核受体介导的中药对药物代谢酶的诱导作用研究
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摘要
中药与化学药合用在临床上非常普遍,但由此引发的相互作用和不良反应尚未得到充分重视。老年人群疾病多用药多,应作为药物相互作用研究的重点对象,但相关流行病学调查目前鲜有报道。本研究首先对1186名60岁以上老年患者的用药情况进行回顾性分析,发现该人群的中药与化学药合用率非常高,占总调查人数的42%,且疾病类型、疾病数目和年龄是影响合用率的重要因素。此外,中药与化学药合用的老年患者具有发生不良反应的潜在风险,其中,银杏叶、丹参、当归与抗凝药物的合用最为常见。
孕烷X受体(PXR)介导的CYP3A4诱导是中药与化学药相互作用的一种重要机制。本文从PXR入手,探讨中药及其成分对CYP3A4的诱导效应,揭示其分子作用机制。首先我们成功构建了基于PXR的报告基因法,应用该方法考察了29种中药对CYP3A4的诱导情况。结果表明,银杏叶、丹参、当归、五味子等大部分中药都能通过PXR途径诱导CYP3A4的表达。由此可见,中药的药酶诱导效应比较普遍,中药与化学药合用时要注意防止潜在的代谢性药物相互作用的发生。
结合临床用药调查和报告基因实验的筛选结果,选择银杏叶、丹参、当归、五味子等四种中药开展进一步的研究,探索其中激活PXR诱导CYP3A4的活性成分。通过报告基因实验结合RT-PCR的方法,发现丹参中的脂溶性成分丹参酮ⅡA和隐丹参酮能通过PXR途径诱导CYP3A4。此外,组成型雄甾烷受体(CAR)、糖皮质激素受体(GR)也参与调控丹参酮化合物对CYP3A4的诱导效应。采用中药提取分离、色谱技术、报告基因实验结合RT-PCR的方法,发现当归中的藁本内酯能激活PXR诱导CYP3A4的表达。本研究还发现,五味子中的五味子甲素、五味子乙素、五味子醇甲、五味子酯甲,银杏叶中的银杏内酯A,反式-白藜芦醇,盐酸小檗碱也是PXR的激动剂。
本研究还尝试采用分子对接的方法分析配体与PXR配体结合区的相互作用。将中药成分与PXR配体结合腔进行分子对接,从配体-受体相互作用的角度分析其对PXR的激活能力。发现五味子酯甲等中药成分能通过氢键和疏水作用与PXR配体结合腔发生广泛的相互作用。
以上研究结果表明,本文初步建立了一套中药对药物代谢酶诱导作用的研究体系,为预测代谢性中药与化学药相互作用,最终指导临床合理用药提供参考依据。
Herb-drug combination use is very popular in our country. However, herb-drug interactions and adverse effects have not been well examined. More attention should be paid to elder patients because polypharmacy is common in this population. A retrospective analysis of combination use and the potential herb-drug interactions among 1186 elder patients was conducted. Our results indicated that combination use was very popular in these elder patients, accounting for 42% of the total subjects. Statistical analysis showed that medical conditions, number of disease and age were three important factors influencing the prevalence of combination use. In addition, this elderly cohort had the risk of herb-drug interactions and 3 herbal medicines (ginkgo biloba, Danshen, Chinese Angelica) and anticoagulant were the prevalent herb-drug interacting pairs.
Induction of CYP3A4 mediated by pregnane X receptor (PXR) represents an important mechanism for herb-drug metabolic interactions. This work attempted to evaluate the inducible potential of CYP3A4 by Traditional Chinese Medicines (TCMs) and their constituents. First, we established a cell-based reporter gene assay and then 29 TCMs were examined. The results showed that most of the TCMs tested, including ginkgo biloba, Danshen, Chinese Angelica and Schisandra chinensis could induce CYP3A4 through PXR pathway.
We further examined trans-activation activities of the constituents from ginkgo biloba. Danshen, Chinese Angelica and Schisandra chinensis on CYP3A4 reporter. Tanshinone IIA and cryptotanshinone from Danshen, ligustilide from Chinese Angelica, schisandrin A, schisandrin B. schisandrol A and schisantherin A from Schisandra chinensis, ginkgolide A from ginkgo biloba, trans-resveratrol, berberine hydrochloride were identified as PXR agonists. Constitutive androstane receptor (CAR) and glucocorticoid receptor (GR) were also involved in tanshinones mediated CYP3A4 induction.
