Metabolism of 7,12-dimethylbenz(a)anthracene. Correlation of dihydrodiol and phenol metabolites with organ susceptibility to carcinogenesis in Sprague-Dawley and long-Evans rats.

The biotransformation of DMBA in uninduced and induced 10,000g organ supernatants derived from female Sprague-Dawley and Long-Evans rats, which are respectively sensitive and resistant to DMBA-induced carcinogenesis, was studied. Qualitative and quantitative differences in the metabolism of DMBA are summarized as a function of organ (liver, lung, kidney, and mammary) and strain and oxidative enzyme induction protocol utilized and are attributed to the differential induction of various cytochrome P-450s. The percent production of 7,12-dimethylbenz(a)anthracene-3,4-dihydrodiol (DMBA-3,4-DHD) and phenol metabolites in 10,000g organ supernatants from beta-napthoflavone induced animals correlated with organ susceptibility to DMBA-induced carcinogenesis in both SD and LE rat strains. A negative correlation was observed between 8,9-DHD production and reported sensitivity to specific organ tumorigenesis, but no other relationship was observed with other metabolites (7- and 12-hydroxymethyl, K-region DHD, and 10,11-DHDs). Similar DMBA metabolite hplc profiles were observed in the same organ S-10 fractions isolated from either SD or LE rats. Thus, the organotropic, but not the strain, selectivity of DMBA-induced carcinogenicity appears to be attributed in part to metabolic activation.