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

Anthocyanidins and anthocyanins are pharmacologically active constituents of various berry fruits, such as blueberry and cranberry. These compounds are also contained in massively used nutritional supplements based on extracts or dry matter from berry fruits. The current study evaluated the effects of anthocyanidins and anthocyanins on the expression and catalytic activity of major drug-metabolizing enzymes CYP2C9, CYP2A6, CYP2B6, and CYP3A4 in primary cultures of human hepatocytes and human liver microsomes. Expression of mRNA was quantified by qRT-PCR. Expression of proteins was evaluated by Western blotting and immunochemiluminescence. The catalytic activity of CYP enzymes was measured by HPLC using specific enzyme substrates. Tested anthocyanidins (6) and anthocyanins (21) did not induce the expression of mRNA and protein of CYP2C9, CYP2A6, CYP2B6, and CYP3A4 genes in human hepatocytes. Catalytic activities of CYP2C9, CYP2A6, CYP2B6, and CYP3A4 enzymes were inhibited by all anthocyanidins to different extents (e.g., delphinidin inhibits CYP3A4 by >90% at 100 μM with IC50 = 32 μM). Of 21 anthocyanins tested, only cyanidin-3-O-rhamnoside (CYP3A4 by >75% at 100 μM with IC50 = 44 μM) and two glycosides of delphinidin significantly inhibited examined cytochromes P450. It may be concluded that in the ranges of common ingestion of either food or dietary supplement an induction or significant inhibition of CYP2C9, CYP2A6, CYP2B6, and CYP3A4 activity is most probably not expected.

• Klíčová slova
• anthocyans, cytochrome P450, food−drug interactions, human hepatocytes, xenobiotics,
• MeSH
• anthokyaniny farmakologie   MeSH
• biokatalýza MeSH
• brusnice s jedlými plody chemie   MeSH
• cytochrom P-450 CYP3A genetika   metabolismus   MeSH
• cytochrom P450 CYP2B6 genetika   metabolismus   MeSH
• cytochrom P450 CYP2C9 genetika   metabolismus   MeSH
• hepatocyty enzymologie   MeSH
• jaterní mikrozomy enzymologie   MeSH
• lidé MeSH
• regulace genové exprese enzymů účinky léků   MeSH
• rostlinné extrakty farmakologie   MeSH
• Vaccinium macrocarpon chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• anthokyaniny MeSH
• cytochrom P-450 CYP3A MeSH
• cytochrom P450 CYP2B6 MeSH
• cytochrom P450 CYP2C9 MeSH
• rostlinné extrakty MeSH

Objectives Cytochromes P450 play a role in human drugs metabolic pathways and their genes are among the most variable in humans. The aim of this study was to analyze genotype frequencies of five common polymorphisms of cytochromes P450 in Roma/Gypsy and Czech (non-Roma) population samples with Czech origin. Methods Roma/Gypsy (n=302) and Czech subjects (n=298) were genotyped for CYP1A2 (rs762551), CYP2A6 (rs4105144), CYP2B6 (rs3745274) and CYP2D6 (rs3892097; rs1065852) polymorphisms using PCR-RFLP or Taqman assay. Results We found significant allelic/genotype differences between ethnics in three genes. For rs3745274 polymorphism, there was increased frequency of T allele carriers in Roma in comparison with Czech population (53.1 vs. 43.7%; p=0.02). For rs4105144 (CYP2A6) there was higher frequency of T allele carriers in Roma in comparison with Czech population (68.7 vs. 49.8%; p<0.0001). For rs3892097 (CYP2D6) there was more carriers of the A allele between Roma in comparison with Czech population (39.2 vs. 38.2%; p=0.048). Genotype/allelic frequencies of CYP2D6 (rs1065852) and CYP1A2 (rs762551) variants did not significantly differ between the ethnics. Conclusions There were significant differences in allelic/genotype frequencies of some, but not all cytochromes P450 polymorphisms between the Czech Roma/Gypsies and Czech non-Roma subjects.

