ENDOGENOUS REGULATORS OF DRUG METABOLISM

药物代谢的内源性调节因子

• 批准号: 2183380
• 负责人: BERNARD Harris SHAPIRO
• 金额: $ 25.99万
• 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/2183380
• 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.

肝脏药物代谢酶的水平受到以下因素的影响： 营养、环境、遗传和激素因素。的情况下 动物的性别会对老鼠的行为产生深远的影响 肝单加氧酶，因为雄性大鼠代谢药物的速率为3- 比雌鼠快5倍。虽然早期的研究表明， 睾丸雄激素是负责诱导 肝酶活性增加，最近的证据表明， 已经表明，这是生长激素（GH）分泌的模式， 由雄激素调节，控制大鼠的性二型 肝单加氧酶使用选择性GH缺乏大鼠， 各种循环模式的大鼠生长激素，我们建议，以确定 超日生长激素谱中的“信号传导”元件调节， 和/或后验地，不同形式的 P450。此外，我们计划确定其他可能的激素因素， 并确定它们如何与GH沿着调节 肝脏形式的P450，以及调节外源性 诱导剂。在细胞水平上，我们建议调查如何生长激素 受体是GH作用的转换器， 在两性异形体中不同的信号元件之间 循环GH的特征。 肝脏单加氧酶和血浆生长激素的性别差异 大鼠中的特征是独特的，并不代表所发现的特征。 在其他物种。正是出于这个原因，我们也选择了 研究老鼠体内激素调节剂的作用。越少 小鼠药物代谢和血浆GH存在明显的性别差异 节奏更能代表其他物种，包括人类。 此外，刺激药物代谢的GH注射方案， 大鼠抑制了小鼠的表达，反之亦然。因此，机制 调节鼠P450表达可能具有更普遍的 应用，包括人类健康益处（即，控制药物 毒性）比在大鼠中发现的。尽管我们对它的了解 小鼠肝脏的P450组成高于大鼠肝脏，两者均为动物模型 可以提供重要的信息。从老鼠的研究中，我们可以了解到， 分子水平，激素的分泌模式如何调节 P450特定形式的表达和抑制。虽然 虽然不那么确定，但小鼠研究至少可以建立一种替代方法， 激素调节肝细胞表达的机制 单加氧酶;一种可能更具有人类特征的机制 条件