Chapter 5: Drug Metabolism

ABBREVIATIONS

COPING WITH XENOBIOTICS

Humans come into contact with thousands of foreign chemicals or xenobiotics (substances foreign to the body) through diet and exposure to environmental contaminants. Fortunately, humans have developed a means to rapidly eliminate xenobiotics so that they do not accumulate in the tissues and cause harm. Plants are a common source of dietary xenobiotics, providing many structurally diverse chemicals, some of which are associated with pigment production and others that are toxins (called phytoalexins) that protect plants against predators. Poisonous mushrooms are a common example: They have many 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 to consume vegetation. While humans can now choose their dietary sources, a typical animal does not have this luxury and as a result is subject to its environment and the vegetation that exists in that environment. Thus, the ability to metabolize unusual chemicals in plants and other food sources is critical for adaptation to a changing environment and ultimately the survival of animals.

Enzymes that metabolize xenobiotics have historically been called drug-metabolizing enzymes by pharmacologists; however, these enzymes are involved in the metabolism of many foreign chemicals to which humans are exposed and are more appropriately called xenobiotic-metabolizing enzymes. Myriad diverse enzymes have evolved in animals to metabolize foreign chemicals. Dietary differences amongst species during the course of evolution could account for the marked species variation in the complexity of the xenobiotic-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 endogenous compounds are detoxified by the same or closely related xenobiotic-metabolizing enzymes.

Drugs are xenobiotics, and the capacity to metabolize and clear drugs involves the same enzymatic pathways and transport systems that are used for normal metabolism of dietary constituents. Indeed, many drugs are derived from chemicals found in plants, some of which have been used in traditional medicines for thousands of years. Of the prescription drugs in use today for cancer treatment, some are also derived from ...