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 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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Aged
-
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
-
Aryl Hydrocarbon Hydroxylases / biosynthesis*
-
Aryl Hydrocarbon Hydroxylases / genetics
-
Blotting, Western
-
Catalysis
-
Cells, Cultured
-
Constitutive Androstane Receptor
-
Cytochrome P-450 CYP2B6
-
Cytochrome P-450 CYP3A
-
Cytochrome P-450 Enzyme System / biosynthesis*
-
Cytochrome P-450 Enzyme System / genetics
-
DNA / biosynthesis
-
DNA / genetics
-
Dipyrone / analogs & derivatives
-
Dipyrone / pharmacology*
-
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
-
RNA / biosynthesis
-
RNA / genetics
-
Receptors, Cytoplasmic and Nuclear / drug effects
-
Receptors, Steroid / drug effects
-
Reverse Transcriptase Polymerase Chain Reaction
-
Transcription Factors / drug effects
Substances
-
Anti-Inflammatory Agents, Non-Steroidal
-
Constitutive Androstane Receptor
-
Isoenzymes
-
Pregnane X Receptor
-
Receptors, Cytoplasmic and Nuclear
-
Receptors, Steroid
-
Transcription Factors
-
RNA
-
Dipyrone
-
DNA
-
Cytochrome P-450 Enzyme System
-
Aryl Hydrocarbon Hydroxylases
-
CYP2B6 protein, human
-
Cytochrome P-450 CYP2B6
-
Cytochrome P-450 CYP3A
-
CYP3A4 protein, human
-
Oxidoreductases, N-Demethylating