Oxidative damages in isolated rat hepatocytes treated with the organochlorine fungicides captan, dichlofluanid and chlorothalonil

The cytotoxicity and lipid peroxidative potency of the organochlorine fungicides captan (N-(trichloromethylthio)-4-cyclohexene-1,2-dicarboximide), dichlofluanid (N-dichlorofluoromethylthio-APM-dimethyl-N-phenylsulfamide) and chlorothalonil (2,4,5,6-tetrachloro-isophthalonitrile) were studied in isolated rat hepatocytes. These fungicides induced cytotoxicity and lipid peroxidation in a dose- and time-dependent manner. Considerable cytotoxicity and lipid peroxidation occurred after cells were treated with 25 muM and more of fungicide. The phosphatidylcholine hydroperoxide (PCOOH) content increased more than 300 times by captan (250-1000 muM), 400 times by dichlofluanid (250-1000 muM) and 20 times by chlorothalonil (25-1000 muM) after 1 h of incubation, as compared with untreated control. Significant cytotoxicity occurred after 20 min (captan), 30 min (dichlofluanid) and 60 min (chlorothalonil) of incubation and lipid peroxidation was induced prior to cytotoxicity. The antioxidant alpha-tocopherol and cytochrome P450 inhibitor SKF-525A effectively prevented cytotoxicity and lipid peroxidation. Our results suggest that metabolites of these fungicides produced by the microsomal cytochrome P450 system, induced membrane phospholipid peroxidation that caused cytotoxicity. (C) 2004 Elsevier Ireland Ltd. All rights reserved.