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

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-Benzo flavone 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. cytotoxicity (1, 14, 20). The enzyme system catalyzes the formation of covalently bound complexes of hydrocarbon with DNA (18, 19, 24) and protein (24). A powerful inhibitor of the enzyme 7,8-BF (59) prevents polycyclic hydrocarbon cytotoxicity (13) and inhibits DMBA tumorigenesis in mouse skin (22); the microsomal complex catalyzes the formation of epoxides of naphthalene (31) and dibenz(a,c)anthracene (47), the latter epoxide being a more potent transforming agent in vitro than the parent hydrocarbon (25). In this paper, we explore the role of the enzyme system in DMBA skin tumorigenesis by examining the mechanism of tumorigenesis inhibition by 7,8-BF. We have studied the effects of 7,8-BF on (a) DMBAand 7-OHMe-12-MBA-induced skin tumor formation, (¿>)mouse skin AHH, (c) the disappearance of DMBA from mouse skin, and (d) the binding of DMBA to the macromolecules of mouse skin epidermis. We have also studied the time required for the metabolic activation stage of DMBA tumorigenesis and the relationship between enzyme level and tumor susceptibility in different mouse strains.