EFFECT OF PEROXISOME PROLIFERATOR NAFENOPIN ON THE CYTOTOXICITY OF DIHALOALKANES IN ISOLATED RAT HEPATOCYTES

Hepatocytes were isolated from nafenopin-treated animals (80 mg/kg bod y weight in 1.2 ml/kg body weight olive oil for 2 consecutive days) an d exposed to various doses of 1,2 dichloroethane (DCE) (64-159 mu mol) and 1,2-dibromoethane (DBE) (5.5-27.5 mu mol) for up to 3 hr to asses s the effect of nafenopin on the toxicity of dihaloalkanes. The activi ty of biotransformation enzymes involved in the activation and detoxic ation of these solvents was measured. Although cytochrome P450IIE1 act ivity was apparently unaltered, glutathione S-transferase activity was significantly reduced; the reduction was 20% for 1-chloro-2,4-dinitro benzene as substrate but 40% and 80%, respectively for DBE and DCE. DB E was more than 10 times more cytotoxic to nafenopin-treated hepatocyt es than DCE, and while very little change in DCE cytotoxicity was obse rved in hepatocytes isolated from nafenopin pretreated rats compared w ith control animals, DBE cytotoxicity was significantly potentiated in cells isolated from nafenopin-pretreated rats compared with cells fro m controls. It is believed that enhanced toxicity of DBE in isolated c ells from nafenopin-treated rats is the result of modulation of dihalo alkane metabolism (glutathione conjugation). Copyright (C) 1996 Elsevi er Science Ltd.