Induction of drug metabolism by forskolin: The role of the pregnane X receptor and the protein kinase A signal transduction pathway
Induction of drug metabolism by forskolin: The role of the pregnane X receptor and the protein kinase A signal transduction pathway
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DOI：
10.1124/jpet.104.076331
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发表时间：
2005-02-01
影响因子：
3.5
通讯作者：
Staudinger, JL
中科院分区：
文献类型：
--
作者：
Ding, XS;Staudinger, JL
几个世纪以来，阿育吠陀的医学中一直使用一种植物的提取物来治疗各种疾病，如甲状腺功能减退、心脏病和呼吸系统疾病。此外，含有这种提取物的复杂草药混合物因其所谓的“燃烧脂肪”特性而在美国越来越受欢迎。Forskohlii提取物中的有效成分是二萜化合物Forsklin。Forsklin是一种广泛使用的生化工具，它激活腺苷环化酶，从而增加细胞内cAMP浓度，从而激活蛋白激酶A(PKA)信号转导途径。在此，我们发现Forsklin和它的非腺基环化酶激活类似物1，9-二脱氧Forsklin都通过作为孕烷X受体(PXR)的激动剂来诱导原代肝细胞中CYP3A基因的表达。我们发现，PKA信号的激活增强了PXR介导的对培养肝细胞中CYP3A基因表达的诱导，并在基于细胞的检测中增加了PXR-辅活化子蛋白-蛋白质相互作用的强度。酶活性检测表明PXR在体外可以作为催化活性PKA的底物。我们的数据为了解Forsklin对肝脏药物代谢酶表达的PKA依赖和非依赖作用的分子机制提供了重要的见解。最后，我们的数据表明，在联合治疗的患者中，由于草药相互作用的可能性，应该谨慎地使用中药提取物进行草药治疗。
An extract of the plant Coleus forskohlii has been used for centuries in Ayurvedic medicine to treat various diseases such as hypothyroidism, heart disease, and respiratory disorders. Additionally, complex herbal mixtures containing this extract are gaining popularity in United States for their putative "fatburning" properties. The active ingredient in C. forskohlii extract is the diterpene compound forskolin. Forskolin is a widely used biochemical tool that activates adenyl cyclase, thereby increasing intracellular concentration of cAMP and thus activating the protein kinase A (PKA) signal transduction pathway. We show herein that both forskolin and its nonadenyl cyclase-activating analog 1,9 dideoxyforskolin induce CYP3A gene expression in primary hepatocytes by functioning as agonists of the pregnane X receptor (PXR). We show that activation of PKA signaling potentiates PXR-mediated induction of CYP3A gene expression in cultured hepatocytes and increases the strength of PXR- coactivator protein-protein interaction in cell-based assays. Kinase assays show that PXR can serve as a substrate for catalytically active PKA in vitro. Our data provide important insights into the molecular mechanism of both the PKA-dependent and - independent effects of forskolin on the expression of drug-metabolizing enzymes in liver. Finally, our data suggest that herbal therapy with C. forskohlii extract should be approached cautiously due to the potential for herb-drug interactions in patients on combination therapy.