N‐Arylhydroxylamines and Chemical Carcinogenicity

1 Introduction 2 Metabolic Activation of AAs and HAAs 3 The Structures of DNA Adducts 4 The Nitrenium Ion Hypothesis 5 The Hypothesis Tested 6 Concluding Remarks Two related classes of carcinogens, arylamines (AAs) and heterocyclic arylamines (HAAs), have played an important role in the development of our understanding of chemical carcinogenesis. AAs are largely industrial products or by-products, but significant exposure also occurs through inhalation of cigarette smoke. HAAs are produced during broiling or frying of meats and fish and are viewed as significant cancer risks in most human populations. AAs and HAAs are properly characterized as procarcinogens because they require metabolic activation into their ultimate carcinogenic forms. Both classes are activated predominately by cytochrome P450 (CYP450) mediated oxidation into N-arylhydroxylamines that are further metabolized into acetic or sulfuric acid esters of the hydroxylamines by the action of N-acetyltransferases (NATs) or sulfotransferases (SULTs). These esters appear to be the ultimate carcinogens in most cases. Research on the metabolism of AAs and HAAs, the structures of DNA adducts derived from their carcinogenic metabolites, and the relationship of DNA adduct conformations and persistence to observed mutations are reviewed. Evidence for the proposal that the reactive intermediate responsible for the formation of DNA adducts is a nitrenium ion derived from the hydroxylamine esters is the main topic of this review. Future prospects for research in this area are considered. Keywords: Arylamines; Heterocyclic arylamines; N-arylhydroxylamines; Cytochrome P450; N-acetyltransferase; Sulfotransferase; C-8 Adduct; N2 Adduct; Nitrenium ions