Covalent and Noncovalent Interactions in Acute Lethal Cell Injury Caused by Chemicals

Abstract

Several chemicals, including some drugs, cause cell injury by mechanisms that are poorly characterized. Although a few drugs are toxins that act directly, most require metabolic activation to form the ultimate toxic species. The concept of metabolic activation was first described by the Millers ( 1) in a review of their pioneering work on aminoazo dyes and 2-acetylaminofluorene as procarcinogens. Brodie et al (2) expanded on this concept to include a role for metabolic activation in acute cell injury. Since that time several reviews (3-12) and books ( 13-15) have discussed the role of metabolic activation in the pathogenesis of a variety of toxicities. Although a substantial body of information is available on the metabolic reactions that produce toxic metabolites and on the chemical nature of these metabolites, considerably less is known about how ultimate toxic species interact with cellular constituents and how the interactions cause cell injury. Reactions of toxic metabolites may result in covalent bond formation between the metabolite and a target molecule, or they may alter (usually by oxidation or reduction) the target molecule without formation of a covalent bond. Some of the more likely targets of these interactions are listed in Table 1.