Potentiation of carbon tetrachloride hepatotoxicity by chlordecone: Dose‐response relationships and increased covalent binding in vivo

Abstract

Chlordecone greatly potentiates carbon tetrachloride (CCl4) hepatotoxicity. In order to quantitate the degree of this potentiation, the effects of a range of doses of CCl4 on two microsomal enzymatic functions and liver enzyme release were examined in chlordecone-treated and control rats. Male Sprague-Dawley rats were pretreated with 15 mg chlordecone per kilogram body weight (BW) intragastrically or with vehicle. After 48 hours, 0 to 250 microliters CCl4 per 100 g body weight were given intraperitoneally (IP), and the rats were killed 24 hours later. Chlordecone treatment produced approximately a 17-fold potentiation of the CCl4-dependent loss of cytochrome P-450 and glucose-6-phosphatase activity, so that a dose of 6 microliters CCl4 per 100 g body weight in the chlordecone-treated animals resulted in a similar amount of damage as observed with 100 microliters CCl4 per 100 g body weight in controls. A similar potentiation by chlordecone was seen with CCl4 induced increases in serum glutamic-oxaloacetic transaminase (SGOT) levels. Chlordecone treatment also increased hepatic cytochrome P-450 levels by 67% and resulted in an increase in the covalent binding of [14-C]-CCl4-derived metabolites to microsomal protein and lipid in vivo.

Atsdr Evaluation of Health Effects of Chemicals

“…Adaptive responses of the liver seen after oral exposure of rats, mice, or gerbils to chlordecone include: (1) increases in liver size or weight (Huber, 1965;Chernoff and Rogers, 1976;Fabacher and Hodgson, 1976;Mehendale et al, 1977bMehendale et al, , 1978bCannon and Kimbrough, 1979;Curtis and Mehendale, 1979;Larson et al, 1979b;Mehendale, 1981b;Fujimori et al, 1983;EPA, 1986c;Schutzmann, 1986, 1987;Simmons et al, 1987;Purushotham et al, 1988); (2) increased hepatocellular hypertrophy (Cannon and Kimbrough, 1979); (3) increased smooth endoplasmic reticulum Lockard et al, 1983a,b;Mehendale et al, 1989); (4) increased microsomal protein (Mehendale et al, 1978b;Mehendale, 1982b, 1983b;Chambers and Trevethan, 1983); (5) increased cytochrome P-450 content (Fabacher and Hodgson, 1976;Mehendale et al, 1978b;Mehendale, 1982b, 1983b;Chambers and Trevethan, 1983;Fujimori et al, 1983;Agarwal and Mehendale, 1984a;Britton et al, 1987;Kitchin and Brown, 1989;Cai and Mehendale, 1990;Chaudhury and Mehendale, 1991;Kocarek et al, 1991); (6) increased NADPH2-cytochrome c reductase (Mehendale et al, 1977b(Mehendale et al, , 1978bChambers and Trevethan, 1983;Fujimori et al, 1983); (7) and/or increased microsomal enzyme activity …”