THE HEPATIC-METABOLISM OF 2 CARCINOGENIC DIMETHYLBENZ[C]ACRIDINES IN CONTROL AND INDUCED RATS - THE DISTRIBUTION AND THE MUTAGENICITY OF METABOLITES

The major and minor metabolites of the potent polycyclic aza-aromatic carcinogens 7,9-dimethylbenz[c]acridine and 7,10-dimethylbenz[c]acridi ne, and the stereochemistry of the dihydrodiol metabolites have been p reviously described. The metabolite distributions produced in incubati ons of the aza-aromatic compounds with liver microsomes from phenobarb ital- and 3-methylcholanthrene-pretreated and untreated rats, and the mutagenicity in the Ames test are described in this paper, The major m etabolites of each were the alcohols produced by oxidation of the meth yl group on the 8,9,10,11-ring for control and phenobarbital-induced p reparations, while with 3-methylcholanthrene-induced preparations both the 7- and 9- (or 10-) monoalcohols were formed, Total monofunctional ized dihydrodiol metabolites, the 5,6- and 3,4-isomers for 7,9-dimethy lbenz[c]acridine, and the 3,4-, 5,6- and 8,9-isomers for 7,10-dimethyl benz[c]acridine, constituted similar to 10% of total metabolites. As w ell, the K-region arene oxide was formed in substantial amounts with b oth compounds, accompanied in the case of 7,10-dimethylbenz[c]acridine with some 8,9-oxide. When incubations were carried out in the presenc e of the epoxide hydrase inhibitor 3,3,3-trichloropropane-1,2-oxide, d ihydrodiol formation was almost completely inhibited and relative amou nts of both phenols and oxides increased, Secondary metabolites were a lso formed to similar to 10% of the total products, The mutagenicity o f synthetic alcohols and isolated purified metabolites was determined in the Salmonella mammalian microsome plate assay (Ames test) with str ain TA100. Limited amounts of metabolites isolated precluded extensive testing, but high mutagenicities were noted for all 3,4-dihydrodiol d erivatives isolated, These exceeded those of the parent aza-aromatic h ydrocarbons. Alcohols were also active but less so than the parent com pounds. The activation of these two dimethylbenz[c]acridines to mutage ns appears to be through bay-region diolepoxides following patterns se en in other aza-aromatic compounds and the polycyclic aromatic hydroca rbons.