Atorvastatin, fluvastatin and rosuvastatin are drugs used for treatment of hypercholesterolemia. They cause numerous drug-drug interactions by inhibiting and inducing drug-metabolizing cytochromes P450. These three statins exist in four optical forms, but they are currently used as enantiopure drugs, i.e., only one single enantiomer. There are numerous evidences that efficacy, adverse effects and toxicity of drugs may be enantiospecific. Therefore, we investigated the effects of optical isomers of atorvastatin, fluvastatin and rosuvastatin on the expression of drug-metabolizing P450s in primary human hepatocytes, using western blots and RT-PCR for measurement of proteins and mRNAs, respectively. The activity of P450 transcriptional regulators, including pregnane X receptor (PXR), aryl hydrocarbon receptor (AhR) and glucocorticoid receptor (GR), was assessed by gene reporter assays and EMSA. Transcriptional activity of AhR was not influenced by any statin tested. Basal transcriptional activity of GR was not affected by tested statins, but dexamethasone-inducible activity of GR was dose-dependently and enantioselectively inhibited by fluvastatin. Basal and ligand-inducible transcriptional activity of PXR was dose-dependently influenced by all tested statins, and the potency and efficacy between individual optical isomers varied depending on statin and optical isomer. The expression of CYP1A1 and CYP1A2 in human hepatocytes was not influenced by tested statins. All statins induced CYP2A6, CYP2B6 and CYP3A4, and the effects on CYP2C9 were rather modulatory. The effects varied between statins and enantiomers and induction potency decreased in order: atorvastatin (RR>RS = SR>SS) > fluvastatin (SR>RS = SS>RR) >> rosuvastatin (only RS active). The data presented here might be of toxicological and clinical importance.

• MeSH
• atorvastatin farmakologie   MeSH
• cytochrom P-450 CYP3A biosyntéza   MeSH
• cytochrom P450 CYP2A6 biosyntéza   MeSH
• cytochrom P450 CYP2B6 biosyntéza   MeSH
• dospělí MeSH
• enzymová indukce účinky léků   MeSH
• fluvastatin MeSH
• hepatocyty cytologie   enzymologie   MeSH
• indoly farmakologie   MeSH
• induktory cytochromu P450 CYP2B6 farmakologie   MeSH
• induktory cytochromu P450 CYP3A farmakologie   MeSH
• kyseliny mastné mononenasycené farmakologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• pregnanový X receptor MeSH
• rosuvastatin kalcium farmakologie   MeSH
• senioři MeSH
• stereoizomerie MeSH
• steroidní receptory biosyntéza   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• atorvastatin MeSH
• CYP2A6 protein, human MeSH Prohlížeč
• CYP2B6 protein, human MeSH Prohlížeč
• CYP3A4 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP3A MeSH
• cytochrom P450 CYP2A6 MeSH
• cytochrom P450 CYP2B6 MeSH
• fluvastatin MeSH
• indoly MeSH
• induktory cytochromu P450 CYP2B6 MeSH
• induktory cytochromu P450 CYP3A MeSH
• kyseliny mastné mononenasycené MeSH
• pregnanový X receptor MeSH
• rosuvastatin kalcium MeSH
• steroidní receptory MeSH

Antifungal drug ketoconazole causes severe drug-drug interactions by influencing gene expression and catalytic activity of major drug-metabolizing enzyme cytochrome P450 CYP3A4. Ketoconazole is administered in the form of racemic mixture of two cis-enantiomers, i.e. (+)-ketoconazole and (-)-ketoconazole. Many enantiopure drugs were introduced to human pharmacotherapy in last two decades. In the current paper, we have examined the effects of ketoconazole cis-enantiomers on the expression of CYP3A4 in human hepatocytes and HepG2 cells and on catalytic activity of CYP3A4 in human liver microsomes. We show that both ketoconazole enantiomers induce CYP3A4 mRNA and protein in human hepatocytes and HepG2 cells. Gene reporter assays revealed partial agonist activity of ketoconazole enantiomers towards pregnane X receptor PXR. Catalytic activity of CYP3A4/5 towards two prototypic substrates of CYP3A enzymes, testosterone and midazolam, was determined in presence of both (+)-ketoconazole and (-)-ketoconazole in human liver microsomes. Overall, both ketoconazole cis-enantiomers induced CYP3A4 in human cells and inhibited CYP3A4 in human liver microsomes. While interaction of ketoconazole with PXR and induction of CYP3A4 did not display enantiospecific pattern, inhibition of CYP3A4 catalytic activity by ketoconazole differed for ketoconazole cis-enantiomers ((+)-ketoconazole IC₅₀ 1.69 µM, Ki 0.92 µM for testosterone, IC₅₀ 1.46 µM, Ki 2.52 µM for midazolam; (-)-ketoconazole IC₅₀ 0.90 µM, Ki 0.17 µM for testosterone, IC₅₀ 1.04 µM, Ki 1.51 µM for midazolam).

