Chapter 6

### COPING WITH EXPOSURE TO XENOBIOTICS

Humans come into contact with thousands of foreign chemicals, medicines, or xenobiotics (substances foreign to the body) through intentional exposure, accidental exposure to environmental contaminants, as well as through diet. Fortunately, humans have developed a means to rapidly eliminate xenobiotics so that they do not accumulate in the tissues and cause harm. The ability of humans to metabolize and clear drugs is a natural process that involves the same enzymatic pathways and transport systems that are used for normal metabolism of dietary constituents. In fact, plants are a common source of xenobiotics in the diet, contributing many structurally diverse chemicals, some of which are associated with pigment production and others of which are toxins (called phytoallexins) that protect plants against predators. For example, poisonous mushrooms produce toxins that are lethal to mammals, including amanitin, gyromitrin, orellanine, muscarine, ibotenic acid, muscimol, psilocybin, and coprine. Animals must be able to metabolize and eliminate such chemicals in order to consume vegetation.

Drugs are considered xenobiotics and most are extensively metabolized in humans. Many drugs are derived from chemicals found in plants, some of which have been used in Chinese herbal medicines for thousands of years. Thus, it is not surprising that humans also metabolize synthetic drugs by pathways that mimic the disposition of chemicals found in the diet. This capacity to metabolize xenobiotics, while mostly beneficial, has made development of drugs very time consuming and costly due in large part to:

• Inter-individual variations in the capacity of humans to metabolize drugs

• Drug-drug interactions

• Metabolic activation of chemicals to toxic and carcinogenic derivatives

• Species differences in expression of enzymes that metabolize drugs, thereby limiting the use of animal models for drug testing to predict effects in humans

A large number of diverse enzymes have evolved in animals that apparently function only to metabolize foreign chemicals. As will be discussed later, there are such large differences among species in the ability to metabolize xenobiotics, that animal models cannot be solely relied upon to predict how humans will metabolize a drug. Enzymes that metabolize xenobiotics have historically been called drug-metabolizing enzymes, although they are involved in the metabolism of many foreign chemicals to which humans are exposed. Thus, a more appropriate name would be xenobiotic-metabolizing enzymes.Dietary differences among species during the course of evolution could account for the marked species variation in the complexity of the drug-metabolizing enzymes. Additional diversity within these enzyme systems has also derived from the necessity to detoxify a host of endogenous chemicals that would otherwise prove harmful to the organism, such as bilirubin, steroid hormones, and catecholamines. Many of these compounds are detoxified by the same or closely related xenobiotic-metabolizing enzymes.

Xenobiotics to which humans are exposed come from sources that include environmental pollution, food additives, cosmetic products, agrochemicals, processed foods, and drugs. In general, most xenobiotics are lipophilic chemicals that, in the absence of metabolism, ...

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