Selective induction of human hepatic cytochromes P450 2B6 and 3A4 by metamizole

• Published in: Clinical pharmacology and therapeutics Vol. 82; no. 3; p. 265
• Main Authors: Saussele, T, Burk, O, Blievernicht, J K, Klein, K, Nussler, A, Nussler, N, Hengstler, J G, Eichelbaum, M, Schwab, M, Zanger, U M
• Format: Journal Article
• Language: English
• Published: United States 01.09.2007
• Subjects: Aged; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Aryl Hydrocarbon Hydroxylases - biosynthesis; Aryl Hydrocarbon Hydroxylases - genetics; Blotting, Western; Catalysis; Cells, Cultured; Cytochrome P-450 CYP2B6; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - biosynthesis; Cytochrome P-450 Enzyme System - genetics; Dipyrone - analogs & derivatives; Dipyrone - pharmacology; DNA - biosynthesis; DNA - genetics; Dose-Response Relationship, Drug; Enzyme Induction - drug effects; Female; Genotype; Hepatocytes - drug effects; Humans; In Vitro Techniques; Isoenzymes - metabolism; Liver - drug effects; Liver - enzymology; Male; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Middle Aged; Oxidoreductases, N-Demethylating - biosynthesis; Oxidoreductases, N-Demethylating - genetics; Plasmids; Pregnane X Receptor; Receptors, Cytoplasmic and Nuclear - drug effects; Receptors, Steroid - drug effects; Reverse Transcriptase Polymerase Chain Reaction; RNA - biosynthesis; RNA - genetics; Transcription Factors - drug effects
• ISSN: 0009-9236
• DOI: 10.1038/sj.clpt.6100138

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 muM) 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.