EFFECT OF ALCOHOL ON HORMONE RESPONSIVE LIVER FUNCTION

酒精对激素反应性肝功能的影响

• 批准号: 3113015
• 负责人: PATRICIA K EAGON
• 金额: $ 9.35万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-04-01 至 1994-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3113015
• 关键词: affinity chromatography; alcoholic beverage consumption; alcoholism /alcohol abuse; androgen receptor; antibody; enzyme linked immunosorbent assay; estrogen receptors; gel filtration chromatography; hormone binding protein; hormone regulation /control mechanism; immunological substance; laboratory mouse; laboratory rabbit; laboratory rat; liver cells; liver function; male; monoclonal antibody; protein purification; radioimmunoassay; sex hormones; tissue /cell culture

Chronic alcoholic men often exhibit a spectrum of sexual dysfunction. These men are frequently hypogonadal and generally have low serum testosterone levels. Since sex hormones exert their influence at the cellular level by interactions with their highly specific hormone receptors, it is predictable that chronic alcohol exposure would alter androgen receptor status and thus the response of the cell to androgens. In a rat model, male rats fed alcohol demonstrate altered responses to androgens. As in human males, these animals have a significant reduction in serum testosterone, demonstrate reduced hepatic androgen receptor levels, and show a parallel reduction in activities of two hepatic androgen-responsive proteins. The research outlined in this proposal addresses the mechanisms for alcohol-induced alterations in sex steroid function by studying the regulation of one of these hepatic androgen-responsive proteins in detail. The protein to be studied is an unusual cytosolic male- and liver-specific protein which has estrogen binding activity (MEB).This MEB protein is the focus of our studies in a rat model of chronic alcohol feeding because: (1) it represents an excellent marker for androgen effects on the liver; (2) the activity of this protein is significantly reduced (50-70%) in the setting of chronic alcohol ingestion; (3) its estrogen binding activity suggests that it may play a role in estrogen homeostasis in the male; and (4) its reduction in alcohol-fed animals is concomitant with a rise in serum estradiol and an increase in the activity of an estrogen-responsive hepatic protein. To better study the role of MEB, we will purify this protein and generate antibodies to it. These antibodies will be used to elucidate the role of this protein, and its regulation in livers of normal and alcohol-fed male rats. Other later experiments will be performed to define the temporal relationship and the reversibility of alcohol-induced changes. The results of this research will provide a basis for understanding the mechanisms responsible for alterations in sex steroid function in the setting of chronic alcohol exposure. By use of such a rat model, we can identify factors which are essential for the regulation of androgen-responsive liver function, and thus may provide a basis for future studies in humans.

慢性酒鬼男性经常表现出多种性功能障碍。 这些男人经常是性质的，通常有低血清 睾丸激素水平。 由于性激素在 通过与高度特异性激素相互作用的细胞水平 受体，可以预见的是，慢性酒精暴露会改变 雄激素受体状态，因此细胞对雄激素的反应。 在大鼠模型中，喂酒精的雄性大鼠表现出对 雄激素。 就像在人类男性中一样，这些动物显着减少 在血清睾丸激素中，证明肝雄激素受体降低 水平，并显示两种肝的活动平行减少 雄激素反应性蛋白。 该提案中概述的研究 解决了酒精引起的性类固醇改变的机制 通过研究这些肝之一的调节来起作用 详细的雄激素反应性蛋白。 要研究的蛋白质是 具有雌激素的异常胞质雄性和肝特异性蛋白 结合活性（MEB）。该MEB蛋白是我们研究的重点 慢性酒精喂养的大鼠模型是因为：（1）它代表 雄激素对肝脏影响的出色标志； （2）活动 在慢性的情况下，该蛋白质大大降低（50-70％） 饮酒； （3）其雌激素结合活性表明它可能 在男性中发挥雌激素稳态的作用； （4）减少 酒精喂养的动物伴随着血清雌二醇和 雌激素反应性肝蛋白的活性增加。 为了更好地研究MEB的作用，我们将净化该蛋白质和 生成抗体。 这些抗体将用于阐明 该蛋白质的作用及其在正常肝脏中的调节 酒精喂养的雄性大鼠。 其他以后的实验将进行 定义时间关系和酒精引起的可逆性 更改。 这项研究的结果将为 了解负责性类固醇改变的机制 在慢性酒精暴露的情况下起作用。 通过使用这样的 大鼠模型，我们可以确定对监管至关重要的因素 雄激素反应性肝功能，因此可以为 未来在人类的研究。