Evidence for an acetoxyarylamine as the ultimate mutagenic reactive intermediate of the carcinogenic aromatic amine 2,4-diaminotoluene.

M L Cunningham, H B Matthews

文献索引：Mutat. Res. 242(2) , 101-10, (1990)

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摘要

2,4-Diaminotoluene (2,4-DAT) is a mutagenic and hepatocarcinogenic aromatic amine, requiring metabolic activation. We have found that the mutagenic potency of 2,4-DAT in Salmonella TA98 is similar when activated by either Aroclor-1254-induced rat primary hepatocytes or 9000 x g supernatant. Previous work has demonstrated that 2,4-DAT is activated by cytochrome P450. The present report describes an investigation of the role of acetyltransferase in 2,4-DAT activation. Substitution of TA98 with the acetyltransferase-deficient strain TA98/1,8-DNP6 resulted in an approximately 90% decrease in the mutagenic potency for 2,4-DAT using S9 activation. The newly engineered acetyltransferase-enhanced Salmonella tester strain YG1024 (TA98(pYG219] demonstrated greatly enhanced sensitivity to the mutagenicity of 2,4-DAT. Inhibition of O-acetyltransferase activity, either with the selective acetyltransferase inhibitor thiolactomycin, or by competitive inhibition with an alternative substrate for the enzyme, reduced the mutagenicity of 2,4-DAT in this acetyltransferase-enhanced bacterial strain. From these data we conclude that following 2,4-DAT activation by N-hydroxylation by cytochrome P450, the resulting hydroxylamino intermediate is further activated in the bacteria via O-acetylation to form the ultimate reactive intermediate, which is postulated to be 4-acetoxyamino-2-aminotoluene.