Pharmacokinetics, Dynamics and Metabolism, Pfizer Worldwide Research and Development, Groton, CT, 06340, USA.
Department of Chemistry, Stanford University, Stanford, CA, 94305, USA.
AAPS J. 2021 Jan 7;23(1):20. doi: 10.1208/s12248-020-00536-y.
Alcohol dehydrogenases (ADHs) are most known for their roles in oxidation and elimination of ethanol. Although less known, ADHs also play a critical role in the metabolism of a number of drugs and metabolites that contain alcohol functional groups, such as abacavir (HIV/AIDS), hydroxyzine (antihistamine), and ethambutol (antituberculosis). ADHs consist of 7 gene family numbers and several genetic polymorphic forms. ADHs are cytosolic enzymes that are most abundantly found in the liver, although also present in other tissues including gastrointestinal tract and adipose. Marked species differences exist for ADHs including genes, proteins, enzymatic activity, and tissue distribution. The active site of ADHs is relatively small and cylindrical in shape. This results in somewhat narrow substrate specificity. Secondary alcohols are generally poor substrates for ADHs. In vitro-in vivo correlations for ADHs have not been established, partly due to insufficient clinical data. Fomepizole (4-methylpyrazole) is a nonspecific ADH inhibitor currently being used as an antidote for the treatment of methanol and ethylene glycol poisoning. Fomepizole also has the potential to treat intoxication of other substances of abuse by inhibiting ADHs to prevent formation of toxic metabolites. ADHs are inducible through farnesoid X receptor (FXR) and other transcription factors. Drug-drug interactions have been observed in the clinic for ADHs between ethanol and therapeutic drugs, and between fomepizole and ADH substrates. Future research in this area will provide additional insights about this class of complex, yet fascinating enzymes.
醇脱氢酶（ADHs）最为人所知的是其在氧化和消除乙醇中的作用。尽管鲜为人知，但 ADHs 也在许多含有醇官能团的药物和代谢物的代谢中发挥着关键作用，如阿巴卡韦（HIV/AIDS）、羟嗪（抗组胺药）和乙胺丁醇（抗结核药）。ADHs 由 7 个基因家族和几种遗传多态形式组成。ADHs 是细胞溶质酶，在肝脏中最为丰富，尽管也存在于其他组织中，包括胃肠道和脂肪组织。ADHs 的物种差异显著，包括基因、蛋白质、酶活性和组织分布。ADHs 的活性部位相对较小，呈圆柱形。这导致其底物特异性有些狭窄。次级醇通常是 ADHs 的较差底物。ADHs 的体内外相关性尚未建立，部分原因是临床数据不足。非那雄胺（4-甲基吡唑）是一种非特异性 ADH 抑制剂，目前被用作甲醇和乙二醇中毒的解毒剂。非那雄胺还有可能通过抑制 ADHs 来防止有毒代谢物的形成，从而治疗其他滥用物质的中毒。ADHs 通过法尼醇 X 受体（FXR）和其他转录因子诱导。在临床上已经观察到 ADHs 与乙醇和治疗药物之间，以及非那雄胺和 ADH 底物之间的药物相互作用。该领域的未来研究将为这一类复杂而迷人的酶提供更多的见解。
