ALCOHOL--DIRECT AND INDIRECT EFFECTS ON DRUG METABOLISM

酒精性肝病（ALD）是第四大死因

Alcohol induced liver disease (ALD) is the fourth leading cause of death among adult men 24-65 years of age residing in urban areas, the eleventh leading cause of deaths overall in the United States, and accounts for billions of dollars annually in medical expenditures. The investigators developed a rat model in which an ethanol-containing diet is infused intragastrically as part of a total enteral nutrition (TEN) system to study the nutrition/ethanol relationships to ALD and ethanol metabolism. They have made several important observations using the TEN model. First, they have identified a diet that prevents ethanol-induced liver injury, even during high ethanol and high unsaturated fat intake for periods reported by others to produce significant hepatic injury. Second, the investigators have identified another diet that produces ethanol-induced liver injury at the same ethanol intake as the first diet. They feel that these two observations together are exciting because study of the differences between these diets could reveal important mechanism underlying ethanol-induced liver injury leading to ALD in humans. Third, the investigators have studied what they feel is an interesting consequence of constant intragastric infusion of ethanol- containing diets, the pulsatile BECs that appear to be due to "cyclic" ethanol metabolism. They do not know the biological significance of this phenomenon in the development of human ALD. However, it is of scientific importance for two reasons: a) ethanol metabolism is thought to be a contributing factor in adverse effects of ethanol; and b) the intragastric rat models are the only practical models that produce ethanol-induced liver injury within a reasonable time frame and expense. Thus, understanding how ethanol is metabolized in this model may be important. Fourth, beer has different metabolic effects than pure ethanol. This is an important observation, because 57 percent of U.S. alcohol drinkers consume their ethanol as beer, not the pure ethanol used in most alcohol research. Their data suggest that there are possible consequences upon the clearance, efficacy and toxicity of medications that may be taken concomitantly with alcoholic beverages. The principal aims of this renewal are to study in detail: 1) the interactions of ethanol and diet on the biochemical and cellular basis of ethanol induced liver injury by proposing novel nutritional and cellular mechanisms involving carbohydrate-regulated and oxygen radical- regulated gene expression, respectively; 2) a unique pulsatile aspect of ethanol metabolism revealed by chronic intragastric infusion of ethanol-containing diets; and 3) the comparative effects of laboratory ethanol and alcoholic beverages (especially beer).