Int. J. Environ. Res. Public Health 2010, 7, 1076-1092; doi:10.3390/ijerph7031076 OPEN ACCESS International Journal of Environmental Research and Public Health ISSN 1660-4601 www.mdpi.com/journal/ijerph Review A New View of Alcohol Metabolism and Alcoholism—Role of the High-Km Class Ⅲ Alcohol Dehydrogenase (ADH3) Takeshi Haseba * and Youkichi Ohno Department of Legal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan; E-Mail: ohno@nms.ac.jp * Author to whom correspondence should be addressed: E-Mail: hasebat@nms.ac.jp; Tel.: +81-03-3822; Fax: +81-03-5814-5680. Received: 4 January 2010; in revised form: 12 February 2010 / Accepted: 22 February 2010 / Published: 15 March 2010 Abstract: The conventional view is that alcohol metabolism is carried out by ADH1 (Class I) in the liver. However, it has been suggested that another pathway plays an important role in alcohol metabolism, especially when the level of blood ethanol is high or when drinking is chronic. Over the past three decades, vigorous attempts to identify the enzyme responsible for the non-ADH1 pathway have focused on the microsomal ethanol oxidizing system (MEOS) and catalase, but have failed to clarify their roles in systemic alcohol metabolism. Recently, using ADH3-null mutant mice, we demonstrated that ADH3 (Class III), which has a high Km and is a ubiquitous enzyme of ancient origin, contributes to systemic alcohol metabolism in a dose-dependent manner, thereby diminishing acute alcohol intoxication. Although the activity of ADH3 toward ethanol is usually low in vitro due to its very high Km, the catalytic efficiency (kcat/Km) is markedly enhanced when the solution hydrophobicity of the reaction medium increases. Activation of ADH3 by increasing hydrophobicity should also occur in liver cells; a cytoplasmic solution of mouse liver cells was shown to be much more hydrophobic than a buffer solution when using Nile red as a hydrophobicity probe. When various doses of ethanol are administered to mice, liver ADH3 activity is dynamically regulated through induction or kinetic activation, while ADH1 activity is markedly lower at high doses (3–5 g/kg). These data suggest that ADH3 plays a dynamic role in alcohol metabolism, either collaborating with ADH1 or compensating for the reduced role of ADH1. A complex two-ADH model that ascribes