Contribution of NADH increases to ethanol's inhibition of retinol oxidation by human ADH isoforms.
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 ScrumPy, 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.
Chase
Jennifer R
JR
School of Health Science, Northwest Nazarene University, Nampa, Idaho 83686, USA. jrchase@nnu.edu
Poolman
Mark G
MG
Fell
David A
DA
D000426:Alcohol Dehydrogenase / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes; D008954:Models, Biological; D009243:NAD / Q000378:metabolism*; D010084:Oxidation-Reduction; D014212:Tretinoin / Q000378:metabolism; D014801:Vitamin A / Q000378:metabolism*
D007527:Isoenzymes; D009243:NAD; D014801:Vitamin A; D000431:Ethanol; D014212:Tretinoin; D000426:Alcohol Dehydrogenase