3 Essential characteristics of each of these important enzyme groups are discussed below that highlight their diversity, structure-function relationships, tissue localization, and development. For additional information, see 5.08 Mechanisms of Toxification and Detoxification which Challenge Drug Candidates and Drugs; 5.10 In Vitro Studies of Drug Metabolism.

Home Detox

Home Detox

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