title: The benzene metabolite para-benzoquinone is genotoxic in human, phorbol-12-acetate-13-myristate induced, peripheral blood mononuclear cells at low concentrations.
abstract: Benzene is one of the most prominent occupational and environmental pollutants. The substance is a proven human carcinogen that induces hematologic malignancies in humans, probably at even low doses. Yet knowledge of the mechanisms leading to benzene-induced carcinogenesis is still incomplete. Benzene itself is not genotoxic. The generation of carcinogenic metabolites involves the production of oxidized intermediates such as catechol, hydroquinone and para-benzoquinone (p-BQ) in the liver. Further activation to the ultimate carcinogenic intermediates is most probably catalyzed by myeloperoxidase (MPO). Yet the products of the MPO pathway have not been identified. If an oxidized benzene metabolite such as p-BQ was actually the precursor for the ultimate carcinogenic benzene metabolite and further activation proceeds via MPO mediated reactions, it should be possible to activate p-BQ to a genotoxic compound in vitro. We tested this hypothesis with phorbol-12-acetate-13-myristate (PMA) activated peripheral blood cells exposed to p-BQ, using the cytokinesis-block micronucleus test. Addition of 20-28 ng/ml PMA caused a significant increase of micronuclei at low and non-cytotoxic p-BQ concentrations between 0.04 and 0.2 microg/ml (0.37-1.85 microM). Thus with PMA or p-BQ alone no reproducible elevation of micronuclei was seen up to toxic concentrations. PMA and p-BQ induce micronuclei when administered jointly. Our results add further support to the hypothesis that MPO is a key enzyme in the activation of benzene.
authors.affiliation: BGFA, Research Institute of Occupational Medicine, German Social Accident Insurance, Ruhr-University Bochum, 44789 Bochum, Germany. westphal@bgfa.ruhr-uni-bochum.de
authors.forename: Götz Alexander
authors.initials: GA
authors.lastname: Westphal
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bünger
authors.forename: Nadine
authors.initials: N
authors.lastname: Lichey
authors.forename: Dirk
authors.initials: D
authors.lastname: Taeger
authors.forename: Angelika
authors.initials: A
authors.lastname: Mönnich
authors.forename: Ernst
authors.initials: E
authors.lastname: Hallier
mesh_terms: D000328:Adult; D001554:Benzene / Q000378:metabolism / Q000633:toxicity*; D016227:Benzoquinones / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003571:Cytochalasin B / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D008297:Male; D015162:Micronucleus Tests; D008875:Middle Aged; D009152:Mutagenicity Tests; D010835:Phytohemagglutinins / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
chemical_list: D016227:Benzoquinones; D010835:Phytohemagglutinins; D003571:Cytochalasin B; C004532:quinone; D001554:Benzene; D013755:Tetradecanoylphorbol Acetate