Effect of peroxisome proliferator nafenopin on the cytotoxicity of dihaloalkanes in isolated rat hepatocytes.
Hepatocytes were isolated from nafenopin-treated animals (80 mg/kg body weight in 1.2 ml/kg body weight olive oil for 2 consecutive days) and exposed to various doses of 1,2 dichloroethane (DCE) (64-159 mumol) and 1,2-dibromoethane (DBE) (5.5-27.5 mumol) for up to 3 hr to assess the effect of nafenopin on the toxicity of dihaloalkanes. The activity of biotransformation enzymes involved in the activation and detoxication of these solvents was measured. Although cytochrome P450IIE1 activity was apparently unaltered, glutathione S-transferase activity was significantly reduced; the reduction was 20% for 1-chloro-2,4-dinitrobenzene as substrate but 40% and 80%, respectively for DBE and DCE. DBE was more than 10 times more cytotoxic to nafenopin-treated hepatocytes than DCE, and while very little change in DCE cytotoxicity was observed in hepatocytes isolated from nafenopin pretreated rats compared with control animals, DBE cytotoxicity was significantly potentiated in cells isolated from nafenopin-pretreated rats compared with cells from controls. It is believed that enhanced toxicity of DBE in isolated cells from nafenopin-treated rats is the result of modulation of dihaloalkane metabolism (glutathione conjugation).
Voskoboinik
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Key Centre for Applied and Nutritional Toxicology, RMIT-University, Melbourne, Victoria 3001, Australia.
Drew
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R
Ahokas
J T
JT