title: Examination of Zolpidem effects on AhR- and PXR-dependent expression of drug-metabolizing cytochromes P450 in primary cultures of human hepatocytes.
abstract: A hypnotic drug Zolpidem is used in clinical practice for more than 25 years. Surprisingly, the effects of Zolpidem on the expression of drug-metabolizing cytochromes P450 (CYPs) were not examined yet. Recently, the unexpected capacity of several "old drugs", such as valproic acid or azoles, to induce CYPs was reported. Therefore, we tested whether Zolpidem induces the expression of important CYPs in primary cultures of human hepatocytes. Cells were treated for 24h with Zolpidem in therapeutic (0.1mg/L) and toxic (1mg/L) concentrations. The levels of CYP1A1, CYP1A2, CY2C9 and CYP3A4 mRNAs were not altered by Zolpidem, whereas model inducers dioxin and rifampicin significantly induced CYP1A and CYP2/3 gene expression, respectively. Consistently, Zolpidem did not activate aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR), the key regulators of cytochromes P450s, as revealed by transient transfection gene reporter assays using HepG2 cells. We conclude Zolpidem be considered a safe drug with respect to the possible interactions through AhR- and PXR-dependent induction of drug-metabolizing CYPs.
authors.affiliation: Department of Cell Biology and Genetics, Faculty of Science, Palacky University Olomouc, Slechtitelu 11, 783 71 Olomouc, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Bachleda
authors.forename: Radim
authors.initials: R
authors.lastname: Vrzal
authors.forename: Jakub
authors.initials: J
authors.lastname: Pivnicka
authors.forename: Boris
authors.initials: B
authors.lastname: Cvek
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Dvorak
mesh_terms: D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics; D008297:Male; D008875:Middle Aged; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D000077297:Pregnane X Receptor; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects*; D011987:Receptors, Steroid / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D000077334:Zolpidem
chemical_list: D006993:Hypnotics and Sedatives; D004364:Pharmaceutical Preparations; D000077297:Pregnane X Receptor; D011725:Pyridines; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D011987:Receptors, Steroid; D000077334:Zolpidem; D003577:Cytochrome P-450 Enzyme System; D008156:Luciferases