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.
- Indicate the metabolic importance of glutathione.
- Appreciate that xenobiotics can cause pharmacologic, toxic, immunologic, and carcinogenic effects.
- Comprehend how knowledge of pharmacogenomics should help to personalize drug use.
Increasingly, humans are subjected to exposure to various foreign chemicals (xenobiotics)—drugs, food additives, pollutants, etc. The situation is well summarized in the following quotation from Rachel Carson: “As crude a weapon as the cave man's club, the chemical barrage has been hurled against the fabric of life.” Understanding how xenobiotics are handled at the cellular level is important in learning how to cope with the chemical onslaught, and thus helping to preserve the environment. For example, building on such information, attempts are being made to modify microorganisms by introducing genes that encode various enzymes involved in metabolizing specific xenobiotics to harmless products. These modified organisms will then be used to help dispose of various pollutants that contaminate the planet.
Knowledge of the metabolism of xenobiotics is basic to a rational understanding of pharmacology and therapeutics, pharmacy, toxicology, management of cancer, and drug addiction. All these areas involve administration of, or exposure to, xenobiotics.
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, and various compounds that have found their way into our environment by one route or another, such as polychlorinated biphenyls (PCBs) and certain insecticides. More than 200,000 manufactured environmental chemicals exist. Most of these compounds are subject to metabolism (chemical alteration) in the human body, with the liver being the main organ involved; occasionally, a xenobiotic may be excreted unchanged. At least 30 different types of enzymes catalyze reactions involved in xenobiotic metabolism; however, this chapter will only cover a selected group of them.
It is convenient to consider the metabolism of xenobiotics 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 cytochrome P450s. 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 phase 2, the hydroxylated or other compounds produced in phase 1 are converted by specific enzymes to various polar metabolites by conjugation with glucuronic acid, sulfate, acetate, glutathione, or certain amino acids, or by methylation.
The overall purpose of the two phases ...