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  • Title: Metabolites of benzene are potent inhibitors of gap-junction intercellular communication.
    Author: Rivedal E, Witz G.
    Journal: Arch Toxicol; 2005 Jun; 79(6):303-11. PubMed ID: 15690152.
    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.
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