The oxidation of acrolein by rat liver aldehyde dehydrogenases. Relation to allyl alcohol hepatotoxicity.
The oxidation of acrolein by aldehyde dehydrogenase was studied in several subcellular fractions of rat liver by measuring acrolein-dependent production of NADH from NAD+. Mitochondrial and cytosolic fractions each contained two aldehyde dehydrogenase activities with Km values for acrolein of 0.4-0.7 mM and 0.015-0.025 mM. Microsomes demonstrated only a high Km (1.5 mM) activity. The low Km activities of mitochondria and cytosol differed in their sensitivity to inhibition by chloral hydrate and in their response to 1 mM MgCl2 (activation vs. inhibition). The metabolism of acrolein by low Km aldehyde dehydrogenase activities was markedly depressed in mitochondrial or cytosolic fractions from rats pretreated with cyanamide (2 mg/kg for 1 hr) or disulfiram (100 mg/kg for 24 hr). The effect of aldehyde dehydrogenase inhibition on allyl alcohol toxicity was determined by pretreating rats with cyanamide or disulfiram prior to treatment with allyl alcohol. Hepatotoxicity was assessed on the basis of elevated serum alanine aminotransferase and sorbitol dehydrogenase activities and the loss of microsomal cytochrome P-450. Pretreatment with the aldehyde dehydrogenase inhibitors enhanced the hepatotoxicity of allyl alcohol in both male and female rats. The results suggest that acrolein metabolism by rat liver aldehyde dehydrogenase isozymes is important for the inactivation of allyl alcohol-derived acrolein.
D000433:1-Propanol / Q000633:toxicity; D000171:Acrolein / Q000378:metabolism*; D000444:Aldehyde Dehydrogenase / Q000032:analysis* / Q000037:antagonists & inhibitors; D000447:Aldehydes / Q000378:metabolism*; D000818:Animals; D003484:Cyanamide / Q000494:pharmacology; D004221:Disulfiram / Q000494:pharmacology; D005260:Female; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008274:Magnesium / Q000494:pharmacology; D015636:Magnesium Chloride; D008297:Male; D020005:Propanols; D051381:Rats; D011916:Rats, Inbred F344; D012737:Sex Factors
D000447:Aldehydes; D020005:Propanols; D015636:Magnesium Chloride; C006463:allyl alcohol; D003484:Cyanamide; D000171:Acrolein; D000433:1-Propanol; D000444:Aldehyde Dehydrogenase; D008274:Magnesium; D004221:Disulfiram