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

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.

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@article{Saussele2007SelectiveIO, title={Selective induction of human hepatic cytochromes P450 2B6 and 3A4 by metamizole.}, author={Tanje Saussele and Oliver Burk and Julia K Blievernicht and K . Klein and Andreas Klaus Nussler and Natascha C. Nussler and Jan G. Hengstler and Michel F Eichelbaum and Matthias Schwab and Ulrich M. Zanger}, journal={Clinical pharmacology and therapeutics}, year={2007}, volume={82 3}, pages={265-74} }