The role of biotransformation-detoxication in acetone-, 2-butanone-, and 2-hexanone-potentiated chloroform-induced hepatotoxicity.
The hepatotoxicity of chloroform (CHCl3) is thought to require biotransformation, by the polysubstrate monooxygenase system (P-450), to a reactive intermediate(s). Therefore, the potentiation of CHCl3-induced hepatotoxicity, which occurs following exposure to certain ketones, may hypothetically be explained by a reduced capacity of the cell to form glutathione conjugates (detoxicate the intermediate) and (or) by an increased rate of reactive intermediate(s) generation secondary to a modification of the P-450 system. To test these hypotheses, liver damage, as indicated by elevation in plasma alanine aminotransferase and ornithine carbamyl transferase activities, was modulated in male Sprague-Dawley rats by varying the time interval (10, 18, 24, 48, 72, 96 h) between acetone, 2-butanone, or 2-hexanone (15 mmol/kg, p.o.) pretreatment and CHCl3 (0.5 mL/kg, p.o.) administration. These data were compared with hepatic glutathione and with various parameters of the polysubstrate monooxygenase system: cytochrome P-450, cytochrome c reductase, cytochrome b5, and microsomal binding of 14CHCl3-derived radiolabel. Reduced detoxication capacity does not appear to be involved as hepatic glutathione levels were not reduced. Globally, a relationship between modifications to the polysubstrate monooxygenase system and potentiation of CHCl3-induced hepatotoxicity appears to exist. The rank order of each ketone's ability to modify P-450 parameters was the same in most instances as that based on peak ability to potentiate CHCl3-induced hepatotoxicity: 2-hexanone greater than 2-butanone greater than or equal to acetone. Therefore, these results suggest that a general relationship exists between the ketone-induced potentiation of CHCl3-induced hepatotoxicity and increased CHCl3 reactive metabolite generation. However, other factors may also contribute to the phenomenon.
Hewitt
L A
LA
Département de pharmacologie, Faculté de médecine, Université de Montréal, Québec, Canada.
Valiquette
C
C
Plaa
G L
GL
D000096:Acetone / Q000633:toxicity*; D000818:Animals; D001711:Biotransformation; D002074:Butanones / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D002725:Chloroform / Q000633:toxicity*; D006588:Hexanones / Q000633:toxicity*; D008658:Inactivation, Metabolic; D007659:Ketones / Q000633:toxicity*; D008099:Liver / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D002074:Butanones; D006588:Hexanones; D007659:Ketones; D011506:Proteins; D000096:Acetone; C005222:methylethyl ketone; D002725:Chloroform; D006899:Mixed Function Oxygenases