Genetic and Hormonal Regulation of Human CYP3A

人类 CYP3A 的遗传和激素调节

• 批准号: 6859367
• 负责人: Kenneth E. Thummel
• 金额: $ 31.04万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6859367
• 关键词: African American; catalyst; caucasian American; clearance rate; clinical research; cytochrome P450; drug metabolism; enzyme activity; enzyme substrate; gastrointestinal epithelium; gene expression; genetic polymorphism; genotype; hormone regulation /control mechanism; human subject; intestinal mucosa; laboratory rat; liver metabolism; pharmacokinetics; phenotype; racial /ethnic difference

DESCRIPTION (provided by applicant): The overall objective of this grant proposal is to identify the genetic and hormonal factors that define inter-individual differences in the expression of CYP3A in humans. We have directed our efforts to the study of CYP3A because of the central role that it has in the metabolic elimination of numerous drugs, including several with a narrow range of efficacious and nontoxic blood concentrations. We will test the hypothesis that "The steady-state level of CYP3A4 in the human small intestine is controlled primarily by 1,25-dihydroxy vitamin D3 signaling through the vitamin D receptor and the CYP3A4 PXR response element," with the following Specific Aims: Aim 1. Determine in healthy adults whether intestinal CYP3A4 phenotype co-varies with CYP24 phenotype, a reporter for intestinal VDR-mediated transcriptional activation. We will also determine whether variability in intestinal CYP3A4 content is regulated by intestinal VDR mRNA content and plasma 1,25-D3 level. Aim 2. Demonstrate that acute 1,25-D3 treatment increases intestinal CYP3A23 transcription in the rat, and that 1,25-D3 replacement therapy can induce CYP3A4 transcription activity in patients with end stage renal disease. We will also test the hypothesis that "Inheritance of an A6981G mutation within intron-3 of the CYP3A5 gene controls the expression of hepatic and intestinal CYP3A5, and influence the oral bioavailability of some CYP3A drug substrates" with the following Specific Aims: Aim 3. Characterize and compare the CYP3A4- and CYP3A5-dependent intrinsic metabolic clearance for 10 different drugs using a heterologous expression system and CYP3A-phenotyped human liver and intestinal microsomes. In addition, we will determine in healthy Caucasian and African-American adults whether the CYP3A5*1 genotype successfully predicts, on average, a higher midazolam clearances than that for subjects with the homozygous CYP3A5*3 genotype. We will also demonstrate that for African-Americans, there is a CYP3A5*1 gene-dose effect for the accumulation of properly spliced mRNA and CYP3A5 protein in duodenal biopsy tissue and for in vivo midazolam clearance. Aim 4. Determine whether variability in the in vivo oral clearance of cyclosporine is determined, in part, by the CYP3A5 genotype. If the proposed hypotheses are validated, it may become possible to develop simple genotyping and phenotyping tests for individualizing therapy with narrow therapeutic index drugs, such as cyclosporine.

描述(由申请者提供)：这项资助的总体目标 建议是确定基因和荷尔蒙因素决定 人类细胞色素P3A表达的个体间差异。我们有 将我们的精力放在了对CyP3A的研究上，因为它的核心作用是 在新陈代谢中消除了许多药物，包括几种具有 有效和无毒的血药浓度范围窄。我们将测试 “人体小肠内细胞色素P3A4的稳态水平”假说 主要受1，25-二羟基维生素D3信号控制 维生素D受体和CYP3A4 PXR反应元件“ 具体目标： 目的1.测定健康成人肠道细胞色素P3A4的表型 与肠道VDR介导的报告基因CYP24表型共同变化 转录激活。我们还将确定是否存在变异性 肠道细胞色素P3A4含量受肠道VDR mRNA含量和 血浆1，25-D3水平。 目的2.证明急性1，25-D3治疗增加肠道细胞色素P3A23 转录，以及1，25-D3替代疗法可以诱导 终末期肾病患者细胞色素P3A4转录活性的研究 我们还将测试这样的假设：“A6981G突变的遗传在 CYP3A5基因内含子-3调控肝脏和肠道的表达 并影响某些药物底物的口服生物利用度。 具体目标如下： 目的3.鉴定和比较细胞色素P3A4和细胞色素P3A5依赖的固有基因 异源表达对10种不同药物的代谢清除作用 系统和CYP3A表型的人肝脏和肠道微生物体。此外, 我们将在健康的高加索人和非裔美国人成年人中确定 平均而言，CYP3A5*1基因可以成功预测咪达唑仑的疗效 与携带纯合子CYP3A5*3的受试者相比，差异有统计学意义(P<0.05)。我们 也将证明对于非裔美国人来说，有一个CYP3A5*1基因剂量 正确剪接的mRNA和CYP3A5蛋白在细胞中积累的作用 十二指肠活检组织和咪达唑仑的体内清除。 目的4.确定阿司匹林体内口服清除量的变异性 环孢素部分由CYP3A5基因决定。 如果所提出的假设得到验证，就有可能开发出 应用简单的基因分型和表型试验进行药物个体化治疗 治疗指标药物，如环孢素。