Metabolism of the glutathione-acrolein adduct, S-(2-aldehydo-ethyl)glutathione, by rat liver alcohol and aldehyde dehydrogenase.
The oxidative and reductive metabolism of the acrolein-glutathione adduct, S-(2,aldehydo-ethyl)glutathione, by rat liver aldehyde dehydrogenase (ALDH) and alcohol dehydrogenase (ADH) was characterized. The glutathione-acrolein adduct is oxidized to the respective acid by two different forms of ALDH contained in rat liver cytosol which are distinct from two forms of ALDH present in the mitochondria also capable of oxidizing the aldehyde moiety of the adduct. Extensive kinetic characterization (Km, Vmax and V/K parameters) of the ALDH enzymes suggest that the glutathione-acrolein adduct is oxidized most efficiently by one form of mitochondrial ALDH which is 3.5 to 175 times more active (based on V/K comparisons) than the other forms of mitochondrial and cytosolic ALDH evaluated. The glutathione-acrolein adduct is also subject to reductive metabolism by rat liver ALH. However, the Km value (877 microM) for reduction of the adduct suggests that this would be a minor pathway of metabolism. Collectively, these results indicate that the glutathione-acrolein adduct formed after exposure to acrolein, or as a result of allyl alcohol oxidation and cyclophosphamide metabolism, can be oxidized by hepatic ALDH or ADH, respectively. However, the kinetic parameters for these pathways suggest that micromolar concentrations of this adduct may accumulate before these enzyme systems mediate significant oxidative or reductive pathways of detoxification. The proposition that the glutathione-acrolein adduct may play a role in acrolein-mediated hepatotoxicity is discussed.
Mitchell
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Hepatobiliary Research Center, School of Pharmacy, University of Colorado Health Science Center, Boulder.
Petersen
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DR
D000426:Alcohol Dehydrogenase / Q000378:metabolism*; D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000818:Animals; D005978:Glutathione / Q000378:metabolism / Q000031:analogs & derivatives; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D013347:Subcellular Fractions / Q000201:enzymology
C061284:S-(2-aldehydoethyl)glutathione; D000426:Alcohol Dehydrogenase; D000444:Aldehyde Dehydrogenase; D005978:Glutathione