Host-mediated mutagenicity experiments with benzo[a]pyrene and two of its metabolites.
Benzo[a]pyrene (BP) and two of its major metabolites, the ultimate mutagen BP-4,5-oxide and the proximate mutagen trans-7,8-dihydro-7,8-dihydroxybenzo[a]pyrene (BP-7,8-diol) were investigated for mutagenicity in Salmonella typhimurium TA1538, TA98 and TA100 using an intrasanguineous host-mediated assay. BP and BP-4,5-oxide were not mutagenic under any experimental conditions. BP-7,8-diol was inactive with the strain TA1538 but was mutagenic with the strains TA98 and TA100. The effect was potentiated by pretreatment of the host mice with the cytochrome P-450 inducer 5,6-benzoflavone. We conclude: (i) one of the reasons for the observed insensitivity of the intrasanguineous host-mediated assay towards BP is that BP-4,5-oxide, which contributes to the microsome-mediated mutagenicity of BP, is inactive in the host-mediated assay; (ii) the finding that BP-7,8-diol is mutagenic in the host-mediated assay demonstrates that the lack of mutagenicity of BP is not intrinsic; (iii) the potentiated mutagenicity after treatment of the hosts with 5,6-benzoflavone suggests that cytochrome P-450 is more important in the activation of BP-7,8-diol in this system than other enzymes (e.g. prostaglandin synthase) that can also activate this compound in vitro.
D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity*; D001571:Benzoflavones / Q000494:pharmacology; D001580:Benzopyrenes / Q000633:toxicity*; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004101:Dihydroxydihydrobenzopyrenes; D008297:Male; D051379:Mice; D009152:Mutagenicity Tests / Q000379:methods*; D009154:Mutation / Q000187:drug effects; D012486:Salmonella typhimurium / Q000187:drug effects; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D001580:Benzopyrenes; D004101:Dihydroxydihydrobenzopyrenes; C017228:benzo(a)pyrene 7,8-dihydrodiol; D001564:Benzo(a)pyrene; C006707:benzo(a)pyrene 4,5-epoxide; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System