Alcohol dehydrogenase 4 (ADH4)

Alcohol dehydrogenase 4 (ADH4), also known as class II alcohol dehydrogenase, is a member of the medium-chain dehydrogenase/reductase superfamily primarily responsible for the oxidation of alcohols and retinoids. It is highly expressed in the liver and the epithelial lining of the upper aerodigestive tract, where it contributes significantly to the first-pass metabolism of ethanol, particularly at high concentrations. Beyond ethanol clearance, ADH4 plays a pivotal role in the synthesis of retinoic acid by converting retinol to retinal, thereby influencing nuclear receptor signaling pathways that govern cellular growth, development, and tissue maintenance. [1, 4, 16] In clinical contexts, ADH4 is recognized as a potential therapeutic target and a significant prognostic biomarker. Its expression is frequently downregulated in hepatocellular carcinoma and other cancers, where low levels are associated with poor patient survival and disease progression. Furthermore, genetic polymorphisms in the ADH4 gene have been strongly linked to susceptibility to alcohol and drug dependence, as well as an increased risk of upper digestive tract cancers. While it is less sensitive to standard inhibitors like fomepizole compared to class I ADHs, its activity is modulated by ethanol consumption, which can lead to localized vitamin A deficiencies and associated pathologies. [1, 9, 14, 15]

Other names

Alcohol dehydrogenase 4 (class II)Alcohol dehydrogenase class II pi chainADH-2HEL-S-4Pi-alcohol dehydrogenaseAlcohol dehydrogenase IVAll-trans-retinol dehydrogenase [NAD(+)] ADH4

Alcohol dehydrogenase 4 functions as a zinc-dependent homodimer that catalyzes the NAD+-dependent oxidation of primary and secondary alcohols to their corresponding aldehydes or ketones. For ethanol, it typically follows an ordered sequential mechanism where the coenzyme NAD+ binds first, followed by the alcohol, producing acetaldehyde and NADH. In retinoid metabolism, it exhibits high catalytic efficiency for the oxidation of retinol to retinal, a critical step in the biosynthesis of retinoic acid, which regulates gene expression and cell differentiation.