The role of aryl hydrocarbon hydroxylase in 7,12-dimethylbenz(a)anthracene skin tumorigenesis: on the mechanism of 7,8-benzoflavone inhibition of tumorigenesis.

Summary Aryl hydrocarbon hydroxylase of mouse skin is inducible by benz(a)anthracene or 7,12-dimethylbenz(a)anthracene (DMBA) and is inhibited by 7,8-benzoflavone. 7,8-Benzoflavone inhibits the formation of covalently bound complexes of DMBA with DNA, RNA, and protein and also inhibits tumor formation caused either by a single application of DMBA, followed by croton oil treatment, or by the repeated application of DMBA. These results indicate that DMBA requires metabolic activation by aryl hydrocarbon hydroxylase for its carcinogenic activity. The inhibitory effect of 7,8-benzoflavone is limited to its application within 12 hr of administration of the DMBA, suggesting that the metabolic activation of DMBA is completed within 12 hr. The level of aryl hydrocarbon hydroxylase and DMBA tumorigenesis varies markedly in different mouse strains, indicating either that there are genetic differences in the profile of DMBA metabolite formation or that metabolic activation is necessary but not sufficient for DMBA tumorigenesis.