ENDOGENOUS REGULATORS OF DRUG METABOLISM

药物代谢的内源性调节因子

• 批准号: 3305188
• 负责人: BERNARD Harris SHAPIRO
• 金额: $ 27.66万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-02-01 至 1996-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3305188
• 关键词: albino mouse; androgens; biological signal transduction; cytochrome P450; drug metabolism; enzyme induction /repression; gender difference; hormone receptor; hormone regulation /control mechanism; isozymes; laboratory rat; liver cells; liver metabolism; oxygenases; posttranslational modifications; somatotropin; species difference

The levels of hepatic drug metabolizing enzymes are affected by nutritional, environmental, genetic and hormonal factors. In the case of the rat, the animal's sex can have a profound effect on the activities of hepatic monooxygenases, as male rats metabolize drugs at a rate 3 to 5 times faster than female rats. While early studies revealed that testicular androgens were the endogenous agents responsible for inducing the increased activities of the hepatic enzymes, more recent evidence has shown that it is the pattern of growth hormone (GH) secretion, regulated by androgens, that controls the sexual dimorphisms in rat hepatic monooxygenases. Using selective GH deficient rats infused with various circulating patterns of rat GH, we propose to identify the "signalling" elements in the ultradian GH profile that regulate, pre- and/or posttranslationally, the expression of the different forms of P450. In addition, we plan to identify other possible hormonal factors, and determine how they, along with GH, regulate the expression of hepatic forms of P450, as well as modulate the effects of exogenous inducers. At the cellular level, we propose to investigate how the GH receptor, the transducer of GH action, recognizes and discriminates between the different signalling elements in the sexually dimorphic profiles of circulating GH. The exaggerated sex differences in hepatic monooxygenases an plasma GH profiles in the rat are unique, and not representative of what is found in other species. It is for this reason that we have also chosen to examine the effects of hormonal regulators in the mouse. The much less pronounced sex differences in murine drug metabolism and plasma GH rhythms are more representative of other species, including humans. Moreover, the injected regimen of GH that stimulates drug metabolism in the rat, suppresses it in the mouse, and vice versa. Thus, mechanisms that regulate expression of murine P450s may have more universal application, including human health benefits (i.e., controlling drug toxicities) than that found in rats. Although much less is known about the P450-composition of mouse liver than rat liver, both animal models can produce important information. From rat studies, we can learn, at a molecular level, how the secretory pattern of a hormone can regulate both the expression and repression of specific forms of P450. Although less definitive, the mouse studies may at least establish an alternative mechanism by which hormones regulate the expression of hepatic monooxygenases; a mechanism that nay be more characteristic of the human condition.

肝脏药物代谢酶水平受以下因素的影响 营养、环境、遗传和荷尔蒙因素。在.的情况下 老鼠，动物的性别可以对活动产生深远的影响 当雄性大鼠以3：1的速率代谢药物时，肝脏单加氧酶的活性 比雌性老鼠快5倍。虽然早期的研究表明 睾丸雄激素是内源性诱导剂 肝酶活性的增加，更新的证据 已经证明这是生长激素(GH)的分泌模式， 受雄激素调节，控制大鼠性二型性 肝单加氧酶。用选择性GH缺陷大鼠输注 大鼠生长激素的不同循环模式，我们建议确定 在超常生长激素配置文件中调节、预- 和/或翻译后，不同形式的 P450。此外，我们计划确定其他可能的荷尔蒙因素， 并确定它们如何与生长激素一起调节 肝脏P450的形态，以及外源性的调节作用 诱导者。在细胞水平上，我们建议研究生长激素是如何 受体，生长激素作用的转导，识别和区分 在不同的信号元素之间的性二型性 循环生长激素的分布情况。 肝单加氧酶和血浆生长激素的性别差异被夸大 老鼠的轮廓是独一无二的，不能代表所发现的东西 在其他物种中。正是出于这个原因，我们也选择了 检查荷尔蒙调节剂对小鼠的影响。少得多 小鼠药物代谢和血浆生长激素的性别差异 节奏更能代表其他物种，包括人类。 此外，促进药物代谢的生长激素注射方案 老鼠在老鼠体内抑制它，反之亦然。因此，机制 调节小鼠P450蛋白的表达可能具有更普遍的意义 应用，包括对人类健康的益处(即管制药物 毒性)而不是在老鼠身上发现的。尽管人们对此知之甚少 小鼠肝脏的P450-组成比大鼠肝脏，两种动物模型 可以产生重要的信息。从老鼠的研究中，我们可以了解到，在 分子水平，荷尔蒙的分泌模式如何调节 特定形式的P450的表达和抑制。虽然 不那么明确的是，对老鼠的研究至少可以建立一种替代方案 激素调节肝脏组织细胞因子表达的机制 单加氧酶；一种更具人类特征的机制 条件。