• Klíčová slova
• Czech majority, Roma/Gypsy, cytochromes P450, polymorphism,
• MeSH
• cytochrom P-450 CYP1A2 genetika   metabolismus   MeSH
• cytochrom P-450 CYP2D6 genetika   metabolismus   MeSH
• cytochrom P450 CYP2A6 genetika   metabolismus   MeSH
• cytochrom P450 CYP2B6 genetika   metabolismus   MeSH
• dospělí MeSH
• genotyp MeSH
• lidé MeSH
• polymorfismus genetický genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• CYP1A2 protein, human MeSH Prohlížeč
• CYP2A6 protein, human MeSH Prohlížeč
• CYP2B6 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP1A2 MeSH
• cytochrom P-450 CYP2D6 MeSH
• cytochrom P450 CYP2A6 MeSH
• cytochrom P450 CYP2B6 MeSH

AIM: Plasma values of nicotine and its metabolites are highly variable, and this variability has a strong genetic influence. In our study, we analysed the impact of common polymorphisms associated with smoking on the plasma values of nicotine, nicotine metabolites and their ratios and investigated the potential effect of these polymorphisms and nicotine metabolite ratios on the successful treatment of tobacco dependence. METHODS: Five variants (rs16969968, rs6474412, rs578776, rs4105144 and rs3733829) were genotyped in a group of highly dependent adult smokers (n=103). All smokers underwent intensive treatment for tobacco dependence; 33 smokers were still abstinent at the 12-month follow-up. RESULTS: The rs4105144 (CYP2A6, P<0.005) and rs3733829 (EGLN2, P<0.05) variants were significantly associated with plasma concentrations of 3OH-cotinine and with 3OH-cotinine: cotinine ratios. Similarly, the unweighted gene score was a significant (P<0.05) predictor of both cotinine:nicotine and 3OH-cotinine:cotinine ratios. No associations between the analysed polymorphisms or nicotine metabolite ratios and nicotine abstinence rate were observed. CONCLUSION: Although CYP2A6 and EGLN2 polymorphisms were associated with nicotine metabolism ratios, neither these polymorphisms nor the ratios were associated with abstinence rates.

• Klíčová slova
• CYP2A6/B6, EGLN2, cotinine, hydroxycotinine, intensive treatment, nicotine metabolism, nicotine-acetylcholine receptors, smoking, tobacco dependence,
• MeSH
• cytochrom P450 CYP2A6 genetika   MeSH
• cytochrom P450 CYP2B6 genetika   MeSH
• dospělí MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé středního věku MeSH
• lidé MeSH
• nikotin krev   metabolismus   MeSH
• nikotinové receptory genetika   MeSH
• poruchy vyvolané užíváním tabáku krev   genetika   metabolismus   terapie   MeSH
• proteiny nervové tkáně genetika   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• CHRNA5 protein, human MeSH Prohlížeč
• CYP2A6 protein, human MeSH Prohlížeč
• CYP2B6 protein, human MeSH Prohlížeč
• cytochrom P450 CYP2A6 MeSH
• cytochrom P450 CYP2B6 MeSH
• nikotin MeSH
• nikotinové receptory MeSH
• proteiny nervové tkáně MeSH