• MeSH
• biokatalýza účinky léků   MeSH
• buňky Hep G2 MeSH
• cytochrom P-450 CYP3A genetika   metabolismus   MeSH
• genetická transkripce účinky léků   MeSH
• hepatocyty účinky léků   enzymologie   MeSH
• jaterní mikrozomy účinky léků   metabolismus   MeSH
• ketokonazol chemie   farmakologie   MeSH
• kinetika MeSH
• lidé MeSH
• messenger RNA genetika   metabolismus   MeSH
• pregnanový X receptor MeSH
• regulace genové exprese enzymů účinky léků   MeSH
• reportérové geny MeSH
• stereoizomerie MeSH
• steroidní receptory genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytochrom P-450 CYP3A MeSH
• ketokonazol MeSH
• messenger RNA MeSH
• pregnanový X receptor MeSH
• steroidní receptory MeSH

Benzimidazole drugs lansoprazole and omeprazole are used for treatment of various gastrointestinal pathologies. Both compounds cause drug-drug interactions because they activate aryl hydrocarbon receptor and induce CYP1A genes. In the current paper, we examined the effects of lansoprazole and omeprazole enantiomers on the expression of key drug-metabolizing enzyme CYP3A4 in human hepatocytes and human cancer cell lines. Lansoprazole enantiomers, but not omeprazole, were equipotent inducers of CYP3A4 mRNA in HepG2 cells. All forms (S-, R-, rac-) of lansoprazole and omeprazole induced CYP3A4 mRNA and protein in human hepatocytes. The quantitative profiles of CYP3A4 induction by individual forms of lansoprazole and omeprazole exerted enantiospecific patterns. Lansoprazole dose-dependently activated pregnane X receptor PXR in gene reporter assays, and slightly modulated rifampicin-inducible PXR activity, with similar potency for each enantiomer. Omeprazole dose-dependently activated PXR and inhibited rifampicin-inducible PXR activity. The effects of S-omeprazole were much stronger as compared to those of R-omeprazole. All forms of lansoprazole, but not omeprazole, slightly activated glucocorticoid receptor and augmented dexamethasone-induced GR transcriptional activity. Omeprazole and lansoprazole influenced basal and ligand inducible expression of tyrosine aminotransferase, a GR-target gene, in HepG2 cells and human hepatocytes. Overall, we demonstrate here that omeprazole and lansoprazole enantiomers induce CYP3A4 in HepG2 cells and human hepatocytes. The induction comprises differential interactions of omeprazole and lansoprazole with transcriptional regulators PXR and GR, and some of the effects were enantiospecific. The data presented here might be of toxicological and clinical importance, since the effects occurred in therapeutically relevant concentrations.

• MeSH
• buňky Hep G2 MeSH
• cytochrom P-450 CYP3A genetika   metabolismus   MeSH
• hepatocyty účinky léků   metabolismus   MeSH
• kultivované buňky MeSH
• lanzoprazol škodlivé účinky   farmakologie   MeSH
• lidé MeSH
• omeprazol škodlivé účinky   farmakologie   MeSH
• pregnanový X receptor MeSH
• protivředové látky škodlivé účinky   farmakologie   MeSH
• receptory glukokortikoidů metabolismus   MeSH
• steroidní receptory metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• CYP3A4 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP3A MeSH
• lanzoprazol MeSH
• omeprazol MeSH
• pregnanový X receptor MeSH
• protivředové látky MeSH
• receptory glukokortikoidů MeSH
• steroidní receptory MeSH