Metabolites of benzene are potent inhibitors of gap-junction intercellular communication.
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.
Rivedal
Edgar
E
Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, 0310, Oslo, Norway. edgarr@labmed.uio.no
Witz
Gisela
G
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
D018031:Connexin 43; D020929:Mitogen-Activated Protein Kinase Kinases; D001554:Benzene