The xenobiotic-mediated induction of three major human liver cytochrome P450 genes, CYP2B6, CYP2C9, and CYP3A4, is known to be regulated by the constitutive androstane receptor (CAR) and the pregnane X receptor (PXR). CAR and PXR are regulated, at least in part, by the glucocorticoid receptor (GR) and the hypothesis of a signal transduction cascade GR-[CAR/PXR]-P450 has been proposed. This study was aimed at testing this hypothesis in primary human hepatocytes by using the tubulin network disrupting agent colchicine. Colchicine (COL) decreased both basal and rifampicin- and phenobarbital-inducible expression of CYP2B6, CYP2C8/9, and CYP3A4. A parallel down-regulation of mRNA expression of CAR, PXR, and tyrosine aminotransferase, a prototypic gene directly regulated by GR, was observed. COL affected neither the level of GR mRNA nor ligand binding to GR. To evaluate the effect of colchicine on GR-mediated gene transactivation, HeLa cells stably or transiently transfected with a GR-responsive element-dependent luciferase reporter gene were used. COL decreased the dexamethasone-induced luciferase expression in stably transfected cell line by 50%, whereas GR transactivation in transiently transfected cells was not affected by COL. In contrast, ligand-dependent GR translocation in the human embryonic kidney 293 cell line transiently transfected with GFP-GR was inhibited by COL. We conclude that alteration of the signal transduction mediated through the GR-[CAR/PXR]-P450 cascade by colchicine is responsible for the down-regulation of CYP2C9 and CYP3A4, implicating cytoskeleton as necessary for correct functioning of this cascade under physiological conditions.

• MeSH
• aromatické hydroxylasy biosyntéza   MeSH
• biologický transport účinky léků   MeSH
• COS buňky MeSH
• cytochrom P-450 CYP3A MeSH
• cytochrom P450 CYP2B6 MeSH
• cytochrom P450 CYP2C8 MeSH
• cytochrom P450 CYP2C9 MeSH
• down regulace účinky léků   MeSH
• enzymová indukce účinky léků   MeSH
• hepatocyty účinky léků   enzymologie   MeSH
• kolchicin farmakologie   MeSH
• kultivované buňky MeSH
• lidé MeSH
• messenger RNA biosyntéza   účinky léků   MeSH
• N-demethylasy biosyntéza   MeSH
• receptory glukokortikoidů účinky léků   metabolismus   MeSH
• regulace genové exprese enzymů účinky léků   MeSH
• systém (enzymů) cytochromů P-450 biosyntéza   účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aromatické hydroxylasy MeSH
• CYP2B6 protein, human MeSH Prohlížeč
• CYP2C8 protein, human MeSH Prohlížeč
• CYP2C9 protein, human MeSH Prohlížeč
• CYP3A protein, human MeSH Prohlížeč
• CYP3A4 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP3A MeSH
• cytochrom P450 CYP2B6 MeSH
• cytochrom P450 CYP2C8 MeSH
• cytochrom P450 CYP2C9 MeSH
• kolchicin MeSH
• messenger RNA MeSH
• N-demethylasy MeSH
• receptory glukokortikoidů MeSH
• systém (enzymů) cytochromů P-450 MeSH

The constitutive androstane receptor (CAR) is a crucial transcriptional regulator of key xenobiotic-metabolizing enzymes such as cytochrome P450 CYP3A4, CYP2C9 and CYP2B6. The flavonoids chrysin, baicalein and galangin have been reported to activate CAR and interfere with EGFR signaling. Nevertheless, it is not known if these flavonoids are direct CAR ligands or indirect phenobarbital-like CAR activators via the inhibition of epidermal growth factor receptor (EGFR) signaling. We analyze the interactions of chrysin, galangin and baicalein and its glycoside baicalin with human CAR. We have employed and validated methods that can study direct interaction with the CAR ligand binding pocket. Secondly, we determined if the compounds affect human EGFR signaling and interact with EGFR. Employing a TR-FRET coactivator assay with recombinant CAR or CAR assembly assay, a consistent activation of CAR with flavonoids and phenobarbital was not observed. It was determined, however, that galangin, chrysin, and baicalein may slightly repress EGFR-Tyr1068 autophosphorylation after EGF treatment, phosphorylation of downstream transcription factor ELK1 and stimulate EGFP-CAR nuclear translocation in primary human hepatocytes. These data suggest that flavonoids chrysin, galangin and baicalein are indirect human CAR activators. This study also demonstrates new approach how to test the direct CAR interaction with its ligands.

