Studies on the induction of gene mutations in bacterial and mammalian cells by the ring-opened benzene metabolites trans, trans-muconaldehyde and trans, trans-muconic acid

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Abstract
T, t-Muconaldehyde and t, t-, muconic acid have been investigated for the induction of gene mutations in Salmonella typhimurium (reversion of the his− strains TA97, TA98, TA100, TAKE, TA104 and TA1535), Escherichia coli (reversion of the trp− strain WP2 uvrA) and Chinese hamster V79 cells (acquisition of resistance toward 6-thioguanine). t, t-Muconaldehyde proved weakly mutagenic in strain TA104 in the presence and absence of NADPH-fortified postmito-chondrial fraction from rat liver homogenate (S9 mix). In strains TA97, TA100 and TA102, weak positive responses were observed only in the presence of S9 mix. In strains TA98, TA1535 and WP2 uvrA, the result was negative. In V79 cells, the mutation frequency was increased from ∼7 x 10−6 to 90 x 10−6 in cultures exposed to t, t-muconaldehyde at optimal concentration (1.7–3 μM in separate experiments). The concentration-response curve showed pronounced hyperlinearity, with no mutagenic effect being observed at a third of the optimal concentration. t, t-Muconic acid was > 100 times less toxic than t, t-muconaklehyde in both bacteria and mammalian cells, and it did not show any mutagenic effect. These results complete a previous mutagenicity study, carried out on benzene and 13 metabolites. It is concluded that the newly investigated metabolites cannot account for the bacterial mutagenicity of bioactivated benzene and benzene-trans-1,2-dihydrodiol, since these compounds exhibited their strongest response in strain TA1535. t, t-Mucon-aldehyde showed similarities in its mutagenicity to p-benzo-quinone and hydroquinone. All three compounds showed, at most, weak effects in bacteria, but were strongly mutagenic in V79 cells. However, p-benzoquinone and hydroquinone were more potent than t, t-muconaldehyde, and they showed no threshold concentration. However, t, t-muconaldehyde and p-benzoquinone proved to be the most cytotoxic benzene metabolites.