Biochemical Mechanisms of Drug Toxicity

Abstract

It has long been known that many drugs can be converted in the body to various metabolites that evoke therapeutic and toxicologic responses. In most instances these metabolites are chemically inert and bring about their effects by combining reversibly with action sites in tissues. In some instances, however, drugs and other foreign compounds can be converted in the body to chemically reactive metabolites which either uncouple integrated biochemical processes in cells or combine cova­ lently with various tissue macromolecules, such as DNA, RNA, protein, and glyco­ gen. During the past several years it has become increasingly evident that chemically reactive metabolites mediate many different kinds of serious toxicity, including carcinogenesis, mutagenesis, cellular necrosis, hypersensitivity reactions, methemo­ globinemia, hemolytic anemia, blood dyscrasias, and fetotoxicities. This review is devoted mainly to the mechanisms by which various kinds of toxicities are mediated by chemically reactive metabolites of drugs and the factors that affect the severity of the toxicities. Since the pioneering work of the Millers in Wisconsin and of Magee and co­ workers in England, it has become increasingly evident that most if not all chemical carcinogens bring about their effects by combining covalently with DNA and other tissue macromolecules or by being transformed to chemically reactive metabolites that in turn combine covalently with tissue macromolecules (1-4). The many studies on the mechanism of formation of carcinogenic metabolites in the body have revealed that chemically inert substances can be converted to chemi­ cally reactive metabolites by a variety of different reactions (Figure I). For example,