title: Inhibition of human alcohol and aldehyde dehydrogenases by aspirin and salicylate: assessment of the effects on first-pass metabolism of ethanol.
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 higher therapeutic levels of blood plasma salicylate (1.5 mM) that the decrease of activities at 2-10 mM ethanol for ADH1A/ADH2 and ADH1B2/ADH1B3 are predicted to be 75-86% and 31-52%, respectively, and that the activity decline for ALDH1A1 and ALDH2 at 10-50 μM acetaldehyde to be 62-73%. Our findings suggest that salicylate may substantially inhibit hepatic FPM of alcohol at both the ADH and ALDH steps when concurrent intaking aspirin.
authors.affiliation: Department of Biological Science and Technology, China Medical University, 91 Hsueh-Shih Road, Taichung 40402, Taiwan. Electronic address: sllee@mail.cmu.edu.tw.
authors.forename: Shou-Lun
authors.initials: SL
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, National Defense Medical Center, 161 Minchuan East Road Section 6, Taipei 11453, Taiwan.
authors.forename: Yung-Pin
authors.initials: YP
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, National Defense Medical Center, 161 Minchuan East Road Section 6, Taipei 11453, Taiwan.
authors.forename: Min-Li
authors.initials: ML
authors.lastname: Wu
authors.affiliation: Department of Biochemistry, National Defense Medical Center, 161 Minchuan East Road Section 6, Taipei 11453, Taiwan.
authors.forename: Yu-Chou
authors.initials: YC
authors.lastname: Chi
authors.affiliation: Department of Biochemistry, National Defense Medical Center, 161 Minchuan East Road Section 6, Taipei 11453, Taiwan.
authors.forename: Chiu-Ming
authors.initials: CM
authors.lastname: Liu
authors.affiliation: Department of Nursing, Chang Gung University of Science and Technology, 261 Wenhwa 1st Road, Kweishan Township, Taoyuan 33303, Taiwan.
authors.forename: Ching-Long
authors.initials: CL
authors.lastname: Lai
authors.affiliation: Department of Biochemistry, National Defense Medical Center, 161 Minchuan East Road Section 6, Taipei 11453, Taiwan.
authors.forename: Shih-Jiun
authors.initials: SJ
authors.lastname: Yin
mesh_terms: D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001241:Aspirin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000378:metabolism*; D006801:Humans; D012459:Salicylates / Q000494:pharmacology*
chemical_list: D012459:Salicylates; D000431:Ethanol; D000426:Alcohol Dehydrogenase; D000444:Aldehyde Dehydrogenase; D001241:Aspirin
keywords: Alcohol dehydrogenase (ADH); Alcohol first-pass metabolism; Aldehyde dehydrogenase (ALDH); Aspirin; Inhibition kinetics; Salicylate