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.

人类研究表明，慢性叶酸缺乏症 酒精中毒是由于乙醇的毒性作用会消耗叶酸以及 饮食中叶酸摄入不足。 这种有毒物质的作用机制 效果尚未完全了解，需要使用动物模型进行研究 进行。 大鼠作为可能的动物模型的适用性 将测试长期使用乙醇引起的叶酸缺乏。 将使用大鼠，因为初步研究表明急性乙醇 治疗会导致血浆叶酸水平降低，类似于 在人类中观察到。 使用乙醇进行饲喂实验 营养充足的流质饮食或缺乏叶酸的流质饮食会 以配对方式使用来评估乙醇的影响。 血 将确定乙醇水平以及血液学和叶酸状态 定期。 叶酸状况将通过微生物学直接测量 分析血液、肝脏、肾脏和尿液样本或间接通过 甲酸从尿中排出。 利用高压液体的测定 用于测定单个叶酸化合物的色谱法 用于测量乙醇引起的组织叶酸变化。 初步的 研究表明，急性发作后血浆叶酸水平下降 乙醇治疗是由于尿叶酸排泄增加所致。 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 喂养实验中，尿叶酸水平将受到密切监测。 此外，还将对消耗乙醇的人类受试者进行研究 测试增加尿叶酸排泄是否是一种方法 血浆叶酸水平降低。 急性口服剂量的乙醇将 给予人类志愿者以及血浆和尿液中的叶酸水平 以 24 小时为周期确定。 最后，增加的机制 通过测试乙醇的影响来研究大鼠的尿液排泄 使用放射性结合测定对体内血浆叶酸结合进行研究 使用清除率研究和叶酸结合进行肾脏重吸收 使用放射性结合测定在体外通过肾小管膜进行检测。 尿叶酸排泄增加机制的确定 将有助于进一步了解叶酸的产生 这种缺乏症在慢性酗酒者中很常见。