THE TOXIC EFFECTS OF ETHANOL ON FOLATE METABOLISM

乙醇对叶酸代谢的毒性作用

• 批准号: 3108961
• 负责人: Kenneth E. McMartin
• 金额: $ 12.35万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-01-01 至 1991-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3108961
• 关键词: alcoholic beverage consumption; blood chemistry; dietary constituent; drug adverse effect; drug interactions; ethanol; excretion; folate; folate antagonist; folate deficiency; high performance liquid chromatography; human subject; laboratory rat; nutrition related tag; renal tubular transport; urinalysis; vitamin metabolism

Studies in humans have indicated that the folate deficiency of chronic alcoholism is due to a toxic effect of ethanol to deplete folate as well as to an inadequate dietary intake of folate. The mechanism of this toxic effect is not completely understood and studies using an animal model need to be conducted. The suitability of the rat as a possible animal model for the induction of folate deficiency by chronic ethanol use will be tested. Rats will be used because preliminary studies have shown that acute ethanol treatment induces a decrease in plasma folate levels similar to that observed in humans. Feeding experiments using ethanol with a nutritionally-sufficient liquid diet or a folate-deficient liquid diet will be employed in a pairfed manner to assess the effects of ethanol. Blood ethanol levels and hematologic and folate status will be determined periodically. Folate status will be measured directly by microbiological analysis of blood, liver, kidney, and urine samples or indirectly by the urinary excretion of formate. An assay utilizing high pressure liquid chromatography for the determination of individual folate compounds will be used to measure the ethanol-induced changes in tissue folates. Preliminary studies have shown that the decreased plasma folate levels after acute ethanol treatment result from increased urinary folate excretion. Hence, this study will evaluate the role of increased urinary folate excretion as a mechanism for the chronic ethanol-induced folate deficiency. In the rat feeding experiment, urinary folate levels will be closely monitored. Furthermore, studies in ethanol-consuming human subjects will be conducted to test whether increased urinary folate excretion is a means by which plasma folate levels are decreased. Ethanol in an acute oral dose will be administered to human volunteers and the folate levels in plasma and urine determined for a 24 hour period. Finally, the mechanism for the increased urinary excretion in rats will be studied by testing the effect of ethanol on plasma folate binding in vivo using a radiobinding assay, on folate reabsorption by the kidney using clearance studies, and on folate binding in vitro by renal tubular membranes using a radiobinding assay. Determination of the mechanism of the increased urinary folate excretion will help to further understanding of the production of the folate deficiency that is very common in chronic alcoholics.

在人类的研究表明，慢性的叶酸缺乏 酒精中毒是由于乙醇耗尽叶酸以及 叶酸的饮食摄入不足。 这种有毒的机制 效果尚未完全理解，并使用动物模型的研究进行研究 进行。 大鼠作为可能的动物模型的适用性 将测试慢性乙醇诱导叶酸缺乏症。 将使用大鼠，因为初步研究表明急性乙醇 治疗诱导血浆叶酸水平的降低类似 在人类中观察到。 使用乙醇与A的喂养实验 营养充足的液体饮食或叶酸不足的液体饮食将 以成对的方式使用以评估乙醇的作用。 血 将确定乙醇水平以及血液学和叶酸状况 定期。 叶酸状态将直接通过微生物学测量 分析血液，肝脏，肾脏和尿液样本，或通过间接分析 甲酸的尿液排泄。 利用高压液体的测定 测定个体叶酸化合物的色谱法将是 用于测量乙醇诱导的组织叶状变化。 初步的 研究表明，急性后血浆叶酸水平降低 乙醇处理是由于尿叶酸排泄增加而导致的。 因此， 这项研究将评估尿叶酸排泄增加的作用 慢性乙醇引起的叶酸缺乏的机制。 在大鼠中 进食实验，将密切监测尿叶酸水平。 此外，将对乙醇耗竭的人类受试者进行研究 测试增加尿叶酸排泄是否是一种手段 血浆叶酸水平降低。 急性口服剂量的乙醇将是 在血浆和尿液中给予人类志愿者和叶酸水平 确定为24小时。 最后，增加的机制 通过测试乙醇的作用，将研究大鼠的尿液排泄 在叶酸上使用放射性物质测定法在体内的血浆叶酸结合上 使用清除研究和叶酸结合通过肾脏吸收 通过肾小管膜在体外使用放射性刺激测定法。 确定增加尿叶酸排泄的机理 将有助于进一步了解叶酸的生产 在慢性酗酒者中非常常见的缺乏症。