title: Metabolites of benzene are potent inhibitors of gap-junction intercellular communication.
abstract: Chronic exposure to benzene has been shown to lead to bone marrow depression and the development of leukemia. The mechanism underlying the carcinogenicity of benzene is unknown, although a number of genetic changes including chromosomal aberrations have been associated with benzene toxicity. Metabolism of benzene is required for the induced toxicological effects. We have investigated the effect of trans,trans-muconaldehyde (MUC), hydroquinone (HQ), and four MUC metabolites on gap-junction intercellular communication (GJIC). Inhibition of GJIC has been considered a possible predictor of tumor promoters and non-genotoxic carcinogens, and shown to result in perturbation of hematopoiesis. MUC was found to be a strong inhibitor of GJIC (EC50=12 micromol L(-1)) in rat liver epithelial cells IAR20, with potency similar to that of chlordane (EC50=7 micromol L(-1)). HQ inhibited GJIC with an EC50 of 25 micromolmol L(-1), and the metabolite OH/CHO with an EC50 of 58 micromol L(-1). The other MUC metabolites tested, CHO/COOH and OH/COOH were weak inhibitors of GJIC whereas COOH/COOH had no effect. Benzene itself had no effect on GJIC when tested in concentrations up to 20 micromol L(-1). The relative potency observed for the metabolites on GJIC is similar to their hematotoxic effects. The effect of MUC on GJIC was observed to take place concordant with a dramatic loss of connexin 43 (Cx43) from the cells as visualized by Western blotting. Substances with the ability to inhibit Cx43-dependent GJIC have previously been observed to interfere with normal hematopoietic development. The ability of benzene metabolites to interfere with gap-junction functionality, and especially the dramatic loss of Cx43 induced by MUC, should therefore be considered as a possible mechanism for benzene-induced hematotoxicity and development of leukemia.
authors.affiliation: Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, 0310, Oslo, Norway. edgarr@labmed.uio.no
authors.forename: Edgar
authors.initials: E
authors.lastname: Rivedal
authors.forename: Gisela
authors.initials: G
authors.lastname: Witz
mesh_terms: D000818:Animals; D001554:Benzene / Q000378:metabolism / Q000633:toxicity*; D015153:Blotting, Western; D002450:Cell Communication / Q000187:drug effects*; D002460:Cell Line; D018031:Connexin 43 / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects*; D017629:Gap Junctions / Q000187:drug effects*; D008099:Liver / Q000166:cytology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D051381:Rats
chemical_list: D018031:Connexin 43; D020929:Mitogen-Activated Protein Kinase Kinases; D001554:Benzene