Intestinal P450 and Xenobiotic Metabolism

肠道 P450 和异生物质代谢

• 批准号: 9632352
• 负责人: Qing-Yu Zhang
• 金额: $ 40.33万
• 依托单位: UNIVERSITY OF ARIZONA
• 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/9632352
• 关键词: Intestinal; P450; Xenobiotic; Metabolism

 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（由申请人提供）：肠道中微粒体细胞色素 P450 (P450) 酶对内源性化合物的体内活性尚未得到充分研究，并且对它们对正常肠道功能或疾病风险的潜在影响知之甚少。许多 P450 酶在肠道中表达。它们在维持内源性化合物的稳态方面发挥着重要作用，并影响对药物和其他外源性物质引起的肠道损伤的易感性。长期目标是确定肠道 P450 酶和 P450 还原酶（CPR，所有微粒体 P450 活性所需）的代谢和生物学功能，特别是它们对疾病风险的影响，包括对当前药物不良反应的敏感性的研究。资助周期提供了明确的证据，证明肠道 P450 在控制许多临床上重要的口服药物和摄入的异生物质的全身生物利用度以及药物引起的肠道毒性方面发挥着重要作用。肠上皮 (IE) 特异性 Cpr 的初步研究 null (IECN) 小鼠中，我们发现肠道 CPR/P450 在调节结肠对右旋糖酐硫酸钠 (DSS) 诱导的结肠炎（一种广泛使用的人类炎症性肠病 (IBD) 动物模型）的敏感性中发挥作用。目前的提议是，在实验性结肠炎动物模型中确定肠道 CPR/P450 与结肠炎症反应之间的机制联系（目标 1），并更广泛地探索小鼠和人类的能力肠道 CPR/P450 酶参与肠道内源性化合物的产生或降解（目标 2） 在目标 1 中，我们将检验 IECN 小鼠结肠对 DSS 诱导的结肠炎的过敏主要是由于缺失的假设。 IE 细胞响应 DSS 诱导的炎症而增加皮质酮 (CC) 产生的能力，并且 CPR 表达整体下降，正如在患有 CPR 的人类个体中所预期的那样缺陷，如 CPR 低小鼠模型所示，也会导致肠道 CPR 依赖性 CC 合成减少，从而增加患实验性结肠炎的可能性。在目标 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。 ，可能包括由肠道微粒体 CPR/P450 产生或降解的新代谢物，其组织水平受到 IE CPR 损失（或减少）的影响。我们还将表征人类肠道微粒体的能力。催化各种已识别的内源性化合物的合成或降解；预计结果将提供有关我们动物研究结果的人类相关性的有价值的信息。