This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Two of the many negative health results of alcohol abuse are fetal alcohol syndrome (FAS), and liver and other aerodigestive cancers. It is broadly believed that alcohol consumption and alcoholism lead to cancer and FAS, at least in part, via inhibition of synthesis of the transcription activator retinoic acid (RA) synthesis from retinol (vitamin A). A better understanding of the mechanism by which alcohol consumption leads to decreased RA production would be valuable for both prevention and amelioration of alcohol-associated disease. It is well established that ethanol directly competes with endogenous retinol for oxidation by several isoforms of alcohol dehydrogenase (ADH, EC 1.1.1.1). There is a widely-held, but unproven, theory that the ethanol-induced shifts in the levels of NADH also play a role in decreased oxidation of retinol by ADH. It has been difficult to design experiments to quantify the roles of the various inhibition mechanisms in retinol oxidation because inhibition is a cell system property rather than a phenomenon assignable to a single enzyme. We have developed a novel computational model of retinol oxidation that can be used to address inhibition in the context of several enzyme systems operating together to allow analysis and manipulation of the significant reactions encompassing ethanol and its interaction with retinol metabolism. The findings from computational studies are evaluated in the lab with recombinant human enzymes and human cell lines expressing alcohol and aldehyde dehydrogenases. We hypothesize that the ethanol-induced NADH increase inhibits RA synthesis in liver cells by inhibition of aldehyde and alcohol dehydrogenases. This represents the novel mechanism by which ethanol may decrease RA synthesis. The NADH-oxidative capacity of susceptible tissue and the potential for ethanol oxidation (producing NADH) are both measurable risk factors for FASD/developmental toxicity and upper airway/GI cancers where alcohol may affect RA signaling. Furthermore, since oxidative stress is implicated as a risk factor contributing to the development of liver cancer, this hypothesis provides an additional mechanism by which elevated NADH levels contribute to the development of the disease state.
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