Mutagenicity and CYP1A induction by azobenzenes correlates with their carcinogenicity

The genotoxicity of six azobenzenes was evaluated in the Ames test, in the presence of an activation system derived from Aroclor 1254-treated rats. Moreover, the ability of these azobenzenes to induce rat hepatic CYP1A activities and apoprotein levels, and stimulate their own bioactivation to mutagens, was also determined. In the presence of the Aroclor 1254-activation system, o-aminoazotoluene and 3-methoxy-4-aminoazobenzene were potent mutagens, whereas 4-amino-azobenzene and 4-diethylaminoazobenzene failed to elicit a positive mutagenic response. A very weak mutagenic response was induced by 2-methyl-4-dimethylaminoazobenzene and by azobenzene. o-Aminoazotoluene and 3-methoxy-4-aminoazobenzene were potent inducers of CYP1A activities and apoprotein levels, whereas the remaining four compounds displayed either very weak or no induction capability. None of the azobenzenes studied could induce its own activation to mutagens in the Ames test. All six azobenzenes displaced [3H]tetrachlorodibenzo-p-dioxin from the cytosolic Ah receptor, with o-aminoazotoluene and 3-methoxy-4-aminoazobenzene being the most effective. A correlation appears to exist between carcinogenic activity of azobenzenes in the rat on one hand, and of their mutagenic potential and hepatic CYP1 induction on the other. Possible mechanisms accounting for this relationship are discussed.