FOLATE METABOLISM IN ALCOHOLISM

酗酒时的叶酸代谢

• 批准号: 3110399
• 负责人: CHARLES HOPKINSON HALSTED
• 金额: $ 22.27万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-04-01 至 1994-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3110399
• 关键词: alcoholic beverage consumption; alcoholism /alcohol abuse; bile; biological models; drug adverse effect; electron microscopy; enzyme linked immunosorbent assay; ethanol; folate; folate deficiency; gastrointestinal nutrient absorption; immunoprecipitation; liver metabolism; nucleic acid hybridization; nutrient drug interaction; nutrition related tag; scintillation counter; swine; vitamin metabolism

Folate deficiency is the most common sign of malnutrition in chronic alcoholic patients, affecting nucleic acid synthesis and turnover of all cells. On the basis of prior studies in chronic alcohol-fed primates, which showed decreased folate absorption and hepatic uptake with increased urinary folate excretion, we propose 1) that chronic alcoholism leads to physical and chemical changes in membranes involved in folate transport. Alternatively, 2) free radical production during ethanol metabolism could accelerate the catabolism of endogenous folates. During the first period of this grant we established a model of control and alcohol feeding in the miniature pig and found a significant reduction in the activity of jejunal brush border folate hydrolase with decreased in vivo hydrolysis of pteroylpolyglutamate (PteGlun), the principal dietary folate. We also found striking changes in the molar ratios of circulating phospholipid fatty acids, which were partly reflected by the fatty acid composition of the jejunal brush border membrane and which were consistent with a defect in fatty acid desaturation. In the proposed renewal, we plan to test the two hypotheses for folate deficiency in pigs fed a higher concentration of ethanol for a minimum of two to three years. Membrane effects, including changes in lipid composition and order parameter will be measured at 4 to 6 month intervals in plasma and tissue biopsies and hepatic microsomal fatty acid desaturase will be isolated and studied in control and alcoholic groups. After killing, the transport of monoglutamyl folate (PteGlu) will be measured in intestinal hepatic, and renal tubular membranes, correlating changes with membrane microviscosity and lipid composition. The effect of chronic alcoholism on the mucosal synthesis and intracellular processing of jejunal brush border folate hydrolase will be studied by mRNA hybridization and by immunoprecipitation of nascent proteins in mucosal explant cultures. Injecting trace amounts of 3H-PteGlu to label endogenous folates in timed liver biopsies, we will measure the effect of chronic alcohol feeding in vivo on the uptake intracellular binding, and metabolism of folate in the liver. In separate experiments with 14C and 3H doubly labeled PteGlu we will determine whether chronic alcoholism accelerates the catabolism and urinary excretion of folate catabolites. These quantitative data will be correlated with studies of hepatic trace mineral and free radical formation and metabolism in both groups of animals. The proposed studies will identify etiologies for folate deficiency in chronic alcoholism. Using folate as an example, these studies will further understanding of the interactions among chronic alcoholism, membrane changes, nutrient metabolism, and malnutrition.

叶酸缺乏是营养不良的最常见的迹象， 慢性酒精中毒患者，影响核酸合成， 所有细胞的周转。 在以往研究的基础上， 酒精喂养的灵长类动物，显示叶酸吸收减少， 肝摄取增加尿叶酸排泄，我们建议 1)慢性酒精中毒会导致身体和化学变化 参与叶酸转运的细胞膜。 或者，2）免费 乙醇代谢过程中自由基的产生可以加速 内源性叶酸的代谢。 在第一阶段， 格兰特，我们建立了一个控制和酒精喂养的模型， 小型猪，并发现显着减少的活动， 空肠刷状缘叶酸水解酶在体内降低 水解蝶酰聚谷氨酸盐（PteGlun），主要的膳食 叶酸。 我们还发现， 循环磷脂脂肪酸，这部分反映了 空肠刷状缘膜的脂肪酸组成 并且与脂肪酸去饱和缺陷一致。 在提议的更新中，我们计划测试两个假设， 猪的叶酸缺乏， 至少两到三年 膜效应，包括 将测量脂质组成和有序参数的变化 在血浆和组织活检以及肝脏中，每隔4至6个月进行一次 微粒体脂肪酸去饱和酶将在 对照组和酒精组。 杀人后，运送 单谷氨酰叶酸（PteGlu）将在肠内测量 肝和肾小管膜，与 膜微粘度和脂质组成。 的影响 慢性酒精中毒对粘膜合成和细胞内 将研究空肠刷状缘叶酸水解酶的加工 通过mRNA杂交和免疫沉淀， 粘膜外植体培养物中的蛋白质。 注射微量的 3 H-PteGlu标记内源性叶酸在定时肝活检，我们 将测量体内慢性酒精喂养对 摄取细胞内结合和代谢的叶酸在 肝脏 在14 C和3 H双标记的单独实验中， 我们将确定慢性酒精中毒是否会加速 叶酸钙的尿排泄。 这些 定量数据将与肝示踪研究相关联 矿物质和自由基的形成和代谢 动物。 拟议的研究将确定病因， 慢性酒精中毒的叶酸缺乏症 使用叶酸作为 例如，这些研究将进一步了解 慢性酒精中毒、细胞膜变化、营养物质之间的相互作用 新陈代谢和营养不良。