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

药物处置的操纵提供了一条提高药物疗效和减少药物不良反应的途径 影响（包括药物毒性和耐药性，药物治疗失败的主要原因）。我们研究 人雄烷X受体（hPXR）、组成型雄烷受体（hCAR）、细胞色素P450的调节 （3）3A4和CYP 3A5，沿着及其在药物处置中的作用。hPXR和hCAR是核受体 由许多结构不同的化学物质调节。它们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） 控制异生质处置和内源性体内平衡，并与药物作用和 人类疾病的发展（例如，糖尿病和癌症）。在我们的理解中， hPXR、hCAR、CYP3A4和CYP3A5的调节。首先，hPXR和hCAR显示配体混杂， 结构灵活性，但化合物如何影响受体活性，以及两种受体如何共同调节药物 性格，仍然难以捉摸。需要创新和系统的努力来开发化学工具， hPXR和hCAR调控的详细信息。第二，CYP3A4和CYP3A5在组织中的差异调节- 和疾病背景依赖的方式是未知的。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，防止药物毒性，并改善 药物生物利用度我们已经朝着这些目标前进，通过发现新的机制， hPXR、hCAR和CYP3A5（包括转录、转录后和翻译后调控，以及 以前未知的蛋白质-蛋白质相互作用），并通过开发特异性靶向 他们在未来五年内，我们将面临3个挑战：（1）hPXR或 hCAR触发不同的细胞结果以差异地影响异生物质代谢仍然没有很好地定义， 阻碍了我们准确评估药效的能力我们将开发化合物并评估其机制 的作用和体内功效。(2)hPXR与hCAR的功能关系及其机制 仍然不清楚，阻止了有效的调节方法。我们将充分描述这种关系， 化合物来调节它和异生物质代谢。(3)CYP3A4和CYP3A5如何差异调节 还不清楚我们将开发CYP3A5特异性抑制剂，鉴定CYP3A5表达的调节剂， 开发适当的细胞模型和先进的技术方法，以研究新的作用， CYP3A5。总之，我们的研究结果将提供对hPXR，hCAR， CYP3A4和CYP3A5;定义了hPXR和hCAR之间先前不清楚的功能关系以及设计 范式转换方法来调节它;揭示CYP3A5的新调节和作用;并产生新的 化学化合物作为治疗的先导，以防止药物毒性和提高药物生物利用度。

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.