Intestinal P450 and Xenobiotic Metabolism

肠道 P450 和异生物质代谢

• 批准号: 9127995
• 负责人: Qing-Yu Zhang
• 金额: $ 37.19万
• 依托单位: WADSWORTH CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9127995
• 关键词: Animal Model; Animals; Aryl Hydrocarbon Hydroxylases; Biological Availability; Biological Process; Cells; Colitis; Colon; Corticosterone; Cytochrome P450; Deoxycorticosterone; Digestive System Disorders; Disease; Enzymes; Experimental Animal Model; Exposure to; Female; Funding; Future; Genetic Polymorphism; Health; Homeostasis; Human; Hypersensitivity; In Vitro; Individual; Inflammation; Inflammatory Bowel Diseases; Inflammatory Response; Injury; Intestinal Mucosa; Intestines; Knockout Mice; Knowledge; Link; Mediating; Metabolic; Metabolism; Microsomes; Mitochondria; Mixed Function Oxygenases; Mus; Mutation; Oral; Outcome; Oxidoreductase; Parents; Pharmaceutical Preparations; Play; Predisposition; Production; Risk; Risk Factors; Role; Small Intestines; Sodium Dextran Sulfate; System; Testing; Tissue Extracts; Tissues; Toxic effect; Wild Type Mouse; Xenobiotic Metabolism; Xenobiotics; disorder risk; in vivo; intestinal epithelium; male; metabolomics; mouse model; new therapeutic target; novel; response; tissue culture

 DESCRIPTION (provided by applicant): The in vivo activities of microsomal cytochrome P450 (P450) enzymes in the intestine toward endogenous compounds are not well studied and their potential impact on normal intestinal function or disease risk is poorly understood. Many P450 enzymes are expressed in the intestine, where they potentially play important roles in maintaining homeostasis of endogenous compounds and influence the susceptibility to intestinal injury induced by drugs and other xenobiotics. Our broad, long-term objective is to determine the metabolic and biological functions of intestinal P450 enzymes and P450 reductase (CPR, required for activities of all microsomal P450s), particularly concerning their impact on disease risks, including susceptibility to adverse drug responses. Studies of the current funding cycle have provided clear evidence for a major role of intestinal P450 in controlling systemic bioavailability of a number of clinically important oral drugs and ingested xenobiotics, and in drug-induced intestinal toxicity. In preliminary studies on intestinal epithelium (IE)-specific Cpr null (IECN) mice, we discovered a role of intestinal CPR/P450 in modulating sensitivity of the colon toward dextran sulphate sodium (DSS)-induced colitis, a widely used animal model of human inflammatory bowel disease (IBD). These findings led to the current proposal, to identify the mechanistic link between intestinal CPR/P450 and inflammatory responses of the colon in an animal model of experimental colitis (Aim 1), and to explore more broadly the capacity of mouse and human intestinal CPR/P450 enzymes in the production or degradation of endogenous compounds in the intestine (Aim 2). In Aim 1, we will test the hypothesis that the hypersensitivity of the colon in IECN mice to DSS-induced colitis is mainly due to a loss of abilit of the IE cells to increase production of corticosterone (CC) in response to DSS-induced inflammation, and that a global decrease in CPR expression, as expected in human individuals with CPR deficiency, and as represented in a Cpr-low mouse model, also leads to decreases in intestinal CPR-dependent CC synthesis, and consequently increased vulnerability to experimental colitis. In Aim 2, we will use a unique metabolomics approach to search for additional endogenous compounds, potentially including novel metabolites, that are produced or degraded by intestinal microsomal CPR/P450, and whose tissue levels are impacted by the loss (or decrease) of IE CPR. We will also characterize the ability of human intestinal microsomes to catalyze the synthesis or degradation of the various identified endogenous compounds; the results are expected to provide valuable information concerning human relevance of the findings from our animal studies.

 描述（由适用提供）：肠道中微粒体细胞色素P450（P450）酶的体内活性对内源性化合物的研究没有很好地研究，并且对正常肠道功能或疾病风险的潜在影响也很差。许多P450酶在肠中表达，它们在维持内源性化合物的稳态方面起着重要作用，并影响药物和其他异生物元素引起的肠道损伤的易感性。我们广泛的长期目标是确定肠道p450酶和P450降低的代谢和生物学功能（CPR，所有微粒体P450的活动所必需的），尤其是涉及其对疾病风险的影响，包括对药物不良反应的敏感性。对当前资金周期的研究为肠道p450在控制许多临床上重要的口服药物和摄入的异种生物以及药物诱导的肠道毒性中的全身生物利用度方面提供了明确的证据。在肠上皮（IE）特异性CPR的初步研究中 NULL（IECN）小鼠，我们发现了肠道CPR/p450在调节硫酸葡萄糖硫酸钠（DSS）诱导的结肠炎的敏感性中的作用，这是一种广泛使用的人类炎症性肠病（IBD）的动物模型。这些发现导致了当前的提议，以确定在实验性结肠炎的动物模型中肠道CPR/P450与结肠炎症反应之间的机械联系（AIM 1），并更广泛地探索小鼠和人类肠道CPR/P450酶在内源性化合物中生产或去分解Intestine in Intestine（AIM 2）中的能力。在目标1中，我们将检验以下假设：IECN小鼠中结肠对DSS诱导的结肠炎的高敏性主要是由于IE细胞增加了IE细胞增加皮质酮（CC）的产生能力，响应DSS诱导的感染而响应DSS诱导的感染，以及在CPR中的全球性降低，以及在CPR中的预期，以及在CPR中，CPR降低了CPR Defients cpr to to n off to n offe to n of cpr to n of cpr to to n of cpr sige cpr to n of cpr septs a cpr-cpr a的CPR降低。在肠道CPR依赖的CC合成中，因此增加了对实验性结肠炎的脆弱性。在AIM 2中，我们将使用独特的代谢组学方法来寻找其他内源性化合物，包括新代谢物，这些化合物是由肠道微粒体CPR/p450产生或降解的，其组织水平受IE CPR的损失（或降低）的影响。我们还将表征人肠微粒体能够催化各种已鉴定的内源性化合物的合成或降解的能力。预计结果将提供有关我们动物研究发现的人类相关性的有价值的信息。