QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.104.009019v1 67/6/1954    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Burk, O. Articles by Eichelbaum, M. Search for Related Content PubMed PubMed Citation Articles by Burk, O. Articles by Eichelbaum, M.

Antimalarial Artemisinin Drugs Induce Cytochrome P450 and MDR1 Expression by Activation of Xenosensors Pregnane X Receptor and Constitutive Androstane Receptor

Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany (O.B., K.A.A., E.S., M.F.F., M.E.); Department of Surgery, Charité, Campus-Virchow-Clinic, Humboldt University, Berlin, Germany (A.K.N., E.E.); Departments of Pharmaceutics and Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, Mississippi (B.A.A., M.A.A.); and Institute of Clinical and Experimental Pharmacology and Toxicology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany (M.F.F.)

Artemisinin drugs are of utmost importance in the treatment of malaria, because they represent the sole class of therapeutically used antimalarial drugs to which malaria parasites have not yet developed resistance. The major disadvantage of these medicines is the comparatively high recrudescence rate, which has been attributed to the remarkable decrease of artemisinin plasma concentrations during multiple dosing. Autoinduction of CYP2B6-mediated metabolism has been implicated as the underlying mechanism. So far, the molecular mechanism of induction by artemisinin has not been resolved. Because the xenosensors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) have been shown to mediate induction of drug-metabolizing enzymes and drug transporters, we investigated the hypothesis that artemisinin induces cytochrome P450 expression by activating PXR and/or CAR. By combining in vitro transfection methods and quantitative analyses of gene expression in cell lines and primary human hepatocytes, we here show that artemisinin drugs activate human PXR as well as human and mouse CAR and induce the expression of CYP2B6, CYP3A4, and MDR1 in primary human hepatocytes and in the human intestinal cell line LS174T. Furthermore, we demonstrate that artemisinin acts as a ligand of both nuclear receptors, because it modulates the interaction of the receptors with coregulators. In conclusion, activation of PXR and CAR and especially the resulting induction of CYP3A4 and MDR1 demonstrate that artemisinin has a higher risk of potential drug interactions than anticipated previously.

Address correspondence to: Dr. Oliver Burk, Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, D-70376 Stuttgart, Germany. E-mail: oliver.burk{at}ikp-stuttgart.de

This article has been cited by other articles:

				L. Svecova, R. Vrzal, L. Burysek, E. Anzenbacherova, L. Cerveny, J. Grim, F. Trejtnar, J. Kunes, M. Pour, F. Staud, et al. Azole Antimycotics Differentially Affect Rifampicin-Induced Pregnane X Receptor-Mediated CYP3A4 Gene Expression Drug Metab. Dispos., February 1, 2008; 36(2): 339 - 348. [Abstract] [Full Text] [PDF]

				L. Cerveny, L. Svecova, E. Anzenbacherova, R. Vrzal, F. Staud, Z. Dvorak, J. Ulrichova, P. Anzenbacher, and P. Pavek Valproic Acid Induces CYP3A4 and MDR1 Gene Expression by Activation of Constitutive Androstane Receptor and Pregnane X Receptor Pathways Drug Metab. Dispos., July 1, 2007; 35(7): 1032 - 1041. [Abstract] [Full Text] [PDF]

				Y. Li, O. Mezei, and N. F. Shay Human and Murine Hepatic Sterol-12-{alpha}-Hydroxylase and Other Xenobiotic Metabolism mRNA Are Upregulated by Soy Isoflavones J. Nutr., July 1, 2007; 137(7): 1705 - 1712. [Abstract] [Full Text] [PDF]

				H. Tegude, A. Schnabel, U. M. Zanger, K. Klein, M. Eichelbaum, and O. Burk Molecular Mechanism of Basal CYP3A4 Regulation by Hepatocyte Nuclear Factor 4{alpha}: Evidence for Direct Regulation in the Intestine Drug Metab. Dispos., June 1, 2007; 35(6): 946 - 954. [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]

				T. M. E. Davis, M. England, A.-M. Dunlop, M. Page-Sharp, N. Cambon, T. G. Keller, J. L. Heidecker, and K. F. Ilett Assessment of the Effect of Mefloquine on Artesunate Pharmacokinetics in Healthy Male Volunteers Antimicrob. Agents Chemother., March 1, 2007; 51(3): 1099 - 1101. [Abstract] [Full Text] [PDF]

				S. R. Faucette, T.-C. Zhang, R. Moore, T. Sueyoshi, C. J. Omiecinski, E. L. LeCluyse, M. Negishi, and H. Wang Relative Activation of Human Pregnane X Receptor versus Constitutive Androstane Receptor Defines Distinct Classes of CYP2B6 and CYP3A4 Inducers J. Pharmacol. Exp. Ther., January 1, 2007; 320(1): 72 - 80. [Abstract] [Full Text] [PDF]

				J. Keiser, X. Shu-Hua, M. Tanner, and J. Utzinger Artesunate and artemether are effective fasciolicides in the rat model and in vitro J. Antimicrob. Chemother., June 1, 2006; 57(6): 1139 - 1145. [Abstract] [Full Text] [PDF]

				S. Ekins, S. Andreyev, A. Ryabov, E. Kirillov, E. A. Rakhmatulin, S. Sorokina, A. Bugrim, and T. Nikolskaya A COMBINED APPROACH TO DRUG METABOLISM AND TOXICITY ASSESSMENT Drug Metab. Dispos., March 1, 2006; 34(3): 495 - 503. [Abstract] [Full Text] [PDF]