Herbal Remedies, Drug Clearance & the Steroid X Receptor

草药疗法、药物清除

• 批准号: 6603877
• 负责人: Barry M. Forman
• 金额: $ 35万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-27 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6603877
• 关键词: P glycoprotein; alternative medicine; cytochrome P450; drug interactions; drug metabolism; drug receptors; genetically modified animals; laboratory mouse; medicinal plants; nuclear receptors; pharmacokinetics; plant extracts; receptor expression; steroid hormone receptor; tissue /cell culture

One very common form of drug-drug interactions occurs when one drug enhances the metabolism of a second unrelated drug. Recent in vitro and in vivo data have demonstrated that many of these interactions are mediated via the orphan nuclear receptor SXR (Steroid and Xenobiotic Receptor). SXR binds to and is activated by a wide array of drugs leading to enhanced transcription of CYP3A4. Since CYP3A4 metabolizes approximately 50 percent of pharmaceutical agents, SXR ligands can have widespread effects on drug metabolism. Moreover, recent results have shown that hyperforin, the active ingredient in the commonly used herbal St. John's Wort, is an extremely potent SXR ligand, indicating that common herbal remedies can have direct effects on this drug metabolizing pathway. We present preliminary data indicating that SXR can have even wider effects on drug clearance. For example, we show that SXR activates expression of CYP2C8 and P-glycoprotein, the product of the MDR1 gene. These findings extend the role of SXR to include additional drug metabolism pathways as well as drug efflux. Since SXR is a highly promiscuous xenobiotic receptor, it is likely to be activated by many yet-to-be examined herbal agents. Thus, we propose to test the ability of other herbal remedies to activate SXR. In addition, we propose to identify other SXR- regulated genes, particularly those involved in drug clearance. Finally, while SXR can be activated by a variety of foreign compounds, its endogenous ligand remains to be determined. This implies that certain herbals could promote drug interactions by stimulating or inhibiting the production of this endogenous ligand. We have identified an endogenous fraction that can activate SXR and we propose to purify and characterize this compound. These studies will provide a molecular basis for understanding and predicting botanical-drug interactions.

当一种药物增强另一种不相关药物的代谢时，就会发生一种非常常见的药物相互作用。最近的体外和体内数据表明，许多相互作用是通过孤儿核受体 SXR（类固醇和异生物质受体）介导的。 SXR 与多种药物结合并被多种药物激活，从而增强 CYP3A4 的转录。 由于 CYP3A4 代谢大约 50% 的药剂，SXR 配体可以对药物代谢产生广泛的影响。 此外，最近的结果表明，常用草药圣约翰草中的活性成分金丝桃素是一种极其有效的SXR配体，这表明常见草药可以对这种药物代谢途径产生直接影响。我们提供的初步数据表明 SXR 对药物清除具有更广泛的影响。 例如，我们发现 SXR 激活 CYP2C8 和 P-糖蛋白（MDR1 基因的产物）的表达。 这些发现扩展了 SXR 的作用，包括其他药物代谢途径以及药物流出。由于 SXR 是一种高度混杂的外源性受体，因此它很可能被许多尚未检验的草药制剂激活。因此，我们建议测试其他草药激活 SXR 的能力。 此外，我们建议鉴定其他 SXR 调节的基因，特别是那些涉及药物清除的基因。最后，虽然 SXR 可以被多种外来化合物激活，但其内源配体仍有待确定。 这意味着某些草药可以通过刺激或抑制这种内源配体的产生来促进药物相互作用。 我们已经确定了一种可以激活 SXR 的内源组分，并建议纯化和表征该化合物。 这些研究将为理解和预测植物药物相互作用提供分子基础。