Inhibition of human alcohol and aldehyde dehydrogenases by acetaminophen: Assessment of the effects on first-pass metabolism of ethanol

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

“…It is also consistent with previous observations that secondary alcohols, such as cyclohexanol and isopropanol, are uniquely more efficient substrates than ethanol for ADH1A in the human ADH family [42,43]. By contrast, acetaminophen and cimetidine, both commonly used drugs, exhibit lower affinity with human ADH1A (K is = 20 mM and 3.2 mM, respectively) than that with ADH2 (K is = 0.90 mM and 0.51 mM, respectively) [44,45]. ADH2 shows a better binding of these two drugs at the bottom of the substrate pocket by molecular docking simulations.…”

“…These inhibition patterns are similar to that of acetaminophen [45], whereas the opposite was observed with cimetidine inhibitions [44]. It may involve different binding modes of the drugs to substrate pockets of the corresponding isozymes.…”

Translational Implications of the Alcohol-Metabolizing Enzymes, Including Cytochrome P450-2E1, in Alcoholic and Nonalcoholic Liver Disease

“…These PTMs include oxidation, disulfide formation, S-nitrosylation, nitration, phosphorylation, acetylation, carbonylation, protein adduct formation, and many others Song, Akbar, et al, 2014). For instance, mitochondrial ALDH2 could be inactivated through various PTMs in experimental models exposed to alcohol (Doorn, Hurley, & Petersen, 2006;Moon et al, 2006;Venkatraman, Landar, Davis, Ulasova, et al, 2004) and other potentially toxic substances Banfi et al, 1994;Landin, Cohen, & Khairallah, 1996;Lee, Liao, et al, 2013;Mali et al, 2014;Méndez et al, 2014;Mitchell & Petersen, 1988;Moon, Kim, & Song, 2005;Moon, Lee, & Song, 2010;Moon, Upreti, et al, 2008). Decreased activity could result from decreased ALDH2 protein levels, as reported in alcoholexposed rats (Venkatraman, Landar, Davis, Chamlee, et al, 2004) and highfat-exposed mice (Eccleston et al, 2011).…”

“…In addition, the ADME of alcohol can be affected by gender, age, nutritional status, compositions of different diets (e.g., contents and composition of foods and fatty acids), biological clocks (e.g., day vs. night), and drugs or smoking, resulting in three-to fourfold differences among different individuals (Cederbaum, 2012b). Unlike many drugs and xenobiotic substances, which are usually excreted via the first-order kinetics in a concentration-dependent manner, alcohol is cleared from the body at a constant rate via pseudolinear near-zero-order kinetics, suggesting its removal in a concentration-independent manner (Cederbaum, 2012b;Lee, Liao, et al, 2013). There are many ADH isozymes expressed in a tissue-specific manner.…”

Alcohol Dehydrogenase from Sheep Liver: Purification, Characterization and Impacts of Some Antibiotics

“…In addition, Lee et al studied inhibition of acetaminophen on recombinant human ADH isoenzymes, recombinant human (aldehyde dehydrogenase A1) ALDH1A1 and ALDH2. They found that acetaminophen showed noncompetitive inhibition for ADH enzymes and ALDH2, but ALDH1A1 showed competitive inhibition (Lee et al, 2013).…”