Potentiation of carbon tetrachloride hepatotoxicity by chlordecone: dose-response relationships and increased covalent binding in vivo.
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.
Britton
R S
RS
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106.
Dolak
J A
JA
Glende
E A
EA
Recknagel
R O
RO
D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000378:metabolism*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D007631:Chlordecone / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D007306:Insecticides / Q000633:toxicity*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D011919:Rats, Inbred Strains
D007306:Insecticides; D003577:Cytochrome P-450 Enzyme System; D005952:Glucose-6-Phosphatase; D007631:Chlordecone