MECHANISM OF BENZO?A?PYRENE CARCINOGENESIS

苯并[a]芘（BP）是一种广泛存在的环境致癌物，已被广泛关注

Benzo[a]pyrene (BP), a widespread environmental carcinogen, has been widely used as a model compound for elucidating the mechanism by which polynuclear aromatic hydrocarbons (PAHs) induce carcinogenicity. It is well recognized that the bay-region diol epoxide metabolites, in particular (+)-anti-BPDE, with cellular DNA is critical for initiating the carcinogenic process induced by BP. However, a poor correlation between the level of (+)-BPDE- DNA adduct in a tissue and tissue susceptibility to BP-induced carcinogenesis does not fully support this concept. This lack of correlation suggest that, in addition to (+)-anti-BPDE-DNA adducts, the DNA adduct(s) of other reactive metabolite(s) of BP may also be of significant relevance in BP-induced carcinogenesis. For BP and other PAHs, the formation of phenolic bay-region diol epoxides (triol epoxides) is recently being recognized as an additional important metabolic reaction by which a hydrocarbon can be activated. Using the 32P-postlabeling technique, our preliminary studies have shown that one of the major DNA adducts formed by microsomal activation of synthetic 3-hydroxy-BP-7,8-diol (BP-triol), a major metabolite of 3-hydroxyBP and also a metabolic precursor of 3- hydroxy-BP-7,8-diol-9,10-epoxide (BPTE), co-chromatographs with anti-BPDE- dG. Therefore, it is likely that in vivo BP-DNA adducts previously believed to be derived from BPDE may in fact also be derived from BPTE. The major objective of the proposed research is to investigate whether any of the major DNA adducts of BP produced in vivo is derived from BPTE. The specific aims of the proposed research are: (i) To synthesize and characterize various deoxyribonucleoside 3'-monophosphate adducts of BPTE; (ii) To analyze and characterize DNA adducts of BP-triol formed after microsomal activation in the presence of DNA; (iii) To analyze and identify DNA adducts of BPDE-, BPTE- or BP-triol-derived DNA adducts; and (iv) To examine the relative persistence of BP-DNA adducts in mouse skin and mouse liver in vivo with particular emphasis on BPTE adducts.