Patrick E. Hanna Pages 195 - 210 ( 16 )
A number of important therapeutic agents, such as the sulfonamide antibacterials, dapsone, and procainamide are primary arylamines. Human exposure to arylamines also occurs through smoking tobacco and consuming cooked meat, and in various occupational settings. The principal detoxification pathway for most primary arylamines involves metabolic conversion to an arylamide in an acetyl coenzyme A-dependent, N-acetyltransferase-catalyzed reaction. Although arylamines produce a wide range of toxicological responses, including hypersensitivity reactions and carcinogenesis, metabolic transformation to an N-hydroxyarylamine is required for most such compounds to manifest their untoward effects. Further conjugative metabolism of the N-hydroxylated arylamines is often involved in the production of reactive, electrophilic metabolites which form covalent adducts with biological macromolecules. This review describes the roles of specific enzyme systems in the biotransformation of arylamines and the chemical characteristics of arylamine metabolites that influence their toxicity, fate and disposition. The influence of interindividual genetic variability on the toxification and detoxification of arylamines is also addressed. In particular, genetic regulation of acetyltransferase activity is an important determinant of susceptibility to the toxicity and carcinogenicity of arylamines.