Abstract
The aim of this work was to evaluate the hypothesis that the carcinogenic potential of a chemical may be related to its propensity to induce the enzyme system(s) responsible for its metabolic activation to reactive intermediates. This was carried out using isomers or structurally related chemicals from the following major classes of carcinogens: the chrysenes, azobenzenes, diaminonaphthalenes and related aromatic amines, and the diaminotoluenes. Furthermore, correlation between the induction of rat hepatic CYP1A and binding to the rat cytosolic Ah receptor was determined for all these compounds. Chrysene, all its methyl isomers and two benzo derivatives were potent inducers of CYP1A activity which was directly related to their avidity for binding to the Ah receptor. The 5-methyl isomer, the most potent carcinogen, did not differ from the other isomers in its ability to induce CYP1A1 activity. Treatment of rats with the various chrysenes did not stimulate their ability to convert them to mutagenic intermediates in the Ames test. Azobenzene and all its substituted isomers varied in their ability to induce CYP1A activity which was directly related to their avidity for binding to the Ah receptor. 3-Methoxy-4-aminoazobenzene and o-aminoazotoluene, the most potent carcinogens were also the most potent inducers of CYP1A activity and displacers of [3H]-TCDD from the Ah receptor. Treatment of rats with the various azobenzenes did not stimulate their ability to convert them to mutagenic intermediates in the Ames test. The diaminonaphthalenes and related aromatic amines differed in their ability to induce CYP1A activity which was directly related to their avidity for binding to the Ah receptor. Only rats treated with the diaminonaphthalenes enhanced their own activation to mutagenic intermediates in the Ames test. Of the diaminotoluenes, the best inducers of CYP1A activity were also the most effective displacers of [3H]-TCDD from the Ah receptor, namely, 2,3-and 2,4-diaminotoluene. 2,4-Diaminotoluene was the only isomer which enhanced its own activation to mutagenic intermediates in the Ames test. Investigation into the binding of a series of structurally diverse aromatic amines to the Ah receptor revealed that a strong positive correlation between binding affinity and propensity to induce both CYP1A1 and CYP1A2 activities. Furthermore, binding to the Ah receptor was achieved by N-hydroxy-2-naphthylamine, a major metabolite of 2-naphthylamine. It can be concluded from this work that the hypothesis that the carcinogenic potential of a chemical may be related to its ability to induce the enzyme systems(s) responsible for its metabolic activation to reactive intermediates has limitations, which need to be taken in to account in order for it to be used as a predictor of chemical toxicity and carcinogenesis.