title: Multiple activation pathways of benzene leading to products with varying genotoxic characteristics.
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)
authors.affiliation: Department of Toxicology, University of Mainz, Federal Republic of Germany.
authors.forename: H
authors.initials: H
authors.lastname: Glatt
authors.forename: R
authors.initials: R
authors.lastname: Padykula
authors.forename: G A
authors.initials: GA
authors.lastname: Berchtold
authors.forename: G
authors.initials: G
authors.lastname: Ludewig
authors.forename: K L
authors.initials: KL
authors.lastname: Platt
authors.forename: J
authors.initials: J
authors.lastname: Klein
authors.forename: F
authors.initials: F
authors.lastname: Oesch
mesh_terms: D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000818:Animals; D001554:Benzene / Q000378:metabolism / Q000633:toxicity*; D001711:Biotransformation; D066298:In Vitro Techniques; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors
chemical_list: D009153:Mutagens; D010088:Oxidoreductases; D000429:Alcohol Oxidoreductases; C023125:dihydrodiol dehydrogenases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C116788:cis-1,2-dihydro-1,2-dihydroxynaphthalene dehydrogenase; D001554:Benzene