Genetic and Hormonal Regulation of Human CYP3A

人类 CYP3A 的遗传和激素调节

• 批准号: 6710639
• 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 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6710639
• 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（由申请人提供）：本基金的总体目标