CYTOCHROME P450 MEDIATED METABOLISM, DIET, AND THE GASTROINTESTINAL TRACT

细胞色素 P450 介导的代谢、饮食和胃肠道

• 批准号: 6325864
• 负责人: ALASTAIR J. J. WOOD
• 金额: $ 26.76万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6325864
• 关键词: Cruciferae; Japanese American; Mexican Americans; P glycoprotein; caffeine; celiac disease; chemoprevention; clinical research; cytochrome P450; diet; dietary sodium; drug metabolism; enzyme activity; gas chromatography; gastrointestinal drug absorption; high performance liquid chromatography; human subject; immunocytochemistry; laboratory rat; liver metabolism; nutrition related tag; oltipraz; pharmacogenetics; pharmacokinetics; racial /ethnic difference; tropical sprue

The oral bioavailability of drugs if determined by their absorption from the gastro-intestinal tract and first-pass metabolism occurring in either the intestinal epithelium and/or the liver. The often marked interindividual variability in plasma concentrations and associated clinical response is frequently determined by these factors. Extensive study has been made of the hepatic component of this effect, but other determinants are largely undefined. For example, CYP3A-mediated metabolism during absorption by the intestinal epithelium and efflux from this tissue associated with P- glycoprotein. Such processes as well as metabolism in the liver may be potentially modulated by dietary-related factors and/or intestinal disease. Accordingly, studies will address some of these determinants that are important in the clinical use of drugs or may be significant in the chemoprevention of cancer resulting from dietary and environmental procarcinogens. In the latter instance, it is though that enzymes like CYP1A, CYP2E1 and CYP3A activate the procarcinogen. Since the chemoprotective effect of vegetables against cancer is well-recognized, it is hypothesized that certain phytochemical may inhibit these enzymes. This will be tested by investigating the ability of cruciferous vegetables and garlic-related products to inhibit the metabolism of in vivo probes of the individual CYP isoforms in humans. Subsequently, studies will be extended to examine the effects of representative pure chemical constituents that are under development as chemoprotective agents (oltipraz, phenethyl isothiocyanate, S-allyl cysteine). The effect of diet of CYP2E1 and CYP3A activities will also be examined in racial groups with different disposition characteristics from Caucasians, as identified in Project 1. In particular, Japanese and Mexican-Americans that routinely eat a "western" diet compared to "native" diet. The mechanism(s) whereby dietary salt affects the plasma concentration-time profile of certain CYP3A/P-glycoprotein substrates will also be examined in both humans and animal models. Finally, the effect of intestinal disease such as celiac disease and tropical sprue on the oral bioavailability of drugs will be determined, since such inflammatory diseases are associated with major disturbances in the structure and functioning of the intestinal epithelium.

药物的口服生物利用度取决于其吸收情况 来自胃肠道和首过代谢的发生 在肠道上皮和/或肝脏中。《常客》 血浆浓度和血浆浓度的显著个体间变异 相关的临床反应通常由这些因素决定 各种因素。已经对肝脏成分进行了广泛的研究 这种影响，但其他决定因素在很大程度上是未知的。为 例如，细胞色素P3A介导的代谢过程中的吸收 肠上皮和肠组织的流出与P- 糖蛋白。这种过程以及肝脏中的新陈代谢 可能潜在地受饮食相关因素和/或 肠道疾病。因此，研究将解决其中的一些问题 在临床用药中很重要的决定因素，或者可能 在化学预防由以下原因引起的癌症方面具有重要意义 饮食和环境致癌物质。在后一种情况下，它 是通过像CYP1A、CYP2E1和CYP3A这样的酶来激活 致癌原。由于蔬菜的化学保护作用 抗癌是公认的，假设一定 植物化学物质可能会抑制这些酶。这将通过以下方式进行测试 调查十字花科蔬菜与大蒜相关的能力 抑制体内探针新陈代谢的产品 人类中的单个CYP亚型。随后，将进行研究 扩展到考察具有代表性的纯化学物质的影响 正在开发中的化学保护剂的成分 (奥替拉兹、异硫氰酸苯乙酯、S-烯丙基半胱氨酸)。的影响 此外，还将研究饮食中的细胞色素P450 2和细胞色素P3 A活性。 具有不同性格特征的种族群体 项目1中确定的高加索人。特别是日本人和 墨西哥裔美国人经常吃“西式”饮食 “原生”饮食。食盐影响人体健康的机制(S) 某些CYP3A/P-糖蛋白的血药浓度-时间曲线 底物也将在人类和动物模型中进行检查。 最后，乳糜泻等肠道疾病的影响 热带主流道上的口服生物利用度药物将 确定，因为这种炎症性疾病与 肠道结构和功能的主要障碍 上皮组织。