Toxicological characterization of a novel in vivo benzo[a]pyrene metabolite, 7-oxo-benz[d]anthracene-3,4-dicarboxylic acid anhydride.
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.
Nordling
Mirjam M
MM
Department of Medical Nutrition, Karolinska Institutet, Huddinge University Hospital, NOVUM, S-141 86 Huddinge.
Nygren
Jonas
J
Bergman
Jan
J
Sundberg
Kathrin
K
Rafter
Joseph J
JJ
D000812:Anhydrides / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001551:Benz(a)Anthracenes / Q000633:toxicity*; D001564:Benzo(a)pyrene / Q000378:metabolism*; D002273:Carcinogens / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000494:pharmacology; D004249:DNA Damage; D003998:Dicarboxylic Acids / Q000633:toxicity*; D009152:Mutagenicity Tests; D051381:Rats; D012486:Salmonella typhimurium / Q000235:genetics
C473090:7-oxo-benz(d)anthracene-3,4-dicarboxylic acid anhydride; D000812:Anhydrides; D001551:Benz(a)Anthracenes; D002273:Carcinogens; D003998:Dicarboxylic Acids; D001564:Benzo(a)pyrene; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases