Effect of 2-butanol and 2-butanone on rat hepatic ultrastructure and drug metabolizing enzyme activity.
The effect of a single oral dose of 2-butanol (2.2 ml/kg) or 2-butanone (1.87 ml/kg) on hepatic ultrastructure and drug-metabolizing enzyme activity was studied in the rat. A 135-197% increase in acetanilide hydroxylase activity was found in rats sacrificed 12-40 h after dosing with 2-butanol or 2-butanone. A 40-h pretreatment with 2-butanone produced a 155% increase in aminopyrine N-demethylase activity. NADPH-cytochrome c reductase activity and the concentrations of cytochromes P-450 and b5 were largely unaltered 2-40 h after dosing with either agent. Electron microscopic examination of hepatocytes from rats sacrificed 16 h after 2-butanol or 2-butanone revealed a marginal increase in the prevalence of smooth endoplasmic reticulum. However, by 40 h, there was a marked proliferation of the smooth endoplasmic reticulum and reduction in rough endoplasmic reticulum in response to both agents. The most marked potentiation of CCl4 hepatotoxicity occurred when rats were pretreated with 2-butanol or 2-butanone 16 h before CCl4 administration. The coincidental finding of maximal CCl4-induced hepatic injury and elevation of microsomal xenobiotic activity within the same time frame following 2-butanol or 2-butanone supports the hypothesis that aliphatic alcohols and ketones potentiate CCl4 hepatotoxicity by enhancing biotransformation of the halocarbon to cytotoxic metabolites.
Traiger
G J
GJ
Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence 66045.
Bruckner
J V
JV
Jiang
W D
WD
Dietz
F K
FK
Cooke
P H
PH
D000633:Aminopyrine N-Demethylase / Q000032:analysis; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000032:analysis*; D000440:Butanols / Q000494:pharmacology*; D002074:Butanones / Q000494:pharmacology*; D002251:Carbon Tetrachloride / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D015786:Cytochromes b5 / Q000032:analysis; D004357:Drug Synergism; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure*; D008297:Male; D008854:Microscopy, Electron; D009251:NADPH-Ferrihemoprotein Reductase / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains
D000440:Butanols; D002074:Butanones; C043958:2-butanol; C005222:methylethyl ketone; D015786:Cytochromes b5; D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride; D001189:Aryl Hydrocarbon Hydroxylases; C023738:acetanilide hydroxylase; D000633:Aminopyrine N-Demethylase; D009251:NADPH-Ferrihemoprotein Reductase