Somatic mutation, DNA damage and cytotoxicity induced by benzo[a]pyrenedione/benzo[a]pyrenediol redox couples in cultured mammalian cells.
BP-3,6-dione was found to be mutagenic, cytotoxic and to induce DNA damage in a transformed line of Syrian hamster fibroblasts at low concentrations, 2 micrograms/ml and less. Inhibition of sulfate and glucuronic acid conjugating enzymes with salicylamide potentiated the above effects of BP-3,6-dione. Diminishing cellular capacity to scavenge superoxide anion radicals also potentiated the mutagenic and cytotoxic action of the dione. The presence of dicumarol, a specific inhibitor of the two-electron reduction of quinones by DT-diaphorase, afforded some protection against cytotoxicity. The results indicate that BP-3,6-dione undergoes two-electron reduction to an unstable hydroquinone, BP-3,6-diol, or one-electron reduction to a semiquinone radical intermediate and that both of these reduced forms undergo rapid univalent oxidation to generate active reduced oxygen species. The data are consistent with the hypothesis that active oxygen species generated by BP-dione/BP-diol redox cycling are responsible, at least in part, for the mutagenic and cytotoxic effects observed with BP-3,6-dione.
D000818:Animals; D001580:Benzopyrenes / Q000378:metabolism / Q000494:pharmacology*; D001711:Biotransformation; D002460:Cell Line; D003114:Colony-Forming Units Assay; D006224:Cricetinae; D004247:DNA / Q000378:metabolism*; D004261:DNA Replication / Q000187:drug effects; D001728:Dicumarol / Q000494:pharmacology; D004351:Drug Resistance; D005347:Fibroblasts / Q000187:drug effects*; D008658:Inactivation, Metabolic; D008647:Mesocricetus; D009154:Mutation; D012457:Salicylamides / Q000494:pharmacology; D013866:Thioguanine / Q000494:pharmacology
D001580:Benzopyrenes; D012457:Salicylamides; D001728:Dicumarol; D004247:DNA; C018003:benzo(a)pyrene-3,6-quinone; C031060:salicylamide; D013866:Thioguanine