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

A. A. Melikian, K. Bagheri, S. S. Hecht

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Abstract

Whereas extensive evidence indicates that 7β,8α-dihydroxy-9α,10α-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 than 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 (t( 1/2 )≃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. Qualititively, 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.

Original languageEnglish (US)
Pages (from-to)5354-5360
Number of pages7
JournalCancer Research
Volume47
Issue number20
StatePublished - 1987

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