FOLATE METABOLISM IN ALCOHOLISM

叶酸缺乏是营养不良的最常见症状 慢性酒精中毒患者，影响核酸合成和 所有单元格的周转。在前人对慢性病研究的基础上 酒精喂养的灵长类动物，表现出叶酸吸收减少和 肝脏摄取与尿叶酸排泄增加，我们建议 1)慢性酒精中毒会导致物理和化学变化 在涉及叶酸运输的膜中。或者，2)免费 乙醇代谢过程中产生的自由基可以加速 内源性叶酸的分解代谢。在这个过程的第一个阶段 格兰特说，我们建立了一个控制和饮酒的模型 发现小型猪的活动显著减少 空肠刷缘叶酸水解酶在体内的降低 主要饲料--翼酰基聚谷氨酸(PteGlun) 叶酸。我们还发现摩尔比发生了惊人的变化 循环中的磷脂脂肪酸，部分反映了 根据空肠刷状缘膜的脂肪酸组成 与脂肪酸脱饱和度缺陷相吻合。 在拟议的更新中，我们计划测试以下两个假设 饲喂高浓度乙醇的猪叶酸缺乏症 至少两到三年。膜效果，包括 将测量脂类组成和有序参数的变化 每隔4至6个月进行一次血浆、组织活检和肝脏检查 微体脂肪酸脱饱和酶将被分离和研究 对照组和酗酒组。在杀戮之后，运输 将在肠道中测量单谷氨酰叶酸(PteGlu) 肝、肾小管膜的变化与 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的影响 空肠刷缘叶酸水解酶的工艺研究 通过mRNA杂交和免疫沉淀法检测新生细胞 粘膜组织培养中的蛋白质。注射微量的 ~3H-PteGlu标记定时肝活检中的内源性叶酸 将测量在体内长期饮酒对 细胞内叶酸的摄取、结合和代谢 肝脏。在14C和~3H双标记的单独实验中 PteGlu我们将确定慢性酒精中毒是否会加速 叶酸分解代谢物的分解代谢和尿液排泄。这些 定量数据将与肝脏痕迹研究相关联 两组矿物质和自由基的形成和代谢 关于动物的。拟议的研究将确定致病原因 慢性酒精中毒的叶酸缺乏。使用叶酸作为一种 例如，这些研究将进一步了解 慢性酒精中毒、膜改变、营养之间的相互作用 新陈代谢和营养不良。

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.