Chronic alcohol abuse leads to a series of health problems that cost thousands of lives annually and accounts for billions of dollars each year in medical expenditures. The biological effects of alcohol are related to the dose consumed, the blood and tissue concentrations obtained, the duration that tissues are exposed to high ethanol concentrations, and the frequency of alcohol intake. There are, of course, other variables such as; gender, age, genetic predisposition, underlying health effects, etc. However, the tissue alcohol concentrations and duration of exposure are by far the most important aspects of alcohol-related health effects and are in good part related to the metabolism of alcohol. Alcohol metabolism is fundamental to alcohol's actions and although the enzymes that metabolize alcohol have been known for years, the mechanisms by which they are regulated are not well understood. Hepatic Class I Alcohol Dehydrogenase (ADH) is the principal alcohol-metabolizing enzyme and is responsible for as much as 95%of alcohol conversion to the toxic metabolite acetaldehyde and is the first step in the eventual clearance of alcohol from the body. Until recently, it was thought that alcohol could not signal the liver to synthesize more ADH when alcohol concentrations became high. We have used the intragastric rodent model of alcoholic liver disease (ALD) to study the molecular regulation of Class I ADH during times when alcohol concentrations become high, such as would occur in alcoholics, and found that alcohol can indeed cause the liver to produce sufficiently more Class I ADH to drive alcohol concentrations down to less toxic concentrations. These findings have far reaching implications for such areas as; 1) the central nervous system (alcohol dependence & tolerance); and 2) the liver (ALD, alcohol-induced diabetes and obesity). Furthermore, we have proposed a plausible mechanism underlying this important process. The major focus of this renewal is regulation of the gene encoding Class I ADH during chronic ethanol intake. Our overall working hypothesis is that chronic ethanol intake causes increased production (expression) of Class I ADH by disrupting hormonal systems that ultimately regulate rat Class I ADH production via intracellular signals (called signal transduction pathways) that are commonly used by hormones (especially insulin) to regulate gene actions. We will employ a series of in vitro (cell culture, molecular biological and biochemical) and in vivo (intragastric infusions of ethanol-containing diets to rats) procedures that we have standardized in our lab to study alcohol metabolism.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-DIG-B (04))
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Gentry, Thomas
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Arkansas Children's Hospital Research Institute
Little Rock
United States
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Ronis, Martin J J; Mercer, Kelly; Suva, Larry J et al. (2014) Influence of fat/carbohydrate ratio on progression of fatty liver disease and on development of osteopenia in male rats fed alcohol via total enteral nutrition (TEN). Alcohol 48:133-44
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Ronis, Martin J J; Butura, Angelica; Sampey, Brante P et al. (2005) Effects of N-acetylcysteine on ethanol-induced hepatotoxicity in rats fed via total enteral nutrition. Free Radic Biol Med 39:619-30

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