Benzodiazepines medazepam and midazolam are activators of pregnane X receptor and weak inducers of CYP3A4: investigation in primary cultures of human hepatocytes and hepatocarcinoma cell lines
Jazyk angličtina Země Nizozemsko Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
20080160
DOI
10.1016/j.toxlet.2010.01.004
PII: S0378-4274(10)00018-4
Knihovny.cz E-zdroje
- MeSH
- anxiolytika toxicita MeSH
- buňky Hep G2 MeSH
- cytochrom P-450 CYP1A1 genetika metabolismus MeSH
- cytochrom P-450 CYP1A2 genetika metabolismus MeSH
- cytochrom P-450 CYP3A genetika metabolismus MeSH
- enzymová indukce účinky léků MeSH
- hepatocelulární karcinom MeSH
- hepatocyty účinky léků enzymologie MeSH
- koaktivátor 1 jaderných receptorů metabolismus MeSH
- kultivované buňky MeSH
- lidé MeSH
- medazepam toxicita MeSH
- messenger RNA metabolismus MeSH
- midazolam toxicita MeSH
- nádory jater MeSH
- pregnanový X receptor MeSH
- regulace genové exprese enzymů účinky léků MeSH
- steroidní receptory metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- anxiolytika MeSH
- cytochrom P-450 CYP1A1 MeSH
- cytochrom P-450 CYP1A2 MeSH
- cytochrom P-450 CYP3A MeSH
- koaktivátor 1 jaderných receptorů MeSH
- medazepam MeSH
- messenger RNA MeSH
- midazolam MeSH
- pregnanový X receptor MeSH
- steroidní receptory MeSH
Benzodiazepines have wide-spread used in pharmacotherapy for their anxiolytic, myorelaxant, hypnotic, amnesic and anticonvulsive properties. Despite benzodiazepines are used in clinics over 50 years, they have not been surprisingly tested for capability to induce major drug-metabolizing cytochromes P450. In the current study, we have examined the potency of Alprazolam, Bromazepam, Chlordiazepoxide, Clonazepam, Diazepam, Lorazepam, Medazepam, Midazolam, Nitrazepam, Oxazepam, Tetrazepam and Triazolam to induce CYP1A2 and CYP3A4 in primary cultures of human hepatocytes. Benzodiazepines were tested in therapeutic concentrations and in concentrations corresponding to their plasma levels in intoxicated patients. We found weak but significant induction of CYP3A4 mRNA by Midazolam and Medazepam, while other benzodiazepines did not induce CYP3A4 expression. None of the tested compounds induced CYP1A2 mRNA in three independent human hepatocytes cultures. In addition, employing gene reporter assays with transiently transfected hepatocarcinoma cells, we found that tested benzodiazepines did not activate aryl hydrocarbon receptor (AhR), whereas Midazolam and Medazepam slightly activated pregnane X receptor (PXR). Consistently, two-hybrid mammalian assay using hybrid fusion plasmids GAL4-PXR ligand-binding domain (LBD) and VP16-SRC-1-receptor-interacting domain (RID) confirmed PXR activation by Midazolam and Medazepam. In conclusion, Alprazolam, Bromazepam, Chlordiazepoxide, Clonazepam, Diazepam, Lorazepam, Nitrazepam, Oxazepam, Tetrazepam and Triazolam can be considered as safe drugs in term of their inability to induce PXR- and AhR-dependent cytochrome P450 enzymes CYP1A2 and CYP3A4. Medazepam and Midazolam slightly activated pregnane X receptor and displayed weak potency to induce CYP3A4 mRNA in human hepatocytes.
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