Lack of direct mitogenic activity of dichloroacetate and trichloroacetate in cultured rat hepatocytes.
Dichloroacetate (DCA) and trichloroacetate (TCA) are hepatocarcinogenic metabolites of the common groundwater contaminant, 1,1,2-trichloroethylene. DCA and TCA have been shown to induce hepatocyte proliferation in vivo, but it is not known if this response is the result of direct mitogenic activity or whether cell replication occurs indirectly in response to tissue injury or inflammation. In this study we used primary cultures of rat hepatocytes, a species susceptible to DCA- but not TCA-induced hepatocarcinogenesis, to determine whether DCA and TCA are direct hepatocyte mitogens. Rat hepatocytes, cultured in growth factor-free medium, were treated with 0.01-1.0 mM DCA or TCA for 10-40 h; cell replication was then assessed by measuring incorporation of 3H-thymidine into DNA and by cell counts. DCA or TCA treatment did not alter 3H-thymidine incorporation in the cultured hepatocytes. Although an increase in cell number was not observed, DCA treatment significantly abrogated the normal background cell loss, suggesting an ability to inhibit apoptotic cell death in primary hepatocyte cultures. Furthermore, treatment with DCA synergistically enhanced the mitogenic response to epidermal growth factor. The data indicate that DCA and TCA are not direct mitogens in hepatocyte cultures, which is of interest in view of their ability to stimulate hepatocyte replication in vivo. Nevertheless, the synergistic enhancement of epidermal growth factor-induced hepatocyte replication by DCA is of particular interest and warrants further study.
Walgren
Jennie L
JL
Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, 171 Ashley Avenue, P.O. Box 250505, Charleston, SC 29425, USA. jennie.walgren@pharmacia.com
Kurtz
David T
DT
McMillan
Joellyn M
JM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002274:Carcinogens, Environmental / Q000633:toxicity; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D003999:Dichloroacetic Acid / Q000633:toxicity*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000473:pathology; D008297:Male; D008934:Mitogens / Q000633:toxicity*; D051381:Rats; D020318:Rats, Long-Evans; D013936:Thymidine / Q000378:metabolism; D014238:Trichloroacetic Acid / Q000633:toxicity*
D002274:Carcinogens, Environmental; D005938:Glucocorticoids; D008934:Mitogens; D014238:Trichloroacetic Acid; D004815:Epidermal Growth Factor; D003907:Dexamethasone; D003999:Dichloroacetic Acid; D013936:Thymidine