Potentiation of CCl4 lethality by chlordecone

Previous studies have dealt with the propensity of chlordecone (CD) to potentiate the hepatotoxicity of CCl4. The effect of this interaction upon CCl4 lethality has never been reported. The objective of the present study was to evaluate the effect of CD on CCl4 lethality and several parameters associated with cytochrome P-450 activity. Male Sprague-Dawley rats (150-200 g) were fed powdered diets containing 0 to 10 ppm CD or 225 ppm phenobarbital (PB) for 15 days. On day 15, rats from each group received an i.p. injection of CCl4 in corn oil and the 48-h LD50 determined. Additional animals were used to measure hepatic microsomal levels cytochrome P-450 and aminopyrine demethylase. CD decrease the LD50 of CCl4 from 2.8 ml/kg to 0.042 ml/kg, representing a 67-fold increase in toxicity, as assessed by lethality. PB in this protocol decreased the LD50 to 1.7 ml/kg, representing a 1.6-fold increase in lethality. However, the induction of cytochrome P-450 and associated parameters of mixed-function oxidase (MFO) activity did not correlate with the lethality data. Hepatic microsomal P-450 was increased over controls by 40% and 76% in CD and PB rats respectively. PB also stimulated aminopyrine demethylase activity to a much greater extent (190%) than CD (49%) relative to controls. These findings provide evidence that the CD-CCl4 interaction results in a marked increase in CCl4 lethality, in addition to the previously reported marked increase in hepatotoxicity. These results remain consistent with the proposal that bioactivation is the mechanisms underlying enhanced CCl4 toxicity, but suggest that specific effects of CD upon CCl4 metabolism may be the pivotal mechanism underlying potentiation.