The role of aryl hydrocarbon hydroxylase in skin tumor initiation by 7,12-dimethylbenz(a)anthracene and 1,2,5,6-dibenzanthracene using DNA binding and thymidine-3H incorporation into DNA as criteria.

Aryl hydrocarbon hydroxylase in mouse skin epidermis was inducible by topical applications of 1,2,5,6-dibenzanthracene (DBA), 7,12-dimethylbenz[a] anthracene (DMBA), and 5,6benzoflavone. 7,8-Benzoflavone given topically inhibited the enzyme activity; phénobarbitalgiven topically had little or no effect on this enzyme activity. 7,8-Benzoflavone given at the same time as DMBA inhibited the formation of skin tumors in a two-stage system of tumorigenesis and also inhibited the formation of covalently bound complexes of DMBA with epidermal DNA, RNA, and protein. However, 7,8-benzoflavone given at the same time as DBA stimulated skin tumor formation but had little or no effect on the binding of DBA to epidermal macromolecules. Phénobarbital had a small inhibi tory effect on DMBA skin tumor initiation and on the binding of DMBA to epidermal macromolecules. However, phénobarbi tal significantly inhibited tumor formation initiated by DBA but did not affect DBA binding to epidermal macromolecules. 5,6-Benzoflavone inhibited slightly both tumor formation and hydrocarbon binding in the case of both DMBA and DBA. Inhibition of epidermal DNA synthesis caused by DMBA (topical application) was partially blocked by simultaneous treatment with 7,8-benzoflavone, 5,6-benzoflavone, and phénobarbital. The order in the degree of modification of the inhibition was the same as that seen for the effect of these three compounds on the binding of DMBA to epidermal DNA. These results indicate that, in the case of the substrate DMBA, 7,8-benzoflavone inhibits enzymes involved in the activation of DMBA to its carcinogenic form to a greater extent than it inhibits enzymes involved in the detoxification of DMBA. However, in the case of the substrate DBA, 7,8-benzoflavone might inhibit enzymes involved in detoxification of DBA to a greater extent than it inhibits activation of DBA. Data obtained with phénobarbital might indicate that DBA but not DMBA has a specific phenobarbital-inducible detoxification system in mouse skin epidermis.