Ultrastructural and biochemical correlates of the specificity of chlordecone‐potentiated carbon tetrachloride hepatotoxicity

Abstract

Previous work demonstrated the specificity of chlordecone (Kepone) potentiated CCI₄ hepatotoxicity in rats on the basis of functional, biochemical, and histochemical indices of liver damage. The present study was undertaken to elucidate mechanisms underlying the pathogenesis of the selectively potentiated hepatotoxic response to CCI₄ after dietary exposure to low levels (10 ppm for 15 d) of chlordecone but not its structural analogs mirex and photomirex. On d 15 of pretreatment of male Sprague‐Dawley rats, either selected parameters of hepatic mixed‐function oxidase (MFO) activity were determined or corn oil or CCI₄ (0.05 ml/kg in corn oll) was injected ip. Biochemical and ultrastructural assessment of liver damage was made 24 h after the injection. When given as the sole agents, photomirex, mirex, and chlordecone significantly increased microsomai pentobarbital hydroxylase and ethylmorphine demethylase activities. Both photomirex and mirex elevated microsomai cytochrome P‐450 content, while only photomirex increased microsomai protein and liver size. Ultrastructural changes in the endoplasmic reticulum were detectable after chlordecone but were more pronounced after photomirex and mirex, indicating good correlation between biochemical and morphological changes. Administration of CCI₄ to chlordecone‐fed rats resulted in a 38‐fold increase in plasma ornithine carbamoyl‐transferase activity and a 64% decrease in hepatic cytochrome P‐450. This dose did not significantly alter these enzyme activities in other groups. Ultrastructural changes produced by CCI₄ were extreme in chlordecone‐fed rats. Many hepatocytes were necrotic and others showed lipid accumulation; dilation of endoplasmic reticulum and swelling of mitochondria were prevalent. CCI₄ alone, photomirex‐CCI₄, and mirex‐CCI₄ produced similar changes in a few hepatocytes, and the low incidence of these structural aberrations were consistent with the biochemical data. These results indicate that the propensity of chlordecone to potentiate CCI₄ hepatotoxicity cannot be directly associated with some commonly measured indices of hepatic microsomai MFO activity.