[A new sight on alcohol metabolism and alcoholism--role of high Km alcohol dehydrogenase ADH3 (Class III)].
Alcohol metabolism is known to be mainly carried out by the classic ADH1 (Class I) of the liver. However, another pathway has been also suggested to play important roles in alcohol metabolism especially at high levels of blood ethanol and under chronic drinking. Over the past three decades, vigorous attempts to identify the enzyme responsible for the non-ADH1 pathway have focused on the microsomal oxidizing system (MEOS) and catalase, but have failed to clarify their roles in systemic alcohol metabolism. Recently, we used ADH3-null mutant mice to demonstrate that high Km ADH3 (Class III), a ubiquitous enzyme of ancient origin, contributes to systemic alcohol metabolism dose-dependently resulting in a diminution of acute alcohol intoxication. Although the ethanol activity of ADH3 in vitro is usually low due to its very high Km, the catalytic efficiency (k(cat)/Km) was markedly enhanced when the solution hydrophobicity of the reaction medium was increased. The hydrophobic activation of ADH3 is also expected in liver cells, because the cytoplasmic solution in mouse liver cell was shown to be much more hydrophobic than the buffer solution by using Nile red as a hydrophobic probe. By acute administrations of ethanol to mice at various doses, liver ADH3 activity was dynamically regulated through induction or kinetic activation, though ADH1 activity was markedly decreased at higher doses (3 - 5 g/kg). These data suggest that ADH3 plays a dynamical share in alcohol metabolism with ADH1, collaborating with it or supplementing the decreased role of ADH1. The two ADH-complex model, which ascribes total liver ADH activity to both ADH1 and ADH3, explained well the dose-dependent changes in pharmacokinetic parameters (beta, CL(T), AUC) of blood ethanol, suggesting that alcohol metabolism in mice is primarily governed by the two ADHs. In patients with alcoholic liver diseases, the liver ADH3 activity increased but the ADH1 activity decreased with an increase in alcohol intake. Furthermore, ADH3 was induced in damaged cells with increased hydrophobicity, whereas ADH1 decreased its activity in severe liver diseases. These data suggest that heavy and chronic drinking shifts the main enzyme in alcohol metabolism from low Km ADH1 to high Km ADH3 to develop alcoholic liver diseases by the nonlinear increase in AUC due to the decrease of the metabolic rate. However, the adaptively increased ADH3 keeps the ability of alcohol metabolism even in patients with alcoholic liver cirrhosis and make possible for them to keep drinking to death. Therefore, the regulation of ADH3 activity may be important to prevent the development of alcoholism.
Haseba
Takeshi
T
Department of Legal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan.
D000445:Aldehyde Oxidoreductases / Q000502:physiology*; D000818:Animals; D000431:Ethanol / Q000378:metabolism*; D006801:Humans; D008108:Liver Diseases, Alcoholic / Q000201:enzymology; D051379:Mice
D000431:Ethanol; C020145:formaldehyde dehydrogenase (glutathione); D000445:Aldehyde Oxidoreductases