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: 6482469
• 负责人: ALASTAIR J. J. WOOD
• 金额: $ 14.08万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6482469
• 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.

如果药物的吸收确定药物的口服生物利用度 从胃 - 肠道和首次代谢发生 在肠上皮和/或肝脏中。 经常 血浆浓度的个体间变异性明显 相关的临床反应经常由这些决定 因素。 已经对肝脏成分进行了广泛的研究 在这种效果中，但其他决定因素在很大程度上是未定义的。 为了 例如，CYP3A介导的新陈代谢在吸收过程中 与p-相关的该组织的肠上皮和外排 糖蛋白。 这样的过程以及肝脏中的代谢 可能会受到饮食相关因素和/或 肠道疾病。因此，研究将解决其中一些 在药物的临床使用中很重要的决定因素或可能 对癌症的化学预防意义 饮食和环境procarcinogens。 在后一种情况下， 尽管认为CYP1A，CYP2E1和CYP3A之类的酶激活 procarcinogen。 由于蔬菜的化学保护作用 反对癌症是公认的，可以假设确定 植物化学可以抑制这些酶。 这将通过 研究十字花科蔬菜和大蒜相关的能力 抑制体内探针代谢的产品 人类的单个CYP同工型。 随后，研究将是 扩展以检查代表性纯化学的影响 作为化学保护剂正在开发的成分 （Oltipraz，异硫氰酸苯乙烯，S-酰基半胱氨酸）。 效果 CYP2E1和CYP3A活动的饮食也将在 种族群体具有不同的处置特征 高加索人，尤其是日语和 与 “本地”饮食。 饮食盐影响的机制 某些CYP3A/P-糖蛋白的等离子体浓度谱图 在人类和动物模型中也将检查底物。 最后，肠道疾病的影响，例如乳糜泻和 药物口服生物利用度的热带浇口将是 确定，由于这种炎症性疾病与 肠结构和功能的重大干扰 上皮。