Evidence for the involvement of organelles in the mechanism of ketone-potentiated chloroform-induced hepatotoxicity.
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.
Hewitt
L A
LA
Department of Pharmacology, Faculty of Medicine, University of Montreal, Quebec, Canada.
Palmason
C
C
Masson
S
S
Plaa
G L
GL
D000818:Animals; D002725:Chloroform / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004357:Drug Synergism; D007659:Ketones / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000648:ultrastructure; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D015388:Organelles / Q000187:drug effects* / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains
D007659:Ketones; D002725:Chloroform; D003577:Cytochrome P-450 Enzyme System