Ketone potentiation of haloalkane-induced hepato- and nephrotoxicity. I. Dose-response relationships.
Carbon tetrachloride (CCl4) induced hepatotoxicity and chloroform (CHCl3) induced nephrotoxicity were evaluated in male Sprague-Dawley rats pretreated with acetone (A), methyl ethyl ketone (MEK), and methyl isobutyl ketone (MiBK). Dose-response relationships for A, MEK, and MiBK potentiation of CCl4-induced hepatotoxicity and CHCl3-induced nephrotoxicity were compared. A, MEK, and MiBK pretreatment at a dosage of 6.8 mmol/kg, given daily for 3 d, markedly potentiated CCl4-induced liver toxicity as indicated by a decrease in the CCl4 ED50 to 3.4, 4.6, and 1.8 mmol/kg, respectively, compared to vehicle-pretreated rats (17.1 mmol/kg). Similarly, pretreatment with these ketones (13.6 mmol/kg) potentiated CHCl3 kidney toxicity but to a lesser degree; CHCl3 ED50 values for vehicle-, A-, MEK-, and MiBK-pretreated rats were 3.4, 1.6, 2.1, and 2.2 mmol/kg, respectively. Our results indicate a potency ranking profile for the potentiation of CCl4 hepatotoxicity of MiBK > A > MEK and of A > MEK > or = MiBK for CHCl3 nephrotoxicity. These dissimilar ranking profiles could be due to differences in mechanisms of action for the two target sites.
Raymond
P
P
Department of Pharmacology, Faculty of Medicine, University of Montreal, Quebec, Canada.
Plaa
G L
GL
D000096:Acetone / Q000008:administration & dosage*; D000818:Animals; D002074:Butanones / Q000008:administration & dosage*; D002251:Carbon Tetrachloride / Q000633:toxicity*; D002725:Chloroform / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007668:Kidney / Q000187:drug effects*; D008099:Liver / Q000187:drug effects*; D008297:Male; D008742:Methyl n-Butyl Ketone / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015430:Weight Gain / Q000187:drug effects
D002074:Butanones; D000096:Acetone; C005222:methylethyl ketone; D008742:Methyl n-Butyl Ketone; D002725:Chloroform; D002251:Carbon Tetrachloride; C005458:methyl isobutyl ketone