Effects of 7,8-Benzoflavone on Skin Tumor-Initiating Activities of Various 7- and 12-Substituted Derivatives of 7,12-Dimenthylbenz[a]anthracene in Mice2

The skin tumor-initiating activities of various 7- and 12-substituted derivatives of 7,12-dimethylbenz[a]anthracene (DMBA) were investigated in female outbred Charles River CD-1 mice. 7-Formyl-12-methylbenz[a]anthracene (7-CHO-12-MBA) at 740 nmoles/mouse was an effective tumor initiator, at a dose 74-fold greater than that of DMBA. 7,8-Benzoflavone (7,8-BF) inhibited the tumor-initiating activity of 7-CHO-12-MBA by 51%. 12-Formyl-7-methylbenztalanthracene and 7,12-diformylbenz[a]anthracene, applied at initiating doses of 740 nmoles and 704 nmoles/mouse, respectively, were much less active than 7-CHO-12-MBA. 7-Bromomethyl-12-methylbenz[a]anthracene (7-BRME-12-MBA) and 7-bromomethylbenz[a]anthracene (7-BRMEBA) were also investigated. 7-BRME-12-MBA was a more effective tumor initiator than 7-BRMEBA, but both were less active than DMBA. 7,8-BF inhibited the tumor-initiating activity of 7-BRME-12-MBA and 7-BRMEBA by 34 and 54%, respectively. 12-Bromomethyl-7-methylbenz[a]anthracene (12-BRME-7-MBA) was as active an initiator as 7-BRME-12-MBA. 7,8-BF inhibited tumor initiation with 12-BRME-7-MBA by 29%. Three naturally occurring flavones, quercetin, myricetin, and 4′,5,7-trihydroxyflavonone, and the cytochrome P450 inhibitor 1-benzylimidazole were investigated after topical application (100 μ9) for their effects on tumor initiation with DMBA. Quercetin inhibited tumor initiation with DMBA by 22%, whereas myricetin and 4,5,7-trihydroxyflavanone enhanced tumor initiation with DMBA by 54 and 29%, respectively. 1-Benzylimidazole had no effect. The abilities of the flavones and 1-benzylimidazole to inhibit aryl hydrocarbon hydroxylase in vitro did not correlate with their effects on tumor initiation with DMBA.

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