6533b82bfe1ef96bd128ce0d

RESEARCH PRODUCT

Multiple activation pathways of benzene leading to products with varying genotoxic characteristics.

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Abstract Benzene and 13 potential metabolites were investigated for genotoxicity in Salmonella typhimurium and V79 Chinese hamster cells. In the presence of NADPH-fortified hepatic postmitochondrial fraction (S9 mix), benzene reverted his- S. typhimurium strains. The effect was strongest in strain TA1535. Among the potential metabolites, only the trans-1,2-dihydrodiol, in the presence of S9 mix, and the diol epoxides, in the presence and absence of S9 mix, proved mutagenic in this strain. The anti-diol epoxide was more potent than the syn-diastereomer. Both enantiomers of the anti-diastereomer showed similar activities. S9 mix did not appreciably affect the mutagenicity of the anti-diol epoxide. However, detoxification was observed when purified rat liver dihydrodiol dehydrogenase (EC 1.3.1.20) was used at concentrations comparable to that present in the liver. The (1S)-anti-diol epoxide was a much better substrate than the (1R)-enantiomer, as was true also for (1S)-versus (1R)-trans-1,2-dihydrodiol. The anti-diol epoxide reverted all six strains of S. typhimurium used and induced all four genotoxic effects studied in V79 cells (sister chromatid exchange greater than acquisition of 6-thioguanine resistance, acquisition of ouabain resistance, micronuclei). However, other potential benzene metabolites showed genotoxic effects in V79 cells, as well: sister chromatid exchange was induced by the syn-diol epoxide, 1,2,4-trihydroxybenzene, hydroquinone, catechol, and 1,2,3-trihydroxybenzene. Elevated frequencies of micronucleated cells were observed after treatment with hydroquinone, 1,2,4-trihydroxybenzene, catechol, phenol, 1,2,3-trihydroxybenzene, and quinone. Mutations to 6-thioguanine resistance were induced by quinone, hydroquinone, 1,2,4-trihydroxybenzene, catechol, and the trans-1,2-dihydrodiol.(ABSTRACT TRUNCATED AT 250 WORDS)