Potentiation of chloroform-induced hepatotoxicity by methyl isobutyl ketone and two metabolites.
The hepatonecrogenic properties of chloroform (CHCl3) can be modified by the administration of various chemicals. The ability of methyl isobutyl ketone (MIBK) and its two major metabolites, 4-methyl-2-pentanol (4MPOL) and 4-hydroxymethyl isobutyl ketone (4-OHMIBK) to potentiate the liver injury induced by CHCl3 was assessed in rats. The parent compound and both metabolites significantly increased the liver damage induced by CHCl3, as demonstrated by the elevation of the plasma activity of two transferases alanine aminotransferase and ornithine carbamoyl transferase and by the severity of the morphological changes. Moreover, the minimally effective dosage needed to potentiate CHCl3-induced hepatotoxicity was approximately 5 mmol/kg for the three compounds. We also studied the inducing properties of MIBK (cytochrome P-450 liver content and the activity of aniline hydroxylase, 7-ethoxycoumarin O-deethylase, and aminopyrine N-demethylase). Cytochrome P-450 content and the oxidation of aniline and 7-ethoxycoumarin were significantly increased with either a single (7.5 mmol/kg or greater) or a multiple (5.0 and 7.5 mmol.kg-1.day-1 for 5 days) administration of MIBK. An increase in the activity of the aminopyrine demethylase was also elicited by the repetitive administration of MIBK. With gel electrophoresis, we found that MIBK significantly increased the 52.1- and 54.1-kDa proteins, corresponding most probably to P-450 isozymes.
Vézina
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Département de pharmacologie, Faculté de médecine, Université de Montréal, Québec, Canada.
Kobusch
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du Souich
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Greselin
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Plaa
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D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D002725:Chloroform / Q000633:toxicity*; D002779:Cholestasis / Q000139:chemically induced / Q000503:physiopathology; D003720:Densitometry; D004357:Drug Synergism; D004591:Electrophoresis, Polyacrylamide Gel; D007659:Ketones / Q000633:toxicity*; D008297:Male; D008742:Methyl n-Butyl Ketone / Q000031:analogs & derivatives / Q000633:toxicity*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D000439:Pentanols / Q000633:toxicity; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D007659:Ketones; D000439:Pentanols; D011506:Proteins; D008742:Methyl n-Butyl Ketone; C055299:4-hydroxymethyl isobutyl ketone; D002725:Chloroform; C024821:isobutylmethylcarbinol; D006899:Mixed Function Oxygenases; C005458:methyl isobutyl ketone