We tried a docking approach to study the ligand-receptor interactions between herb constituents and PXR ligand binding domain. Based on our docking model, schisantherin A was found to interact with polar residue Ser247 and other 12 hydrophobic residues lining in the ligand binding pocket of PXR.
Taken together, PXR can be served as a useful tool to study CYP3A4 induction mediated by TCMs.
孕烷X受体(PXR)介导的CYP3A4诱导是中药与化学药相互作用的一种重要机制。本文从PXR入手,探讨中药及其成分对CYP3A4的诱导效应,揭示其分子作用机制。首先我们成功构建了基于PXR的报告基因法,应用该方法考察了29种中药对CYP3A4的诱导情况。结果表明,银杏叶、丹参、当归、五味子等大部分中药都能通过PXR途径诱导CYP3A4的表达。由此可见,中药的药酶诱导效应比较普遍,中药与化学药合用时要注意防止潜在的代谢性药物相互作用的发生。
结合临床用药调查和报告基因实验的筛选结果,选择银杏叶、丹参、当归、五味子等四种中药开展进一步的研究,探索其中激活PXR诱导CYP3A4的活性成分。通过报告基因实验结合RT-PCR的方法,发现丹参中的脂溶性成分丹参酮ⅡA和隐丹参酮能通过PXR途径诱导CYP3A4。此外,组成型雄甾烷受体(CAR)、糖皮质激素受体(GR)也参与调控丹参酮化合物对CYP3A4的诱导效应。采用中药提取分离、色谱技术、报告基因实验结合RT-PCR的方法,发现当归中的藁本内酯能激活PXR诱导CYP3A4的表达。本研究还发现,五味子中的五味子甲素、五味子乙素、五味子醇甲、五味子酯甲,银杏叶中的银杏内酯A,反式-白藜芦醇,盐酸小檗碱也是PXR的激动剂。
本研究还尝试采用分子对接的方法分析配体与PXR配体结合区的相互作用。将中药成分与PXR配体结合腔进行分子对接,从配体-受体相互作用的角度分析其对PXR的激活能力。发现五味子酯甲等中药成分能通过氢键和疏水作用与PXR配体结合腔发生广泛的相互作用。
以上研究结果表明,本文初步建立了一套中药对药物代谢酶诱导作用的研究体系,为预测代谢性中药与化学药相互作用,最终指导临床合理用药提供参考依据。
Herb-drug combination use is very popular in our country. However, herb-drug interactions and adverse effects have not been well examined. More attention should be paid to elder patients because polypharmacy is common in this population. A retrospective analysis of combination use and the potential herb-drug interactions among 1186 elder patients was conducted. Our results indicated that combination use was very popular in these elder patients, accounting for 42% of the total subjects. Statistical analysis showed that medical conditions, number of disease and age were three important factors influencing the prevalence of combination use. In addition, this elderly cohort had the risk of herb-drug interactions and 3 herbal medicines (ginkgo biloba, Danshen, Chinese Angelica) and anticoagulant were the prevalent herb-drug interacting pairs.
Induction of CYP3A4 mediated by pregnane X receptor (PXR) represents an important mechanism for herb-drug metabolic interactions. This work attempted to evaluate the inducible potential of CYP3A4 by Traditional Chinese Medicines (TCMs) and their constituents. First, we established a cell-based reporter gene assay and then 29 TCMs were examined. The results showed that most of the TCMs tested, including ginkgo biloba, Danshen, Chinese Angelica and Schisandra chinensis could induce CYP3A4 through PXR pathway.
We further examined trans-activation activities of the constituents from ginkgo biloba. Danshen, Chinese Angelica and Schisandra chinensis on CYP3A4 reporter. Tanshinone IIA and cryptotanshinone from Danshen, ligustilide from Chinese Angelica, schisandrin A, schisandrin B. schisandrol A and schisantherin A from Schisandra chinensis, ginkgolide A from ginkgo biloba, trans-resveratrol, berberine hydrochloride were identified as PXR agonists. Constitutive androstane receptor (CAR) and glucocorticoid receptor (GR) were also involved in tanshinones mediated CYP3A4 induction.
We tried a docking approach to study the ligand-receptor interactions between herb constituents and PXR ligand binding domain. Based on our docking model, schisantherin A was found to interact with polar residue Ser247 and other 12 hydrophobic residues lining in the ligand binding pocket of PXR.
Taken together, PXR can be served as a useful tool to study CYP3A4 induction mediated by TCMs.
引文
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