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-N'N'-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 microM and more of fungicide. The phosphatidylcholine hydroperoxide (PCOOH) content increased more than 300 times by captan (250-1000 microM), 400 times by dichlofluanid (250-1000 microM) and 20 times by chlorothalonil (25-1000 microM) after 1h 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.
Suzuki
Toshihide
T
Faculty of Pharmaceutical Sciences, Teikyo University, 1091-1 Sagamiko-machi, Tsukui-gun, Kanagawa 199-0195, Japan. toshi-su@pharm.teikyo-u.ac.jp
Nojiri
Hisao
H
Isono
Hideo
H
Ochi
Takafumi
T
D000814:Aniline Compounds / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D002215:Captan / Q000737:chemistry / Q000633:toxicity*; D005659:Fungicides, Industrial / Q000737:chemistry / Q000633:toxicity; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D007306:Insecticides / Q000737:chemistry / Q000633:toxicity; D008297:Male; D009570:Nitriles / Q000737:chemistry / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
D000814:Aniline Compounds; D005659:Fungicides, Industrial; D007306:Insecticides; D009570:Nitriles; C016370:dichlofluanid; D002215:Captan; C005806:tetrachloroisophthalonitrile