RELATIONSHIP BETWEEN ALCOHOL TOXICITY AND GLUTATHIONE

母亲饮酒对胎儿的不良影响 几个世纪前就被认可了。 胎儿酒精综合征（FAS） 其特征在于产前和产后生长迟缓，智力迟钝， 行为缺陷和面部畸形 尽管许多动物 研究酒精产生作用的生化机制 对发育中的胎儿的影响尚不清楚。 脑功能障碍与谷胱甘肽（GSH）缺乏有关。 几项研究表明，给成年大鼠注射酒精 导致肝脏谷胱甘肽水平下降。 GSH已被证明 对药物毒性有保护作用。 硫醇化合物如半胱氨酸， 谷胱甘肽的前体，已被证明可以保护细胞免受 会消耗谷胱甘肽的药物 我们实验室的初步研究显示肝脏和大脑的GSH水平 在接受酒精的大鼠胎儿中， 怀孕 谷胱甘肽耗竭是由酒精剂量造成的， 生长迟缓 L-丁硫氨磺酰亚胺（BSO）的给药 在整个妊娠期对孕鼠进行了一次注射， 后代，也产生了产前生长迟缓。 初步 研究还表明，酒精诱导的GSH耗竭可以防止 当同时给予GSH前体N-乙酰-L-半胱氨酸（NAC）时， 用酒精 NAC治疗还消除了一些酒精诱导的 致畸作用 本提案中描述的实验将测试以下内容 假设：宫内暴露于酒精产生的致畸作用 由胎儿谷胱甘肽水平降低引起。 我们将探讨 此外，酒精、谷胱甘肽 消耗和致畸性。 我们将确定是否致畸 酒精的影响是由于，至少部分是由于谷胱甘肽水平降低， 胎儿 我们将确定降低母体和胎儿的GSH水平 与BSO将产生致畸作用的大鼠， 由酒精产生。 我们还将确定BSO是否会加强 酒精致畸 我们建议， 酒精和BSO的管理将产生致畸作用， 与单独给予酒精相比，酒精剂量较低的后代。 它 将确定南汽是否会采取保护行动并减少 酒精产生的致畸作用。 我们假设 给予NAC将防止酒精诱导的GSH耗竭， 防止酒精引起的致畸作用。

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 been 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 and 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.