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 the animals received a single ip injection of either corn oil or a subtoxic dose of CCl4 (25-200 microliter/kg) in corn oil vehicle (1 ml/kg). The animals were sacrificed 12 hrs later. Liver microsomal cytochrome P-450 and Ca++ 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 in a dose range of 25-200 microliter/kg did not significantly alter the cytochrome P-450 levels. These findings are consistent with greater bioactivation of CCl4 after the above two pretreatments. There was a massive accumulation of Ca++ in chlordecone and phenobarbital pretreated animals after CCl4 administration. Cytosolic Ca++ levels remained high despite the mitochondrial and microsomal sequestration. This perturbation of hepatocellular Ca++ homeostasis might lead to hepatic lesion and hepatic failure. Chlordecone or phenobarbital alone do not alter hepatic Ca++ levels. These findings suggest that excessive accumulation of Ca++ may be causally related to the progression of hepatotoxic response due to CCl4 in chlordecone treated animals.