MUTAGENICITY OF CHRYSENE, ITS METHYL AND BENZO DERIVATIVES, AND THEIRINTERACTIONS WITH CYTOCHROMES-P-450 AND THE AH-RECEPTOR - RELEVANCE TO THEIR CARCINOGENIC POTENCY

The genotoxicity in the Ames test of chrysene, of its six methyl and o f two benzo-derivatives, and their ability to induce rat hepatic CYP1A and epoxide hydrolase activities, and stimulate their own bioactivati on were determined. The primary objective is to provide a rationale fo r the higher carcinogenic potency of 5-methylchrysene when compared to that of the parent compound and the other methyl isomers. In the pres ence of Aroclor 1254-induced hepatic microsomes chrysene, its 5- and 4 -methyl derivatives and to a lesser extent the 2- and 3-methyl derivat ives and benzo[c]chrysene elicited a positive mutagenic response. Chry sene, all derivatives studied and especially benzo[c]chrysene were pot ent inducers of rat hepatic CYP1A1 activity as exemplified by the O-de ethylation of ethoxyresorufin (30-180-fold when activities are express ed per nmol of total cytochrome P-450). All compounds studied displace d [H-3]TCDD from the cytosolic Ah receptor at a concentration of 10(-1 0)-10(-9) M. Benzo[c]chrysene and to a lesser extent 6-methylchrysene were the only compounds capable of stimulating epoxide hydrolase activ ity, but the effect was modest. None of the compounds studied could in duce its own activation to mutagens in the Ames test. The present find ings indicate that the higher carcinogenic potency of 5-methylchrysene cannot be related to its mutagenic potential or its ability to enhanc e its own activation through induction of CYP1A1 and epoxide hydrolase activities.