Contrasting disposition and metabolism of topically applied benzo(a)pyrene, trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene, and 7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene in mouse epidermis in vivo.

Whereas extensive evidence indicates that 7 beta,8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (anti-BPDE) is a major ultimate carcinogen of benzo(a)pyrene (BaP) in mouse skin, tumorigenicity studies have consistently shown that anti-BPDE is less active then BaP in this model system. In order to investigate factors responsible for this apparent contradiction, we have compared the disposition, metabolism, and DNA binding of [3H]BaP, (+/-)-trans-7,8-[14C]dihydroxy-7,8-dihydrobenzo(a)pyrene [(+/-)-[14C]BaP-7,8-diol), and (+/-)-anti-[3H]BPDE in mouse epidermis in vivo. There were remarkable differences in the total radioactivity recovered in epidermis at various times after topical application of BaP, BaP-7,8-diol, and anti-BPDE. BaP and its metabolites were removed from epidermis gradually (t1/2 approximately equal to 2 h). However, 60-65% of anti-BPDE disappeared from mouse epidermis within 3 min of application, while a second slower phase of removal of radioactivity was observed between 8 min and 2 h. The kinetics of removal of BaP-7,8-diol and its metabolites were intermediate between those of BaP and anti-BPDE. The half-life of anti-BPDE in mouse epidermis was measured by trapping it with 2-mercaptoethanol. The initial half-life was about 6 min, similar to that observed in vitro. However, following the initial rapid penetration of anti-BPDE through epidermis most of the remaining material became immobilized in an epidermal binding site in which its half-life was greater than 2 h. Qualitatively, the metabolite patterns of BaP, BaP-7,8-diol, and anti-BPDE were similar to expectations based on in vitro studies. However, the kinetics of metabolite formation from BaP were different from those of BaP-7,8-diol or anti-BPDE. The extents of formation of anti-BPDE-DNA adducts 24 h after application of BaP, BaP-7,8-diol, or anti-BPDE to mouse skin were similar despite the fact that the levels of anti-BPDE present in epidermis were about 50 to 100 times greater after application of BaP-7,8-diol or anti-BPDE than after application of BaP. The results of this study demonstrate that the quantitative aspects of BaP-7,8-diol and anti-BPDE metabolism and disposition in mouse skin are different from those of BaP and indicate that the relatively low tumorigenicity of BaP-7,8-diol and anti-BPDE in mouse skin may be partially attributable to differences between the disposition of these metabolites when topically applied compared to when they are generated intracellularly from BaP.