The Role of CAR and PXR in Gender Predominant P450 Expression and Induction

CAR 和 PXR 在性别优势 P450 表达和诱导中的作用

• 批准号: 8072528
• 负责人: William S Baldwin
• 金额: $ 1.5万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-21 至 2010-08-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8072528
• 关键词: Agonist; CYP3A4 gene; Chemicals; Complementary DNA; Cytochrome P450; Cytochromes; Data; Dexamethasone; Drug Metabolic Detoxication; Enzymes; Europe; Exposure to; Family; Family member; Female; Gender; Goals; Half-Life; Health; Hepatic; Hepatocyte; Human; In Vitro; Individual; Knockout Mice; Laboratories; Life; Liver; Mediating; Metabolism; Modeling; Mus; Nuclear Receptors; Occupations; Paralysed; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phenobarbital; Play; Protein Isoforms; Proteins; RXRA gene; Rattus; Reaction; Regulation; Research; Role; SXR receptor; Sex Characteristics; Testing; United States; Xenobiotics; Zoxazolamine; base; constitutive androstane receptor; drug maintenance; in vivo; killings; male; member; nonylphenol; pregnane X receptor; public health relevance; sex; toxicant; toxicant interaction

DESCRIPTION (provided by applicant): My laboratory investigates the role of the nuclear receptors, CAR and PXR, in the regulation and induction of the sex-specific and sex-predominant drug-metabolizing P450s. Adverse drug reactions kill approximately 100,000 people each year, and induction of the drug metabolizing enzymes such as the P450s cause a number of these adverse drug reactions. Identification of the chemicals that induce P450s may help us predict potential adverse drug reactions, determine susceptible groups based on sex or occupation, and ultimately save lives. Nonylphenol (NP) is one of the most commonly found toxicants in the United States and Europe, and is considered a toxicant of concern because of its long half-life. Our data demonstrates that NP activates mouse and human CAR in vitro and in vivo, and in turn induces P450s involved in chemical detoxification. Preliminary data indicates that NP also activates rat, mouse, and human pregnane X-receptor (PXR) in vitro, but we have not examined the relevance of this interaction in vivo. Therefore, we will test whether NP activates PXR and induces P450s in vivo using wild-type, PXR-null, and humanized PXR (hPXR) mice. Humanized mice containing the human nuclear receptor in the place of the mouse nuclear receptor are essential in determining the significance of our observations to human health. In addition, we will determine CAR and PXR's role in maintaining gender differences, and inducing gender specific and gender predominant P450s in mice. Many of the xenobiotic-metabolizing P450s in the CYP2 and 3 families are gender predominant. We will (1) test whether CAR and PXR in part regulate or help maintain gender differences in P450 expression of several isoforms of the CYP2 and 3 families. We will (2) examine whether the toxicant NP, the CAR agonist TCPOBOP, and the PXR agonist Dexamethasone induce these P450 isoforms in a gender specific or gender predominant fashion in wild-type, CAR-null, and PXR-null mice. Furthermore, we will (3) test whether the gender predominant effects observed are pharmacologically relevant using zoxazolamine clearance and paralysis as a model for drug-toxicant interactions. Lastly, in order to determine the relevance of our in vivo observations to human health we will (4) determine if NP and other CAR/PXR activators such as dexamethasone and phenobarbital induce CYPs in a gender predominant fashion in primary human hepatocytes. We hypothesize that CAR and PXR play roles in the maintenance of the drug-metabolizing P450s and their gender predominance. Furthermore, we hypothesize that some of these P450s are induced in a gender predominant fashion by CAR and PXR agonists, which may cause pharmacologically relevant gender predominant effects. PUBLIC HEALTH RELEVANCE: The purpose of this project is to further characterize the nuclear receptors CAR and PXR, as well as determine if they are involved in gender differences in P450 expression and adverse drug reactions.

描述（由申请人提供）：我的实验室研究了核受体CAR和PXR在调节和诱导性别特异性和性别主导的药物代谢P450中的作用。药物不良反应每年导致大约10万人死亡，药物代谢酶如P450的诱导导致许多这些药物不良反应。识别诱导P450的化学物质可以帮助我们预测潜在的药物不良反应，根据性别或职业确定易感人群，并最终挽救生命。壬基酚（NP）是美国和欧洲最常见的有毒物质之一，由于其半衰期长而被认为是一种令人关注的有毒物质。我们的数据表明，NP在体外和体内激活小鼠和人CAR，进而诱导参与化学解毒的P450。初步数据表明，NP也激活大鼠，小鼠和人的X-receptor（PXR）在体外，但我们还没有检查这种相互作用在体内的相关性。因此，我们将使用野生型、PXR缺失和人源化PXR（hPXR）小鼠测试NP是否激活PXR并在体内诱导P450。含有人核受体代替小鼠核受体的人源化小鼠对于确定我们的观察对人类健康的意义至关重要。此外，我们还将确定CAR和PXR在维持小鼠性别差异和诱导性别特异性和性别主导的P450中的作用。CYP 2和3家族中的许多异源代谢P450是性别主导的。我们将（1）测试CAR和PXR是否部分调节或帮助维持CYP 2和3家族几种亚型P450表达的性别差异。我们将（2）检查毒物NP、CAR激动剂TCPOBOP和PXR激动剂地塞米松是否以性别特异性或性别主导的方式在野生型、CAR缺失和PXR缺失小鼠中诱导这些P450亚型。此外，我们将（3）使用唑唑胺清除率和麻痹作为药物-毒物相互作用的模型，检验观察到的性别主导效应是否具有性别相关性。最后，为了确定我们的体内观察结果与人类健康的相关性，我们将（4）确定NP和其他CAR/PXR激活剂（如地塞米松和苯巴比妥）是否以性别主导的方式在原代人肝细胞中诱导CYP。我们假设CAR和PXR在维持药物代谢P450及其性别优势方面发挥作用。此外，我们假设这些P450中的一些是由CAR和PXR激动剂以性别主导的方式诱导的，这可能导致与性别相关的性别主导效应。公共卫生关系：该项目的目的是进一步表征核受体CAR和PXR，并确定它们是否参与P450表达和药物不良反应的性别差异。