Inhibition of human alcohol and aldehyde dehydrogenases by aspirin and salicylate: assessment of the effects on first-pass metabolism of ethanol

Biochemical Pharmacology
Shou-Lun LeeShih-Jiun Yin

Abstract

Previous studies have reported that aspirin significantly reduced the first-pass metabolism (FPM) of ethanol in humans thereby increasing adverse effects of alcohol. The underlying causes, however, remain poorly understood. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), principal enzymes responsible for metabolism of ethanol, are complex enzyme families that exhibit functional polymorphisms among ethnic groups and distinct tissue distributions. We investigated the inhibition profiles by aspirin and its major metabolite salicylate of ethanol oxidation by recombinant human ADH1A, ADH1B1, ADH1B2, ADH1B3, ADH1C1, ADH1C2, ADH2, and ADH4, and acetaldehyde oxidation by ALDH1A1 and ALDH2, at pH 7.5 and 0.5 mM NAD(+). Competitive inhibition pattern was found to be a predominant type among the ADHs and ALDHs studied, although noncompetitive and uncompetitive inhibitions were also detected in a few cases. The inhibition constants of salicylate for the ADHs and ALDHs were considerably lower than that of aspirin with the exception of ADH1A that can be ascribed to a substitution of Ala-93 at the bottom of substrate pocket as revealed by molecular docking experiments. Kinetic inhibition equation-based simulations show at highe...Continue Reading

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Citations

Jun 29, 2016·Genes and Environment : the Official Journal of the Japanese Environmental Mutagen Society·Takahiro HamoyaMichihiro Mutoh
Feb 3, 2016·Nihon eiseigaku zasshi. Japanese journal of hygiene·Akiko Matsumoto
Aug 8, 2019·Praxis·Paolo M Suter, Ludwig Perger
Feb 2, 2018·Nihon eiseigaku zasshi. Japanese journal of hygiene·Akiko Matsumoto
Mar 11, 2020·Alcoholism, Clinical and Experimental Research·Hyun-Jin KimJu-Seop Kang
Jun 15, 2016·Alimentary Pharmacology & Therapeutics·Y Lu
Apr 18, 2019·Scientific Reports·Gianluca FarrugiaRena Balzan
Oct 5, 2016·MedChemComm·Zhiqiang WuZhenqiang Wu

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