CCL4-INDUCED ALTERATIONS IN CA++ HOMEOSTASIS IN CHLORDECONE AND PHENOBARBITAL PRETREATED ANIMALS

Male S-D rats were maintained on normal powdered diet or on the same diet containing 10 ppm chlordecone or 225 ppm phenobarbital for 15 days. On day 15, all animals received a single i.p. injection of corn oil or a subtoxic dose of CCl4 (25-200 .mu.l/kg) in corn oil vehicle (1 ml/kg). The animals were sacrificed 12 h later. Liver microsomal cytochrome P-450 and Ca2+ levels in whole liver, mitochondria, microsomes and cytosol were determined. Cytochrome P-450 induction was greater with phenobarbital pretreatment than with chlordecone but the CCl4 induced destruction of cytochrome P-450 was almost similar in both groups and progressive with the dose of CCl4. CCl4 given to animals on normal diet 25-200 .mu.l/kg did not significantly alter cytochrome P-450 levels. These findings were consistent with greater bioactivation of CCl4 after the 2 pretreatments. There was a massive accumulation of Ca2+ in chlordecone and phenobarbital pretreated animals after CCl4 administration. Cytosolic Ca2+ levels remained high despite the mitochondrial and microsomal sequestration. This perturbation of hepatocellular Ca2+ homeostasis might have led to hepatic lesion and hepatic failure. Chlordecone or phenobarbital alone did not alter hepatic Ca2+ levels. Excessive accumulation of Ca2+ may have been related to the progression of hepatotoxic response due to CCl4 in chlordecone treated animals.