Hormonal regulation of human CYP3A

人类 CYP3A 的激素调节

• 批准号: 7867175
• 负责人: Kenneth E. Thummel
• 金额: $ 30.71万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-16 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7867175
• 关键词: 6' ,7' -dihydroxybergamottin; Acute; Adverse drug effect; Adverse effects; Affect; Age; Agonist; Applications Grants; Archives; Biological Availability; Biopsy; Blood; Bystander Effect; CYP3A4 gene; CYP3A5 gene; Calcium; Carbamazepine; Carrier Proteins; Catabolism; Cells; Cholecalciferol; Chronic; Consumption; Data; Diagnostic; Disease; Dose; Drug Industry; Drug usage; Endoscopy; Enterocytes; Environment; Enzyme Induction; Enzymes; Epithelium; Exposure to; Failure; Feedback; Fracture; Gastrointestinal Endoscopy; Gene Activation; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Transcription; Genetic Variation; Genomics; Grapefruit juice; Homeostasis; Hormones; Human; Individual; Individual Differences; Intestines; Lead; Liver; Maintenance; Mediating; Messenger RNA; Metabolic; Metabolism; Midazolam; Minerals; Molecular; Oral; Oral Administration; Osteocalcin; Osteomalacia; Osteoporosis; Parathyroid Hormones; Parents; Pathology; Patients; Pharmaceutical Preparations; Phenytoin; Physiological; Placebos; Prevention; Production; Progress Reports; Proteins; RNA; Receptor Gene; Regulatory Pathway; Response Elements; Rifampin; Risk; Safety; Sampling; Small Intestines; Study Subject; Syndrome; Testing; Therapeutic; Toxic effect; Transcript; Transcriptional Activation; Vitamin D; Vitamin D3 Receptor; Woman; base; bone; bone health; calbindin; calcium absorption; dihydroxy-vitamin D3; drug candidate; drug clearance; drug metabolism; healthy volunteer; hormone regulation; human PTH protein; ileum; improved; in vivo; indexing; inhibitor/antagonist; prevent; public health relevance; response; suicide inhibitor; uptake; volunteer

DESCRIPTION (provided by applicant): Inter-individual differences in the expression and activity of CYP3A4 in the mucosal epithelium of the small intestine contribute to a low and variable oral bioavailability that is observed for many drugs that are CYP3A substrates. This high degree of variability appears to be the result of large inter-individual differences in the specific content of CYP3A4 and CYP3A5 in human duodenal enterocytes. From a therapeutic perspective, large inter-patient differences in first-pass intestinal extraction efficiency can lead to differences in systemic exposure to the parent drug and its metabolites and pharmacological effects following oral administration of doses that are appropriate for the }average} patient, increasing the risk of therapeutic failure and adverse toxicity. The cause of variable intestinal CYP3A expression is largely unknown, but thought to involve both genetic and environmental/physiological factors. For example, we have shown previously that the most biologically active form of vitamin D, 1,25-(OH)2-vitamin D3, enhances transcription of the major drug metabolizing enzyme CYP3A4 in a VDR-dependent manner, and that CYP3A4 in turn can catalyze the metabolic clearance of 1,25- (OH)2-D3. The overall objectives of this grant proposal are to determine whether 1,25-(OH)2-D3 regulates the expression of CYP3A4 in the human small intestine in vivo, and whether the administration of drugs that affect CYP3A4 function through enzyme induction or inhibition alter the synthesis and function of intestinal calcium transport proteins through changes in 1,25-(OH)2-D3 disposition within the mucosal enterocyte. Specifically, we will test the hypothesis that 1,25-(OH)2-D3 enhances intestinal CYP3A4 expression and function by assessing the effects of oral 1,25-(OH)2-D3 administration on duodenal gene targets of the activated vitamin D receptor and CYP3A-dependent drug clearance. We will also test whether activation of CYP3A4 transcription provides auto-feedback control of VDR-mediated genomic effects by assessing the effects of CYP3A4 inhibitors and inducers on the responsiveness of human enterocytes to 1,25-(OH)2-D3. Finally, we will test whether activation of hPXR by known agonists enhances CYP3A4-dependent intestinal 1,25-(OH)2-D3 metabolism, resulting in a decrease in the transcription of intestinal VDR gene targets and a change in systemic indices of calcium homeostasis. Elucidating the molecular basis of inter-individual differences in CYP3A-dependent drug metabolism could enhance the ability of the drug industry to develop safe and efficacious drugs through a clearer understanding of how other medications, the environment, and disease states might impinge on the disposition of new drug candidates that are intestinal CYP3A substrates. In addition, if our hypothesis about the participation of CYP3A4 in negative feedback control of 1,25-(OH)2-D3 genomic effects within enterocytes of the small intestine proves to be correct, it could point to relatively simple ways (e.g., moderate daily grapefruit juice consumption) to prevent the adverse effects of potent hPXR agonists on bone health in }at-risk} patients. PROJECT NARRATIVE Completion of the specific aims proposed in this grant application should improve our understanding of the molecular basis for inter-individual differences in CYP3A4-dependent drug metabolism and potentially enhance the safety and efficacy of existing and new drugs used to treat disease. Moreover, it may provide a scientific basis for the effective prevention of some adverse drug effects that lead to osteoporosis. Public Health Relevance: Completion of the specific aims proposed in this grant application should improve our understanding of the molecular basis for inter-individual differences in CYP3A4-dependent drug metabolism and potentially enhance the safety and efficacy of existing and new drugs used to treat disease. Moreover, it may provide a scientific basis for the effective prevention of some adverse drug effects that lead to osteoporosis.

