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Previous studies have shown that 5-methylchrysene (5-MeC) is more carcinogenic on mouse skin than the other methylchrysenes and that the structural requirements favoring tumorigenicity of methylated polynuclear aromatic hydrocarbons are the presence of a bay region methyl group and free peri position, both adjacent to an unsubstituted angular ring. The purpose of this study was to extend these structure-activity relationships to dimethylchrysenes. The following dimethylchrysenes were synthesized: 1,5-dimethylchrysene (1,5-diMeC), 5,6-diMeC, 5,7-diMeC, 5,12-diMeC, 1,6-diMeC, 6,7-diMeC, and 6,12-diMeC. Bioassays of these compounds for tumor-initiating activity on mouse skin demonstrated that all were significantly less tumorigenic than 5-MeC; only 5,6-diMeC had significant tumorigenic activity. Since the relatively low activities of 5,7-diMeC and 5,6-diMeC were unexpected on the basis of the structural requirements stated above, anti-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5,7-dimethylchrysene+ ++ (anti-5,7-diMeC-1,2-diol-3,4-epoxide) was synthesized. Its mutagenicity in Salmonella typhimurium and reactivity with calf thymus DNA were compared to those of the major ultimate carcinogen of 5-MeC, anti-5-MeC-1,2-diol-3,4-epoxide. It was strongly mutagenic (2500 revertants/nmol), although less active than anti-5-MeC-1,2-diol-3,4-epoxide (7200 revertants/nmol). Its reactivity with calf thymus DNA was similar to that of anti-5-MeC-1,2-diol-3,4-epoxide. The results of this study demonstrate that the structural requirements which favor tumorigenicity of monomethylchrysenes are not sufficient for high tumorigenicity of dimethylchrysenes.

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The metabolism in mouse epidermis of benzo[b]fluoranthene (BbF) was studied. [3H]BbF was applied topically, mice were killed at various intervals, and metabolites were extracted from the epidermis and analyzed by h.p.l.c. The major metabolites were identified by comparisons to standards as 4-, 5-, and 6-hydroxyBbF. Sulfate and glucuronide conjugates of these hydroxyBbF were also detected. Minor metabolites included 12-hydroxyBbF, BbF-1,2-diol, and BbF-11,12-diol. BbF-9,10-diol, the only known tumorigenic oxygenated derivative of BbF, was not detected. The further metabolism of BbF-9,10-diol was studied in vitro, using rat liver 9000 g supernatant. The major metabolites were identified by their spectral characteristics as 5- and 6-hydroxyBbF-9,10-diol. Little if any BbF-9,10,11,12-tetraol was detected. 5- and 6-HydroxyBbF-9,10-diol were not detected as metabolites of [3H]BbF in mouse epidermis. Several known and potential BbF metabolites--BbF-1,2-diol, BbF-11,12-diol, BbF-9,10-diol, BbF-9,10-diol-11,12-epoxide, 5- and 6-hydroxyBbF-9,10-diol, 1-hydroxyBbF, 5-hydroxyBbF, and 6-hydroxyBbF--were tested for tumor initiating activity on mouse skin. Among these, only BbF-9,10-diol showed high tumorigenic activity, but no evidence has been obtained for its formation in vivo from BbF. These studies do not support the hypothesis that BbF is metabolically activated through formation of the bay region diol epoxide, BbF-9,10-diol-11,12-epoxide.