![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
|
|
|
|
|
||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Received for publication August 19, 2004.
Revised September 26, 2004.
Accepted for publication September 30, 2004.
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 'fat-burning' properties. The active ingredient in Coleus 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 PKA signal transduction pathway. We show here that both forskolin and its non-adenyl cyclase-activating analog 1,9 dideoxyforskolin induce CYP3A gene expression in primary hepatocytes by functioning as agonists of the pregnane X receptor. 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 the PKA-independent effects of forskolin on the expression of drug-metabolizing enzymes in liver. Finally, our data suggest that herbal therapy with Coleus forskohlii extract should be approached cautiously due to the potential for herb-drug interactions in patients on combination therapy.
Key words:
CYP3A, Drug Interaction, coleus forskohlii, forskolin, pregnane x receptor, protein kinase A
This article has been cited by other articles:
|
|
 |
|
  K. Lichti-Kaiser and J. L. Staudinger The Traditional Chinese Herbal Remedy Tian Xian Activates Pregnane X Receptor and Induces CYP3A Gene Expression in Hepatocytes Drug Metab. Dispos., August 1, 2008; 36(8): 1538 - 1545. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Pinto, D. Papa, M. Hubner, T.-C. Mou, G. H. Lushington, and R. Seifert Activation and Inhibition of Adenylyl Cyclase Isoforms by Forskolin Analogs J. Pharmacol. Exp. Ther., April 1, 2008; 325(1): 27 - 36. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Ekins, C. Chang, S. Mani, M. D. Krasowski, E. J. Reschly, M. Iyer, V. Kholodovych, N. Ai, W. J. Welsh, M. Sinz, et al. Human Pregnane X Receptor Antagonists and Agonists Define Molecular Requirements for Different Binding Sites Mol. Pharmacol., September 1, 2007; 72(3): 592 - 603. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. L. Urquhart, R. G. Tirona, and R. B. Kim Nuclear Receptors and the Regulation of Drug-Metabolizing Enzymes and Drug Transporters: Implications for Interindividual Variability in Response to Drugs J. Clin. Pharmacol., May 1, 2007; 47(5): 566 - 578. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Wang, H. Huang, H. Li, D. G. Teotico, M. Sinz, S. D. Baker, J. Staudinger, G. Kalpana, M. R. Redinbo, and S. Mani Activated Pregnenolone X-Receptor Is a Target for Ketoconazole and Its Analogs Clin. Cancer Res., April 15, 2007; 13(8): 2488 - 2495. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Ding, K. Lichti, I. Kim, F. J. Gonzalez, and J. L. Staudinger Regulation of Constitutive Androstane Receptor and Its Target Genes by Fasting, cAMP, Hepatocyte Nuclear Factor {alpha}, and the Coactivator Peroxisome Proliferator-activated Receptor {gamma} Coactivator-1{alpha} J. Biol. Chem., September 8, 2006; 281(36): 26540 - 26551. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Ding, K. Lichti, and J. L. Staudinger The Mycoestrogen Zearalenone Induces CYP3A through Activation of the Pregnane X Receptor Toxicol. Sci., June 1, 2006; 91(2): 448 - 455. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Orans, D. G. Teotico, and M. R. Redinbo The Nuclear Xenobiotic Receptor Pregnane X Receptor: Recent Insights and New Challenges Mol. Endocrinol., December 1, 2005; 19(12): 2891 - 2900. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Ding and J. L. Staudinger The Ratio of Constitutive Androstane Receptor to Pregnane X Receptor Determines the Activity of Guggulsterone against the Cyp2b10 Promoter J. Pharmacol. Exp. Ther., July 1, 2005; 314(1): 120 - 127. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
