ALCOHOL LIVER DISEASE AND S ADENOSYLMETHIONINE

酒精性肝病与腺苷甲硫氨酸

• 批准号: 2667590
• 负责人: CRAIG J. MCCLAIN
• 金额: $ 17.25万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-03-01 至 2000-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2667590
• 关键词: AIDS therapy; HIV infections; S adenosylmethionine; alcoholic hepatitis; choline deficiency; clinical research; clinical trials; diet therapy; dietary supplements; hepatotoxin; human subject; human therapy evaluation; hypoxia; intravenous administration; laboratory rat; liver disorder chemotherapy; malnutrition; nutrition related tag; protein deficiency; tumor necrosis factor alpha

Chronic ethanol abuse is a serious public health problem which has a significant role in the development of liver injury as well as in enhanced susceptibility to HIV and development of AIDS. However, biochemical mechanisms to explain the role of ethanol in the pathophysiology of hepatic injury or AIDS are not completely understood. Increasing evidence suggests that a systemic deficiency of S-adenosylmethionine (Adomet) has a pivotal role in the pathogenesis of both diseases. This proposal will examine this role of Adomet deficiency and will evaluate exogenous Adomet as a therapy in these diseases. Systemic Adomet deficiency was first identified by us as an acquired metabolic disorder in alcoholic subjects. Similar observations were made in animals administered ethanol rich diets. Adomet deficiency results in depletion of the intracellular antioxidant tripeptide glutathione and patients with alcoholic liver disease and AIDS have subnormal plasma glutathione. We postulate that deficiencies of Adomet and glutathione increase intracellular oxidative stress and activate the redox-sensitive transcription factor NFkappaB which increases production of the inflammatory cytokine tumor necrosis factor alpha(TNF). TNF has been postulated to play a role in the development of alcoholic liver disease, the progression of AIDS, and the clinical complications of both processes. Adomet deficiency also alters membrane fluidity and integrity. Further, we propose that exogenous Adomet attenuates glutathione depletion, oxidative stress, NFkappaB, TNF production, and membrane integrity and fluidity. These objectives will be tested by the following specific objectives: (1) Determine changes in hepatic Adomet concentrations and Adomet synthetase activity in animals administered ethanol rich Tsukamoto-French diet and examine whether exogenous Adomet attenuates this liver injury. (2) Determine whether Adomet deficiency produced in three animal models developed in our laboratory - viz., choline deficient, malnourished, or hypoxic - enhances lipopolysaccharide hepatotoxicity and determine whether Adomet supplementation attenuates this injury. (3) Determine whether Adomet administration improves hepatic functions and attenuates cytokine production and immunocompetence in patients with Adomet deficiency. (4) Examine the mechanisms by which Adomet deficiency may increase TNF production and sensitize cells to TNF cytotoxicity. Our long-term goal is to evaluate the effectiveness of Adomet therapy especially since Adomet may not only act as a glutathione precursor but also improve its mitochondrial transport by normalizing membrane functions.

慢性乙醇滥用是一个严重的公共卫生问题 在肝损伤的发展以及增强中的重要作用 对艾滋病毒的敏感性和艾滋病的发展。 但是，生化 解释乙醇在病理生理学中的作用的机制 肝损伤或艾滋病尚不完全理解。 越来越多的证据 表明S-腺苷甲硫氨酸（ADOMET）的全身性缺陷已有 两种疾病的发病机理中的关键作用。 该提议将 检查ADOMET缺乏的这种作用，并将评估外源地位 作为这些疾病的疗法。 系统性的ADOMET缺乏首先 我们被我们确定为酒精受试者中获得的代谢障碍。 在富含乙醇饮食的动物中也有类似的观察结果。 ADOMET缺乏导致细胞内抗氧化剂的耗竭 三肽谷胱甘肽和酒精性肝病和艾滋病患者 具有亚正常血浆谷胱甘肽。 我们假设缺乏 Adomet和谷胱甘肽会增加细胞内氧化应激和 激活氧化还原敏感的转录因子NFKAPPAB，该因子增加 炎性细胞因子肿瘤坏死因子α（TNF）的产生。 TNF已被认为在酒精的发展中发挥作用 肝病，艾滋病的进展和临床并发症 这两个过程。 ADOMET缺乏还会改变膜的流动性和 正直。 此外，我们提出了外源的admote衰减 谷胱甘肽耗竭，氧化应激，NFKAPPAB，TNF产生和 膜完整性和流动性。 这些目标将通过 以下特定目标：（1）确定肝脏Adomet的变化 施用动物的浓度和ADOMET合成酶活性 富含乙醇的Tsukamoto-french饮食并检查外源地位是否是否 减轻了这种肝损伤。 （2）确定是否缺乏 在我们的实验室中开发的三种动物模型中生产的，即 胆碱缺乏，营养不良或低氧 - 增强脂多糖 肝毒性并确定补充剂是否减弱 这种伤害。 （3）确定ADOMET管理是否改善了肝 功能并减轻细胞因子的产生和免疫能力 患有ADOMET缺乏症的患者。 （4）检查的机制 ADOMET缺乏可能会增加TNF的产生并使细胞对TNF敏感 细胞毒性。 我们的长期目标是评估 ADOMET疗法尤其是因为Adomet不仅可以充当谷胱甘肽 前体，但也通过标准化来改善其线粒体传输 膜功能。