Grant D M, Josephy P D, Lord H L, Morrison L D
Guelph-Waterloo Center for Graduate Work in Chemistry, Department of Chemistry and Biochemistry, University of Guelph, Canada.
Cancer Res. 1992 Jul 15;52(14):3961-4.
Epidemiological studies have established the carcinogenic risk of occupational exposure to aromatic amines such as benzidine, beta-naphthylamine, and 4-aminobiphenyl. Metabolic activation of these chemicals to reactive, genotoxic electrophiles, via enzymatic N-oxidation and subsequent conjugation reactions, is necessary for their carcinogenic potential to be realized. Many aromatic amines are mutagenic in prokaryotic test systems, in the presence of exogenous mammalian activating enzymes such as those contained in hepatic 9000 x g supernatant. However, in the Ames (Salmonella typhimurium) assay, induction of mutations by aromatic amines and nitroarenes is also almost completely dependent upon the activity of the endogenous bacterial enzyme, N-acetyltransferase/O-acetyltransferase. The relevance of this assay to the prediction of the carcinogenic potential of aromatic amines in humans is thus restricted by the likelihood that the bacterial and human enzymes possess different substrate specificities. In this paper we report the construction and use of new tester strains of S. typhimurium that express high levels of functional human arylamine N-acetyltransferases, NAT1 and NAT2, retaining characteristic arylamine substrate specificities that are distinct from those of the bacterial enzyme. These new strains support the mutagenic activation of benzidine, 2-aminofluorene and 2-amino-3,4-dimethylimidazo[4,5-f]quinoline in the Ames test and may provide a new tool for evaluating the carcinogenic potential of aromatic amines.
流行病学研究已证实职业接触联苯胺、β-萘胺和4-氨基联苯等芳香胺具有致癌风险。这些化学物质通过酶促N-氧化及随后的结合反应代谢活化为具有反应性、基因毒性的亲电试剂，是实现其致癌潜力所必需的。许多芳香胺在原核测试系统中具有致突变性，在外源哺乳动物激活酶（如肝9000×g上清液中所含的酶）存在的情况下也是如此。然而，在艾姆斯（鼠伤寒沙门氏菌）试验中，芳香胺和硝基芳烃诱导的突变几乎也完全依赖于内源性细菌酶N-乙酰转移酶/O-乙酰转移酶的活性。因此，由于细菌酶和人类酶可能具有不同的底物特异性，该试验在预测人类芳香胺致癌潜力方面的相关性受到限制。在本文中，我们报告了鼠伤寒沙门氏菌新测试菌株的构建和使用，这些菌株表达高水平的功能性人类芳胺N-乙酰转移酶NAT1和NAT2，保留了与细菌酶不同的特征性芳胺底物特异性。这些新菌株在艾姆斯试验中支持联苯胺、2-氨基芴和2-氨基-3,4-二甲基咪唑并[4,5-f]喹啉的诱变活化，可能为评估芳香胺的致癌潜力提供一种新工具。
