Evidence for the involvement of organelles in the mechanism of ketone‐potentiated chloroform‐induced hepatotoxicity

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Abstract
ABSTRACT— Ketones can potentiate the hepatotoxicity of haloalkanes in animals. This may be due, in part, to changes in organelle susceptibility. Male Sprague‐Dawley rats were administered 15 mmol/kg (po) acetone, 2‐butanone, 2‐hexanone or 50 mg/kg (po) chlordecone or mirex (a nonketonic analog of chlordecone). Eighteen hours later, tests of organelle structure/function were performed (osmotic stress, respiration, and calcium pump activity). Other rats were given 14CHCl3 (0.5 or 1.0 ml/kg, po) 18 h after chlordecone or mirex administration. Three hours later, the organelle distribution of 14C was evaluated. In a final experiment, ketone‐pretreated (chlordecone or 2‐hexanone) animals were killed 6 h after CHCl3 administration and evaluated morphologically for evidence of modified organelle response. Acetone and chlordecone, when given alone, enhanced lysosomal fragility to osmotic stress; no changes in functional capacity of mitochondria or microsomes were observed. CHCl3‐derived 14C in the mitochondrial fraction increased 2‐fold in chlordecone‐treated rats. Morphological evaluation suggested mitochondria respond differently to CHCl3 in ketone‐pretreated (chlordecone or 2‐hexanone) animals compared to corn oil‐pretreated controls. These results support the concept that modifications of organelles contribute to the mechanism of ketone‐potentiation of CHCl3‐induced hepatotoxicity.