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

操纵药物处置为提高药物疗效和减少药物不良反应提供了一条途径 影响(包括药物毒性和耐药性，这是药物治疗失败的主要原因)。我们研究了 人孕烷X受体(HPXR)、构成雄烷受体(HCAR)、细胞色素P450的调节 (CYP)3A4和CYP3A5及其在药物处置中的作用。HPXR和HCAR是核受体 受许多结构不同的化学物质的调节。它们在转录上调节转运蛋白和药物- 代谢酶(包括代谢50%以上的处方药的细胞色素P3A4和细胞色素P3A5) 控制外来生物的处置和内生生物的动态平衡，并与药物效应和 人类疾病(如糖尿病和癌症)的发展。在我们的理解中仍然存在几个关键差距 HPXR、HCAR、CYP3A4、CYP3A5的调控。首先，hPXR和HCAR显示了配体的混杂和 结构灵活性，但化合物如何影响受体活性，以及这两个受体如何共同调节药物 性情，仍然难以捉摸。需要创新和系统的努力来开发化学工具来解剖 HPXR和HCAR的详细规定。第二，细胞色素P3A4和细胞色素P3A5在组织中是如何不同地被调控的-- 而疾病上下文依赖的方式尚不清楚。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和 人类疾病，以及2)开发化学工具来阐明它们的调节，防止药物毒性，并改善 药物生物利用度。通过发现新的调控机制，我们朝着这些目标前进 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 他们。在接下来的五年里，我们将面对三个挑战：(1)hPXR或 HCAR触发不同的细胞结果以不同的方式影响异体代谢仍然没有很好的定义， 阻碍了我们准确评估药物效果的能力。我们将开发化合物并评估其机理 药效和体内药效。(2)hPXR和hCAR的功能关系及其机制 仍然不清楚，阻碍了有效的调节方法。我们将充分描述两国关系的特点并发展 调节它和异种生物代谢的化合物。(3)细胞色素P3A4和细胞色素P3A5的差异调控 目前还不清楚。我们将开发针对CYP3A5的抑制剂，确定CYP3A5表达的调节因子，并 开发合适的细胞模型和先进的技术方法来研究新的作用 细胞色素P3A5。综上所述，我们的发现将提供对hPXR、Hcar、 定义了hPXR和HCAR之间以前不清楚的功能关系和设计 范式转换的方法来调节它；揭示新的调控和作用；并产生新的 化合物作为预防药物毒性和提高药物生物利用度的治疗的先导。

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.