Ethanol co-exposure increases lethality of allyl alcohol in male Sprague-Dawley rats.
Since allyl alcohol and ethanol are both metabolized by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), ethanol could affect allyl-alcohol induced toxicity under in vivo coexposure conditions. Male Sprague-Dawley rats were treated with ethanol (2 g/kg, i.p.) simultaneously or 2 h before with allyl alcohol (40 mg/kg, i.p.). Coexposure to allyl alcohol and ethanol resulted in neither enhancement nor protection in allyl alcohol-induced hepatotoxicity at 24 h. However, markedly increased lethality was observed under our coexposure conditions. Pretreatment with 4-methylpyrazole (4-MP) to inhibit ADH did not result in increased lethality to allyl alcohol or ethanol alone, but significantly reduced the lethality of the combined treatment. In contrast, ALDH inhibition increased the lethality of allyl alcohol alone as well as that of the combined allyl alcohol and ethanol treatment. Kinetic studies revealed that combined treatment with allyl alcohol and ethanol resulted in higher blood allyl alcohol levels compared to allyl alcohol alone, and these were accompanied by greater lethality. ADH inhibition increased allyl alcohol blood levels significantly when rats were treated with allyl alcohol alone or allyl alcohol plus ethanol, leading to protection against lethality. In contrast, ALDH inhibition did not affect blood allyl alcohol levels, but resulted in increased lethality. These data suggest a possible role for a metabolite of allyl alcohol, acrolein, in the increased lethality of allyl alcohol and ethanol coexposure in rats.
Lee
J Y
JY
College of Pharmacy, Seoul National University, Korea.
Chung
S M
SM
Lee
M Y
MY
Chung
J H
JH
D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors; D000818:Animals; D003484:Cyanamide / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000633:toxicity*; D000077604:Fomepizole; D006519:Hepatitis, Alcoholic / Q000201:enzymology / Q000209:etiology*; D008111:Liver Function Tests; D008297:Male; D020005:Propanols / Q000378:metabolism / Q000633:toxicity*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012997:Solvents / Q000633:toxicity*