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https://hdl.handle.net/2440/44124
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Type: | Journal article |
Title: | Selective induction of human hepatic cytochromes P450 2B6 and 3A4 by metamizole |
Author: | Saussele, T. Burk, O. Blievernicht, J. Nussler, A. Nussler, N. Hengstler, J. Eichelbaum, M. Schwab, M. Zanger, U. |
Citation: | Clinical Pharmacology and Therapeutics, 2007; 82(3):265-274 |
Publisher: | Mosby Inc |
Issue Date: | 2007 |
ISSN: | 0009-9236 1532-6535 |
Statement of Responsibility: | T Saussele, O Burk, J K Blievernicht, K Klein, A Nussler, N Nussler, J G Hengstler, M Eichelbaum, M Schwab, and U M Zanger |
Abstract: | The pyrazolone drug metamizole is a widely used analgesic. Analysis of liver microsomes from patients treated with metamizole revealed selectively higher expression of cytochromes P450, CYP2B6 and CYP3A4 (3.8- and 2.8-fold, respectively), and 2.9-fold higher bupropion hydroxylase activity compared with untreated subjects. Further investigation of metamizole and various derivatives on different potential target genes in human primary hepatocytes demonstrated time- and concentration-dependent induction by metamizole of CYP2B6 (7.8- and 3.1-fold for mRNA and protein, respectively, at 100 M) and CYP3A4 (2.4- and 2.9-fold, respectively), whereas other genes (CYP2C9, CYP2C19, CYP2D6, NADPH:cytochrome P450 reductase, ABCB1, constitutive androstane receptor (CAR), pregnane X receptor (PXR)) were not substantially altered. Using reporter gene assays, we show that metamizole is not acting as a direct ligand to either PXR or CAR, suggesting a phenobarbital-like mechanism of induction. These data warrant further studies to elucidate the drug-interaction potential of metamizole, especially in patients with long-term treatment. |
Keywords: | Liver Cells, Cultured Microsomes, Liver Hepatocytes Humans Dipyrone Cytochrome P-450 Enzyme System Aryl Hydrocarbon Hydroxylases Isoenzymes Oxidoreductases, N-Demethylating Receptors, Cytoplasmic and Nuclear Receptors, Steroid Transcription Factors DNA RNA Anti-Inflammatory Agents, Non-Steroidal Blotting, Western Reverse Transcriptase Polymerase Chain Reaction Enzyme Induction Dose-Response Relationship, Drug Genotype Plasmids Catalysis Aged Middle Aged Female Male Cytochrome P-450 CYP3A In Vitro Techniques Cytochrome P-450 CYP2B6 Pregnane X Receptor Constitutive Androstane Receptor |
Rights: | © 2008 American Society for Clinical Pharmacology and Therapeutics |
DOI: | 10.1038/sj.clpt.6100138 |
Published version: | http://dx.doi.org/10.1038/sj.clpt.6100138 |
Appears in Collections: | Aurora harvest 6 Pharmacology publications |
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