Salmonella typhimurium strains expressing human arylamine N-acetyltransferases: metabolism and mutagenic activation of aromatic amines.
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.
Grant
D M
DM
Guelph-Waterloo Center for Graduate Work in Chemistry, Department of Chemistry and Biochemistry, University of Guelph, Canada.
Josephy
P D
PD
Lord
H L
HL
Morrison
L D
LD
D001191:Arylamine N-Acetyltransferase / Q000378:metabolism*; D001560:Benzidines / Q000378:metabolism; D001711:Biotransformation; D005449:Fluorenes / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D009152:Mutagenicity Tests; D012486:Salmonella typhimurium / Q000201:enzymology*
D001560:Benzidines; D005449:Fluorenes; D007527:Isoenzymes; C029876:benzidine; C012177:2-aminofluorene; D001191:Arylamine N-Acetyltransferase