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: 6107500
• 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: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6107500
• 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（通过吸收确定） 来自胃肠道和首过代谢发生 在肠上皮和/或肝脏中。 经常 血浆浓度存在明显的个体差异 相关的临床反应通常由这些决定 因素。 对肝脏成分进行了广泛的研究 的影响，但其他决定因素很大程度上未定义。 为了 例如，CYP3A 介导的吸收过程中的代谢 肠上皮和从该组织流出的物质与 P-相关 糖蛋白。 这些过程以及肝脏中的代谢 可能受到饮食相关因素和/或的潜在调节 肠道疾病。因此，研究将解决其中一些问题 药物临床使用中重要的或可能的决定因素 对癌症的化学预防具有重要意义 饮食和环境致癌物。 在后一种情况下，它 虽然 CYP1A、CYP2E1 和 CYP3A 等酶会激活 致癌物。 由于蔬菜具有化学保护作用 抗癌作用已得到广泛认可，据推测，某些 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 抑制体内探针代谢的产品 人类个体 CYP 同工型。 随后，研究将 扩展到检查代表性纯化学物质的影响 正在开发作为化学保护剂的成分 （吡噻硫酮、异硫氰酸苯乙酯、S-烯丙基半胱氨酸）。 的效果 饮食中的 CYP2E1 和 CYP3A 活性也将在 具有不同性格特征的种族群体 项目 1 中确定的白种人。特别是日本人和 与墨西哥裔美国人相比，他们通常吃“西方”饮食 “本土”饮食。 膳食盐影响的机制 某些 CYP3A/P-糖蛋白的血浆浓度-时间曲线 还将在人类和动物模型中检查底物。 最后，肠道疾病（如乳糜泻）的影响 热带口炎性腹泻对药物口服生物利用度的影响 确定，因为此类炎症性疾病与 肠道结构和功能的严重紊乱 上皮。