性状（由申请方提供）：小肠粘膜上皮细胞中CYP 3A 4表达和活性的个体间差异导致口服生物利用度低且可变，这在许多作为CYP 3A底物的药物中观察到。这种高度变异性似乎是人十二指肠上皮细胞中CYP 3A 4和CYP 3A 5的具体含量存在较大个体间差异的结果。从治疗的角度来看，首过肠道提取效率的患者间差异较大可能导致口服适合于}平均}患者的剂量后母体药物及其代谢物的全身暴露和药理学作用的差异，从而增加治疗失败和不良毒性的风险。可变的肠道CYP 3A表达的原因在很大程度上是未知的，但认为涉及遗传和环境/生理因素。例如，我们之前已经证明，维生素D的最具生物活性的形式，1，25-（OH）2-维生素D3，以VDR依赖性方式增强主要药物代谢酶CYP 3A 4的转录，并且CYP 3A 4反过来可以催化1，25-（OH）2-D3的代谢清除。本资助提案的总体目标是确定1，25-（OH）2-D3是否在体内调节人小肠中CYP 3A 4的表达，以及通过酶诱导或抑制影响CYP 3A 4功能的药物给药是否通过改变粘膜肠上皮细胞内1，25-（OH）2-D3的分布来改变肠钙转运蛋白的合成和功能。具体而言，我们将通过评估口服1，25-（OH）2-D3对激活的维生素D受体的十二指肠基因靶点和CYP 3A依赖性药物清除率的影响来检验1，25-（OH）2-D3增强肠道CYP 3A 4表达和功能的假设。我们还将通过评估CYP 3A 4抑制剂和诱导剂对人肠上皮细胞对1，25-（OH）2-D3的反应性的影响，检测CYP 3A 4转录的激活是否提供VDR介导的基因组效应的自反馈控制。最后，我们将测试已知激动剂对hPXR的激活是否会增强CYP 3A 4依赖性肠道1，25-（OH）2-D3代谢，导致肠道VDR基因靶点转录减少和钙稳态全身指数变化。阐明CYP 3A依赖性药物代谢的个体间差异的分子基础，可以通过更清楚地了解其他药物、环境和疾病状态如何影响作为肠道CYP 3A底物的新药候选物的处置，提高制药行业开发安全有效药物的能力。此外，如果我们关于CYP 3A 4参与小肠肠细胞内1，25-（OH）2-D3基因组效应的负反馈控制的假设被证明是正确的，那么它可以指向相对简单的方法（例如，中等的每日葡萄柚汁消耗）以预防有效的hPXR激动剂对处于风险中的患者的骨健康的不利影响。完成本资助申请中提出的具体目标应能提高我们对CYP 3A 4依赖性药物代谢个体间差异的分子基础的理解，并可能提高用于治疗疾病的现有和新药的安全性和有效性。而且，它可能为有效预防某些导致骨质疏松的药物不良反应提供科学依据。 公共卫生相关性：完成本资助申请中提出的具体目标应能提高我们对CYP 3A 4依赖性药物代谢个体间差异的分子基础的理解，并可能提高用于治疗疾病的现有和新药的安全性和有效性。而且，它可能为有效预防某些导致骨质疏松的药物不良反应提供科学依据。