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提高药品效率和降低广告药物提供了途径 影响（包括药物毒性和耐药性，是药物治疗失败的主要原因）。我们研究 人类孕妇X受体（HPXR），本构雄烷受体（HCAR），细胞色素P450的调节 （CYP）3A4和CYP3A5，以及它们在药物处置中的作用。 HPXR和HCAR是核接收器 由许多结构上多样化的化学物质调节。他们在转录调节转运蛋白和药物 代谢酶（包括CYP3A4和CYP3A5，代谢超过50％的处方药） 控制异种生物的性格和内向生物稳态，并暗示药物作用和 人类疾病的发展（例如糖尿病和癌症）。我们对 HPXR，HCAR，CYP3A4和CYP3A5的调节。首先，HPXR和HCAR显示配体滥交和 结构灵活性，但是化合物如何影响受体活动，以及两个受体如何共同调节药物 处置，仍然难以捉摸。需要创新和系统的努力来开发化学工具以剖析化学工具 HPXR和HCAR调节。其次，在组织中，CYP3A4和CYP3A5的调节方式不同 和疾病依赖性的方式是未知的。我们的两个长期目标是1）全面 了解HPXR，HCAR，CYP3A4和CYP3A5的调节及其对药物处置的影响 人类疾病和2）开发化学工具以阐明其调节，预防药物毒性并改善 药物生物利用度。我们通过发现调节的新型机制来朝着这些目标迈进 HPXR，HCAR和CYP3A5（包括转录，转录后和翻译后调节，以及 以前未知的蛋白质 - 蛋白质相互作用），并通过开发专门针对的新型化合物 他们。在接下来的五年中，我们将面临3个挑战：（1）HPXR或HPXR粘合剂的机制 HCAR触发的细胞结局变化不同，以不同的影响异种代谢，仍然没有很好地定义， 阻碍我们准确评估药物作用的能力。我们将开发化合物并评估其机制 作用和体内效率。 （2）HPXR和HCAR与基本机制之间的功能关系 尚不清楚，防止有效的调节方法。我们将充分表征这种关系并发展 化合物调节它和异生物代谢。 （3）CYP3A4和CYP3A5如何受到差异调节 不清楚。我们将开发CYP3A5特异性抑制剂，确定CYP3A5表达的调节剂，并 开发适当的细胞模型和高级技术方法来研究 CYP3A5。总之，我们的发现将对HPXR，HCAR，HCAR的调节提供更广泛的理解。 CYP3A4和CYP3A5;定义HPXR和HCAR与设计之间以前不清楚的功能关系 范式转移方法调节它；揭示CYP3A5的新调节和作用；并产生小说 化合物作为预防药物毒性并改善药物生物利用度的疗法的铅。