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Toxicological Characterization of a Novel in Vivo Benzo[ a ]pyrene Metabolite, 7-Oxo-benz[ d ]anthracene-3,4-dicarboxylic Acid Anhydride

2002; American Chemical Society; Volume: 15; Issue: 10 Linguagem: Inglês

10.1021/tx025549l

1520-5010

Mirjam M. Nordling, Jonas Nygren, Jan Bergman, Kathrin Sundberg, Joseph Rafter,

Cancer therapeutics and mechanisms

Recently, we described a new in vivo pathway in the metabolism of benzo[a]pyrene (BP) that involves an opening of the aromatic ring system. One of the products of this pathway, isolated from rat urine, was the anhydride of 7-oxo-benz[d]anthracene-3,4-dicarboxylic acid (ABADA). We have now investigated the effect of ABADA on several cellular targets, known to be important in tumor formation. ABADA was as efficient as BP-7,8-diol-9,10-epoxide in inducing direct strand breaks but not alkali labile sites in DNA in HT-29 cells and exhibited weak mutagenic activity in Salmonella typhimurium strain TA 102. The cytotoxicity of ABADA to HCT 116 cells appeared to be due to apoptosis, as caspase-3 activity and poly-ADP-ribose polymerase (PARP) cleavage was observed. COX-2 promoter activity was induced by ABADA in HCT 116 cells. In conclusion, this novel metabolic pathway may also be contributing to the carcinogenicity of BP.