After studying this chapter, you should be able to:
Describe the two phases of xenobiotic metabolism, the first involving mainly hydroxylation reactions catalyzed by cytochromes P450 and the second conjugation reactions.
Describe the metabolic importance of glutathione.
Describe how xenobiotics can have toxic, immunological, and carcinogenic effects.
We are exposed to a wide variety of compunds that are foreign to the body (xenobiotics, from the Greek xenos = foreign); 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, therapeutics, and toxicology. Many of the xenobiotics in plant foods have potentially beneficial effects (eg, acting as antioxidants, Chapter 45).
Understanding the mechanisms involved in xenobiotic metabolism will permit the development of transgenic microorganisms and plants containing genes that encode enzymes that can be used to render potentially hazardous pollutants harmless. Similarly, transgenic organisms may be used for biosynthesis of drugs and other chemicals.
WE ENCOUNTER MANY XENOBIOTICS THAT MUST BE METABOLIZED BEFORE BEING EXCRETED
The main xenobiotics of medical relevance are drugs, chemical carcinogens, naturally occurring compounds in plant foods, and a wide variety of compounds that have found their way into our environment, such as polychlorinated biphenyls (PCBs), and insecticides and other pesticides. Most of these compounds are metabolized, 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.
The metabolism of xenobiotics occurs in two phases. In phase 1, the major reaction involved is hydroxylation, catalyzed by enzymes that are monooxygenases or cytochromes P450. In addition to hydroxylation, these enzymes catalyze a wide range of other reactions, including deamination, dehalogenation, desulfuration, epoxidation, peroxygenation, and reduction. Reactions involving hydrolysis (eg, catalyzed by esterases) and other non-P450–catalyzed reactions also occur in phase 1.
Phase 1 metabolism renders compounds more reactive, introducing groups that can be conjugated with glucuronic acid, sulfate, acetate, glutathione, or amino acids in phase 2 metabolism. This produces polar compounds that are water-soluble and can therefore be excreted in urine or bile.
In some cases, phase 1 metabolic reactions convert xenobiotics from inactive to biologically active compounds. In these instances, the original xenobiotics are referred to as prodrugs or procarcinogens. Sometimes, additional phase 1 reactions (eg, further hydroxylation reactions) convert these active compounds into less active or inactive forms prior to conjugation. In other cases, it is the conjugation reactions that convert the active products ...