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Contribution of NADH Increases to Ethanol’s Inhibition of Retinol Oxidation by Human ADH Isoforms
Author(s) -
Chase Jennifer R.,
Poolman Mark G.,
Fell David A.
Publication year - 2009
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.2008.00871.x
Subject(s) - alcohol dehydrogenase , nad+ kinase , ethanol , biochemistry , chemistry , ethanol metabolism , alcohol oxidoreductase , oxidase test , metabolism , cofactor , enzyme
Background: A decrease in retinoic acid levels due to alcohol consumption has been proposed as a contributor to such conditions as fetal alcohol spectrum diseases and ethanol‐induced cancers. One molecular mechanism, competitive inhibition by ethanol of the catalytic activity of human alcohol dehydrogenase (EC 1.1.1.1) (ADH) on all‐trans‐retinol oxidation has been shown for the ADH7 isoform. Ethanol metabolism also causes an increase in the free reduced nicotinamide adenine dinucleotide (NADH) in cells, which might reasonably be expected to decrease the retinol oxidation rate by product inhibition of ADH isoforms. Methods: To understand the relative importance of these two mechanisms by which ethanol decreases the retinol oxidation in vivo we need to assess them quantitatively. We have built a model system of 4 reactions: (1) ADH oxidation of ethanol and NAD + , (2) ADH oxidation of retinol and NAD + , (3) oxidation of ethanol by a generalized Ethanol oxidase that uses NAD + , (4) NADH oxidase which carries out NADH turnover. Results: Using the metabolic modeling package S crum P y , we have shown that the ethanol‐induced increase in NADH contributes from 0% to 90% of the inhibition by ethanol, depending on (ethanol) and ADH isoform. Furthermore, while the majority of flux control of retinaldehyde production is exerted by ADH, Ethanol oxidase and the NADH oxidase contribute as well. Conclusions: Our results show that the ethanol‐induced increase in NADH makes a contribution of comparable importance to the ethanol competitive inhibition throughout the range of conditions likely to occur in vivo, and must be considered in the assessment of the in vivo mechanism of ethanol interference with fetal development and other diseases.