Kliewer S A, Lehmann J M, Milburn M V, Willson T M
Department of Molecular Endocrinology, Glaxo Wellcome Research and Development, Research Triangle Park, North Carolina 27709, USA.
Recent Prog Horm Res. 1999;54:345-67; discussion 367-8.
Traditional pharmacologic approaches had identified several classes of xenobiotics that elicited characteristic biological effects in vivo but that lacked defined molecular mechanisms of action. Among these xenobiotics were the peroxisome proliferators, the thiazolidinediones (TZDs), and a set of compounds that induced the expression of cytochrome P450 (CYP) 3A genes and promoted the metabolism of other xenobiotics. All three classes of xenobiotics are now known to exert their actions through activation of orphan members of the nuclear receptor family of ligand-activated transcription factors. Peroxisome proliferators are a diverse group of amphipathic acids that include the fibrate class of triglyceride- and cholesterol-lowering drugs. TZDs sensitize tissues such as skeletal muscle, liver, and adipose to the actions of insulin and lower glucose and lipid levels in type 2 diabetics. The peroxisome proliferators and TZDs are now known to mediate their effects through the peroxisome proliferator-activated receptors (PPARs) alpha and gamma, respectively. The activities of these compounds established the PPARs as key regulators of glucose and lipid homeostasis. We and others have recently shown that various naturally occurring fatty acids and eicosanoids serve as PPAR ligands, suggesting a novel regulatory mechanism whereby dietary lipids and their metabolites can regulate gene transcription and impact overall energy balance. The third class of xenobiotics we have studied induces the expression of CYP3A genes, mono-oxygenases responsible for the metabolism of natural steroids as well as a variety of xenobiotics, including > 60% of all drugs. We have recently shown that compounds that induce CYP3A gene expression do so through activation of novel orphan receptors, termed the pregnane X receptors (PXRs). Many of the PXR activators are widely used drugs such as dexamethasone, lovastatin, and rifampicin, whose induction of CYP3A levels causes them to promote the metabolism of other drugs, often with adverse consequences. Thus, the finding that the PXRs regulate CYP3A gene expression provides a basis for the efficient identification and elimination of candidate drugs that will interact with other medicines. Searches for natural ligands have revealed that the PXRs are activated by C21 steroids, including pregnenolone and progesterone, suggesting that these orphan receptors define a novel steroid hormone signaling pathway. In sum, work from our laboratories and others has demonstrated that peroxisome proliferators, TZDs, and inducers of CYP3A gene expression exert their biological actions through the activation of orphan nuclear receptors. These findings provide insights into new endocrine signaling pathways and have important implications for the discovery of safer and more efficacious drugs for the treatment of a variety of diseases.
传统药理学方法已鉴定出几类外源性物质，它们在体内可引发特征性生物学效应，但缺乏明确的分子作用机制。这些外源性物质包括过氧化物酶体增殖剂、噻唑烷二酮类（TZDs）以及一组可诱导细胞色素P450（CYP）3A基因表达并促进其他外源性物质代谢的化合物。现在已知这三类外源性物质均通过激活配体激活转录因子核受体家族中的孤儿成员来发挥作用。过氧化物酶体增殖剂是一类多样的两亲性酸，包括贝特类降低甘油三酯和胆固醇的药物。TZDs可使骨骼肌、肝脏和脂肪等组织对胰岛素的作用敏感，并降低2型糖尿病患者的血糖和血脂水平。现在已知过氧化物酶体增殖剂和TZDs分别通过过氧化物酶体增殖物激活受体（PPARs）α和γ来介导其效应。这些化合物的活性确立了PPARs作为葡萄糖和脂质稳态关键调节因子的地位。我们和其他人最近表明，各种天然存在的脂肪酸和类花生酸可作为PPAR配体，这提示了一种新的调节机制，即膳食脂质及其代谢产物可调节基因转录并影响整体能量平衡。我们研究的第三类外源性物质可诱导CYP3A基因表达，CYP3A是负责天然类固醇以及多种外源性物质（包括60%以上的所有药物）代谢的单加氧酶。我们最近表明，诱导CYP3A基因表达的化合物是通过激活新型孤儿受体（称为孕烷X受体（PXRs））来实现的。许多PXR激活剂是广泛使用的药物，如地塞米松、洛伐他汀和利福平，它们诱导CYP3A水平升高会导致它们促进其他药物的代谢，常常产生不良后果。因此，PXRs调节CYP3A基因表达这一发现为有效识别和排除会与其他药物相互作用的候选药物提供了依据。对天然配体的搜索表明，PXRs可被C21类固醇（包括孕烯醇酮和孕酮）激活，这提示这些孤儿受体定义了一条新的类固醇激素信号通路。总之，我们实验室和其他实验室的研究工作表明，过氧化物酶体增殖剂、TZDs以及CYP3A基因表达诱导剂通过激活孤儿核受体来发挥其生物学作用。这些发现为新的内分泌信号通路提供了见解，并对发现更安全、更有效的治疗多种疾病的药物具有重要意义。
