RELATIONSHIP BETWEEN ALCOHOL TOXICITY/GLUTATHIONE

母体饮酒对胎儿的不良影响 早在几个世纪前就得到了认可。胎儿酒精综合征(FAS)是 特点是出生前和出生后发育迟缓，智力迟缓， 行为缺陷和面部畸形。尽管有许多动物 酒精产生作用的生化机制研究(S) 对发育中的胎儿的影响还不是很清楚。 大脑功能障碍与谷胱甘肽(GSH)缺乏有关。 多项研究表明，对成年大鼠灌胃酒精 会降低肝脏中谷胱甘肽的水平。GSH已被证明可以 对药物毒性有保护作用。硫醇化合物，如半胱氨酸， 作为谷胱甘肽的前体，已经被证明可以保护细胞免受 消耗谷胱甘肽的药物。 我们实验室的初步研究表明，肝脏和大脑中的谷胱甘肽水平 在整个过程中饮酒的大鼠的胚胎中 怀孕了。谷胱甘肽耗竭是由酒精剂量引起的，这会导致产前 发育迟缓。L-丁硫氨酸亚磺胺的给药 在整个怀孕过程中对怀孕的大鼠产生了GSH的降低 子代也会产生产前生长迟缓。初步 研究还表明，酒精引起的谷胱甘肽耗竭是可以预防的。 同时给予还原型谷胱甘肽前体N-乙酰-L-半胱氨酸 带着酒精。NAC治疗还取消了部分酒精诱导的 致畸作用。 本提案中描述的实验将测试以下内容 假设：宫内酒精暴露引起的致畸作用 源于胎儿谷胱甘肽水平的降低。我们将探索 此外，酒精、谷胱甘肽之间的剂量反应关系 精疲力竭和致畸。我们将确定致畸性是否 酒精的影响至少部分是由于体内GSH水平的降低 胎儿。我们将确定是否降低孕妇和胎儿的GSH水平 BSO对大鼠产生的致畸作用与所产生的 通过酒精。我们还将确定BSO是否会增强酒精诱导的 畸形症。我们建议同时服用酒精 BSO在低度酒精条件下会对子代产生致畸作用 剂量要比酒精本身给药时的剂量大。将确定NAC是否 会有保护作用，减少所产生的致畸作用 通过酒精。我们假设NAC的管理部门将阻止 酒精性谷胱甘肽耗竭，预防酒精性畸形。

The adverse effects of the maternal consumption of alcohol on the fetus have been recognized for centuries. Fetal Alcohol Syndrome (FAS) is characterized by pre and postnatal growth retardation, mental retardation, behavioral deficits and facial deformities. In spite of numerous animal studies, the biochemical mechanism(s) by which alcohol produces its effects on the developing fetus are not well understood. Brain dysfunction has been associated with glutathione (GSH) deficiency. Several studies have shown that the administration of alcohol to adult rats produces a decrease in the hepatic levels of GSH. GSH has been shown to have a protective role in drug toxicity. Thiol compounds such as cysteine, a precursor of GSH, have ben shown to protect cells from damage produced by drugs which deplete GSH. Preliminary studies in our laboratory have shown liver and brain GSH levels are decreased in fetuses of rats that have received alcohol throughout pregnancy. GSH depletion was produced by alcohol doses that cause prenatal growth retardation. The administration of L-buthionine sulfoximine (BSO) to pregnant rats throughout gestation produced a decrease in GSH in the offspring and also produced prenatal growth retardation. Preliminary studies have also shown that alcohol-induced GSH depletion is prevented when N-acetyl-L-cysteine (NAC), a GSH precursor, is given concomitantly with alcohol. NAC treatment also abolished some of the alcohol-induced teratogenic effects. The experiments described in this proposal will test the following hypothesis: Teratogenesis produced by the in utero exposure to alcohol arises from reductions in fetal glutathione levels. We will explore further, the dose-response relationships between alcohol, glutathione depletion and teratogenicity. We will determine whether the teratogenic effects of alcohol are due, at least in part, to reduced levels of GSH in the fetus. We will determine if reducing maternal and fetal GSH levels with BSO will produce teratogenic effects in rats that mimic those produced by alcohol. We will also determine if BSO will potentiate alcohol-induced teratogenesis. We propose that the concomitant administration of alcohol and BSO will produce teratogenic effects in the offspring at lower alcohol doses than when alcohol is given by itself. It will be determined if NAC will have a protective action and decrease the teratogenic effects produced by alcohol. We hypothesize that the administration of NAC will prevent alcohol-induced GSH depletion and prevent alcohol-induced teratogenesis.