Inhibition of rat hepatic mitochondrial aldehyde dehydrogenase–mediated acetaldehyde oxidation by trans-4-hydroxy-2-nonenal

Authors

  • David Y. Mitchell,

    1. Alcohol and Hepatobiliary Research Centers, University of Colorado Health Sciences Center, Denver, Colorado 80262
    2. School of Pharmacy, University of Colorado, Boulder, Colorado 80309–0297
    Current affiliation:
    1. Pfizer Central Research, Groton, CT 06340
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  • Dennis R. Petersen

    Corresponding author
    1. Alcohol and Hepatobiliary Research Centers, University of Colorado Health Sciences Center, Denver, Colorado 80262
    2. School of Pharmacy, University of Colorado, Boulder, Colorado 80309–0297
    • University of Colorado, School of Pharmacy, Campus Box 297, Boulder, CO 80309-0297
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Abstract

The hepatic oxidation of ethanol has been demonstrated to cause peroxidation of cellular membranes, resulting in the production of aldehydes that are substrates for hepatic aldehyde dehydrogenases. It was the purpose of this study to evaluate the cooxidation of the lipid peroxidation product, trans-4-hydroxy-2-nonenal, and acetaldehyde by high-affinity mitochondrial aldehyde dehydrogenase, which is of prominent importance in the oxidation of ethanol-derived acetaldehyde. Experiments were performed for determination of kinetic parameters for uninhibited acetaldehyde and 4-hydroxynonenal oxidation by semipurified mitochondrial aldehyde dehydrogenase prepared from male Sprague-Dawley rat liver. The affinity of the enzyme for the substrate at low substrate concentrations and the Michaelis-Menten constant of mitochondrial aldehyde dehydrogenase for acetaldehyde were 25 and 10 times greater, respectively, than those determined for 4-hydroxynonenal. Coincubation of acetaldehyde with physiologically relevant concentrations of 4-hydroxynonenal (0.25 to 5.0μmol/L) with mitochondrial aldehyde dehydrogenase demonstrated that 4-hydroxynonenal is a potent competitive or mixed-type inhibitor of acetaldehyde oxidation, with concentration of 4-hydroxynonenal required for a twofold increase in the slope of the Lineweaver-Burk plot for acetaldehyde oxidation by ALDH of 0.48 μmol/L. The results of this study suggest that the aldehydic lipid peroxidation product, trans-4-hydroxy-2-nonenal, is a potent inhibitor of hepatic acetaldehyde oxidation and may potentiate the hepatocellular toxicity of acetaldehyde proposed to be an etiological factor of alcoholic liver disease. (HEPATOLOGY 1991;13:728–734.)

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