Regulation of xenobiotic receptors PXR and CAR, and CYP3A: implications in drug disposition

外源性受体 PXR 和 CAR 以及 CYP3A 的调节：对药物处置的影响

• 批准号: 10595631
• 负责人: Taosheng Chen
• 金额: $ 44.88万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595631
• 关键词: Adverse drug effect; Affect; Biological Availability; CYP3A4 gene; CYP3A5 gene; Cell model; Chemicals; Comprehension; Cytochrome P450; Development; Diabetes Mellitus; Disease; Drug Prescriptions; Drug resistance; Drug toxicity; Enzymes; Genetic Transcription; Goals; Homeostasis; Human; Ligands; Malignant Neoplasms; Nuclear Receptors; Outcome; Pharmaceutical Preparations; Pharmacotherapy; Post-Translational Regulation; Regulation; Role; Technology; Therapeutic; Tissues; Toxicology; Treatment Efficacy; Treatment Failure; Xenobiotic Metabolism; Xenobiotics; constitutive androstane receptor; design; drug disposition; drug efficacy; flexibility; human disease; improved; in vivo; inhibitor; innovation; novel; posttranscriptional; pregnane X receptor; prevent; protein protein interaction; receptor; tool

Manipulation of drug disposition offers an avenue toward enhancing drug efficacy and reducing adverse drug effects (including drug toxicity and drug resistance, the leading causes of drug treatment failure). We study the regulation of human pregnane X receptor (hPXR), constitutive androstane receptor (hCAR), cytochromes P450 (CYP)3A4 and CYP3A5, along with their roles in drug disposition. hPXR and hCAR are nuclear receptors modulated by many structurally diverse chemicals. They transcriptionally regulate transporters and drug- metabolizing enzymes (including CYP3A4 and CYP3A5, which metabolize more than 50% of prescribed drugs) to control xenobiotic disposition and endobiotic homeostasis, and are implicated in drug effects and in the development of human diseases (e.g., diabetes and cancer). Several key gaps remain in our understanding of the regulation of hPXR, hCAR, CYP3A4, and CYP3A5. First, hPXR and hCAR display ligand promiscuity and structural flexibility, but how compounds affect receptor activities, and how the two receptors co-regulate drug disposition, remain elusive. An innovative and systematic effort is needed to develop chemical tools to dissect hPXR and hCAR regulation in detail. Second, how CYP3A4 and CYP3A5 are differentially regulated in a tissue- and disease-context–dependent manner is unknown. Our two long-term goals are 1) to comprehensively understand the regulation of hPXR, hCAR, CYP3A4, and CYP3A5 and its implications for drug disposition and human diseases, and 2) to develop chemical tools to elucidate their regulation, prevent drug toxicity, and improve drug bioavailability. We have advanced toward these goals by discovering novel mechanisms that regulate hPXR, hCAR, and CYP3A5 (including transcriptional, post-transcriptional, and post-translational regulation, and previously unknown protein–protein interactions), and by developing novel compounds that specifically target them. We will meet 3 challenges during the next five years: (1) The mechanism by which binders of hPXR or hCAR trigger varying cellular outcomes to differentially affect xenobiotic metabolism is still not well defined, hindering our ability to accurately assess drug effects. We will develop compounds and assess their mechanisms of action and in vivo efficacy. (2) The functional relation between hPXR and hCAR and the underlying mechanism remain unclear, preventing an effective modulating approach. We will fully characterize the relation and develop compounds to modulate it and xenobiotic metabolism. (3) How CYP3A4 and CYP3A5 are differentially regulated is unclear. We will develop CYP3A5-specific inhibitors, identify the regulators of CYP3A5 expression, and develop appropriate cell models and advanced technological approaches to investigate the novel roles of CYP3A5. Together, our findings will provide a broader comprehension of the regulation of hPXR, hCAR, CYP3A4, and CYP3A5; define the previously unclear functional relation between hPXR and hCAR and design paradigm-shifting approaches to modulate it; reveal novel regulation and roles of CYP3A5; and generate novel chemical compounds as leads for therapies to prevent drug toxicity and improve drug bioavailability.

对药物处置的操纵为增强药物和减少不良药物提供了途径 效应（包括药物抗药性和耐药性，是药物治疗失败的主要原因） 调节人妊娠X受体（HPXR），组成型雄激素受体（HCAR），细胞色素P450 （CYP）3A4和CYP3A5，以及药物处置中的作用。 由许多结构上的化学物质调节。 代谢酶（包括CYP3A4和CYP3A5，代谢超过50％的原依药） 控制异种生物的处置和内向生物稳态，并与药物作用有关 人类疾病的发展（例如，糖尿病和癌症）。 HPXR，HCAR，CYP3A4和CYP3A5的调节。 结构灵活性，但综合如何影响受体活动，以及两个受体如何共同调节药物 处置，仍然难以捉摸。 HPXR和HCAR调节详细。 和疾病依赖性的方式是不幸的。 了解HPXR，HCAR，CYP3A4和CYP3A4和CYP3A5和CYP3A4的调节 人类疾病和2）开发化学工具以阐明其调节，防止药物质量并改善 我们通过发现调节的新型机制来朝着这些目标发展 HPXR，HCAR和CYP3A5（包含转录，转录后和翻译后调节，并 以前未知的蛋白质 - 蛋白质相互作用），并通过开发特定靶向的新型化合物 他们将在接下来的五年中遇到3个挑战：（1） HCAR触发变化的细胞结局会影响差异影响异种生物代谢，但仍未得到很好的定义， 阻碍我们准确评估药物作用的能力。 作用和体内功效。 保持叔叔，防止有效的调制方法。 化合物可将其模块化和异生物代谢。 是不清楚的。 开发适当的细胞模型和先进的技术方法来研究 CYP3A5。 CYP3A4和CYP3A5； 范式转移的方法是启用CYP3A5的新型调节和生成小说的作用 化学化合物作为预防药物毒性并改善药物生物宽白的疗法的铅。