Mammalian alcohol dehydrogenase functional and structural implications

Mammalian alcohol dehydrogenase (ADH) constitutes a complex system with dif ferent forms and extensive multiplicity (ADH1-ADH6) that catalyze the oxida tion and reduction of a wide variety of alcohols and aldehydes. The ADH1 en zymes, the classical liver forms, are involved in several metabolic pathway s beside the oxidation of ethanol, e.g. norepinephrine, dopamine, serotonin and bile acid metabolism. This class is also able to further oxidize aldeh ydes into the corresponding carboxylic acids, i.e, dismutation. ADH2, can b e divided into two subgroups, one group consisting of the human enzyme toge ther with a rabbit form and another consisting of the rodent forms. The rod ent enzymes almost lack ethanol-oxidizing capacity in contrast to the human form, indicating that rodents are poor model systems for human ethanol met abolism. ADH3 (identical to glutathione-dependent formaldehyde dehydrogenas e) is clearly the ancestral ADH form and S-hydroxymethylglutathione is the main physiological substrate, but the enzyme can still oxidize ethanol at h igh concentrations. ADH4 is solely extrahepatically expressed and is probab ly involved in first pass metabolism of ethanol beside its role in retinol metabolism. The higher classes, ADH5 and ADH6, have been poorly investigate d and their substrate repertoire is unknown. The entire ADH system can be s een as a general detoxifying system for alcohols and aldehydes without gene rating toxic radicals in contrast to the cytochrome P450 system. Copyright (C) 2001 National Science Council. ROC and S. Karger AG. Basel.