Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants, many of which are capable of inducing mutagenicity and carcinogenicity. For some time, PAHs have been known to require metabolic activation for producing their biological effects, but only recent evidence has implicated the bay-region diol epoxides as the ultimate mutagen/carcinogen of several PAHs. There is now growing evidence to indicate that metabolites other than (anti)-trans-7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (anti-BPDE) may be involved in the carcinogenesis of benzo(a)pyrene(BP). While definite evidence for the structure of reactive metabolite(s) other than anti-BPDE is lacking, we propose 3-hydroxy-anti-BPDE as a most probable candidate based on the following reasons: (i) 3-Hydroxy-anti-BPDE should be a better electrophile than anti-BPDE due to electronic reasons, (ii) 3-Hydroxy-anti-BPDE is the suspected intermediate in the metabolic activation of 3-hydroxy-BP and anti-BPDE, and (iii) The analogous triol-epoxide has been identified as a reactive intermediate in the metabolic activation of chrysene.
Our specific aims are: (1) to synthesize 3-hydroxy-BP-7,8-diol and their diastereomeric epoxides, 3-hydroxy-anti-BPDE and 3-hydroxy-syn-BPDE, (2) to compare the metabolic activation of BP-7,8-diol and 3-hydroxy-BP-7,8-diol to mutagenic products using Ames assay, (3) to assess the mutagenic activity of diastereomeric BPDEs and 3-hydroxy-anti-BPDEs using Ames assay, (4) to determine the extent to which BP is converted to 3-hydroxy-BP-7,8-diol by mouse liver microsomes, and (5) to assess the tumorigenic activity of 3-hydroxy-BP-7,8-diol and its diastereomeric epoxides. This assay will only be done if these compounds will show high mutagenic activity in Ames assay (see nos. 2 and 3). The long term goal is to understand the mechanism(s) involved in the mutagenesis/carcinogenesis of PAHs.
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