In vivo contribution of Class III alcohol dehydrogenase (ADH3) to alcohol metabolism through activation by cytoplasmic solution hydrophobicity
| Autor: | Akio Shimizu, Youkichi Ohno, Takeshi Haseba, Kouji Kameyama, Isao Yamamoto, Gregg Duester |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Male
Class I ADH Cytoplasm Acute alcohol intoxication Mice Inbred Strains Class III ADH Activation by solution hydrophobicity Microsomal ethanol oxidizing system Mice chemistry.chemical_compound Knockout mouse In vivo Animals Enzyme kinetics Ethanol metabolism Molecular Biology Alcohol dehydrogenase Mice Knockout chemistry.chemical_classification Ethanol Behavior Animal biology Alcohol metabolism Chemistry Alcohol Dehydrogenase Enzyme Activation Isoenzymes Enzyme Liver Biochemistry Catalase biology.protein Molecular Medicine Hydrophobic and Hydrophilic Interactions Oxidation-Reduction |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1762:276-283 |
| ISSN: | 0925-4439 |
| DOI: | 10.1016/j.bbadis.2005.11.008 |
| Popis: | Alcohol metabolism in vivo cannot be explained solely by the action of the classical alcohol dehydrogenase, Class I ADH (ADH1). Over the past three decades, attempts to identify the metabolizing enzymes responsible for the ADH1-independent pathway have focused on the microsomal ethanol oxidizing system (MEOS) and catalase, but have failed to clarify their roles in systemic alcohol metabolism. In this study, we used Adh3-null mutant mice to demonstrate that Class III ADH (ADH3), a ubiquitous enzyme of ancient origin, contributes to alcohol metabolism in vivo dose-dependently resulting in a diminution of acute alcohol intoxication. Although the ethanol oxidation activity of ADH3 in vitro is low due to its very high Km, it was found to exhibit a markedly enhanced catalytic efficiency (kcat/Km) toward ethanol when the solution hydrophobicity of the reaction medium was increased with a hydrophobic substance. Confocal laser scanning microscopy with Nile red as a hydrophobic probe revealed a cytoplasmic solution of mouse liver cells to be much more hydrophobic than the buffer solution used for in vitro experiments. So, the in vivo contribution of high-Km ADH3 to alcohol metabolism is likely to involve activation in a hydrophobic solution. Thus, the present study demonstrated that ADH3 plays an important role in systemic ethanol metabolism at higher levels of blood ethanol through activation by cytoplasmic solution hydrophobicity. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect