ArylamineN‐Acetyltransferases

Abstract

Arylamine N ‐acetyltransferases (NATs) are phase II xenobiotic‐conjugating enzymes that have a restricted substrate preference for the N ‐ or O ‐acetylation of aromatic amine and their N ‐oxidized metabolites. Although the number of clinically useful drugs whose disposition depends on acetylation is relatively small, the risk for toxicity from these agents is significant. In addition, a much larger number of potentially hazardous environmental aromatic amines may be acetylated, and this process may contribute to either the detoxication or the metabolic activation of such chemicals into reactive electrophiles with the potential to damage cellular macromolecules. The structures of the two human NAT enzymes NAT1 and NAT2 have been determined; the structural features allow for the detailed description of a two‐step catalytic mechanism and for a rationalization of their distinct substrate preferences. Although the human isoniazid acetylation polymorphism is controlled by allelic variation at the NAT2 gene locus, a considerable variation exists in the NAT1 gene. Numerous associations have been reported between variable NAT function and risk for cancers associated with exposure to aromatic amines. In addition, possible novel roles for NAT1 and its mammalian orthologs in folate homeostasis and in cellular proliferation are being actively explored.