Potentiation of CCl4 hepatotoxicity by chlordecone: evidence of increased metabolism of CCl4 in vivo

Chlordecone (CD) has been shown to dramatically increase CCl4 hepatotoxicity, but the mechanisms by which this effect occurs are not clear. Dose-response studies were performed to determine the size of CD's potentiating action on CCl4-induced liver enzyme release and loss of hepatic microsomal enzymatic functions. Rats were pretreated with 15 mg CD/kg BW i.g., or vehicle. After 48 hrs, 0-250 μ1 CCl4/100g BW were given i.p., and the rats were killed 24 hrs later. In CD-treated rats, 6 μ1 CCl4/100 resulted in a mean SGOT level similar to that found after administration of 100 μ1/100g to control animals. CD also potentiated the CCl4-dependent loss of cytochrome P-450 and glucose-6-phosphatase, with the 6 μ1 CCl4/100g dose in the CD-treated rats being equieffective to the 100 μ1/100g dose in the controls. Since CD treatment increased cytochrome P-450 content by 67%, an experiment was performed to see if this induction increased the metabolism of 14CCl4 to reactive products (14C covalently bound to microsomal protein and lipid after 1 hr). An increase in the metabolism of the 6 μ1/100g dose of CCl4 was observed in the CD-treated rats with binding of 14C to both protein and lipid being increased 2.7- and 1.7-fold, respectively; there was no difference in binding at the 100 μ1/100g dose. These results suggest that an increase in CCl4 metabolism may contribute to the potentiation of CCl4 hepatotoxicity by CD