• Klíčová slova
• Constitutive androstane receptor, Cytochrome P450, Flavonoids, Gene regulation, Nuclear receptors,
• MeSH
• buněčné linie MeSH
• cytochrom P450 CYP2B6 metabolismus   MeSH
• erbB receptory účinky léků   MeSH
• fenobarbital farmakologie   MeSH
• flavanony farmakologie   MeSH
• flavonoidy farmakologie   MeSH
• hepatocyty účinky léků   metabolismus   MeSH
• konstitutivní androstanový receptor MeSH
• lidé MeSH
• protein Elk-1 s doménou ets účinky léků   genetika   MeSH
• receptory cytoplazmatické a nukleární agonisté   MeSH
• transport proteinů účinky léků   MeSH
• vazebná místa účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• baicalein MeSH Prohlížeč
• chrysin MeSH Prohlížeč
• cytochrom P450 CYP2B6 MeSH
• ELK1 protein, human MeSH Prohlížeč
• erbB receptory MeSH
• fenobarbital MeSH
• flavanony MeSH
• flavonoidy MeSH
• galangin MeSH Prohlížeč
• konstitutivní androstanový receptor MeSH
• protein Elk-1 s doménou ets MeSH
• receptory cytoplazmatické a nukleární MeSH

Essential oils (EOs) are extensively used in food industry, gastronomy and alternative medicine. They are multicomponent mixtures of bioactive compounds; hence, their potential for food-drug interactions is substantial. In this study, we investigated the effects of 31 EOs of culinary herbs and spices on the transcriptional activity of pregnane X receptor (PXR) and expression of cytochrome P450 3A4 (CYP3A4), using human intestinal and hepatic in vitro models. All tested EOs activated PXR in intestinal LS180 cells transiently transfected with PXR, as revealed by a reporter gene assay. Consistently, all EOs induced CYP3A4 mRNA expression in PXR-transfected LS180 cells, primary human hepatocytes and wild-type hepatic progenitor HepaRG cells. EO-mediated induction of CYP3A4 mRNA expression was nullified in PXR-knock out HepaRG cells, suggesting the involvement of PXR in these effects. Collectively, we showed that EOs of culinary herbs and spices might be common activators of PXR and inducers of CYP3A4 at doses present in foods, thereby, they might have a potential for food-drug interactions. Follow-up studies are warranted to identify the bioactive constituents in the tested EOs.

• Klíčová slova
• Cytochrome P450, Essential oils, Food-drug interactions, Human hepatocytes, Xenobiotics,
• MeSH
• aktivace transkripce účinky léků   MeSH
• buněčné linie MeSH
• cytochrom P-450 CYP3A biosyntéza   MeSH
• cytochrom P450 CYP2B6 biosyntéza   genetika   MeSH
• enzymová indukce účinky léků   MeSH
• hepatocyty účinky léků   MeSH
• játra účinky léků   metabolismus   MeSH
• koření analýza   MeSH
• lidé MeSH
• oleje prchavé farmakologie   MeSH
• P-glykoproteiny biosyntéza   MeSH
• pregnanový X receptor MeSH
• primární buněčná kultura MeSH
• reportérové geny MeSH
• steroidní receptory účinky léků   metabolismus   MeSH
• střeva účinky léků   MeSH
• střevní sliznice metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ABCB1 protein, human MeSH Prohlížeč
• CYP2B6 protein, human MeSH Prohlížeč
• CYP3A4 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP3A MeSH
• cytochrom P450 CYP2B6 MeSH
• oleje prchavé MeSH
• P-glykoproteiny MeSH
• pregnanový X receptor MeSH
• steroidní receptory MeSH

PURPOSE: Tobacco/nicotine dependence has a significant heritable component. Genome-wide association studies have associated the single nucleotide polymorphisms (SNPs) rs578776, rs16969968, rs6474412, rs3733829 and rs4105144 with nicotine dependence in Western European populations. We examined whether these SNPs influence nicotine dependence and successful treatment of tobacco dependence in the Czech middle-European population. MATERIALS AND METHODS: Variants were analysed by PCR-RFLP or by TaqMan assay in 807 adult heavy tobacco-dependent smokers - patients of the Centre for Treatment of Tobacco Dependence (Prague) as well as 1,362 self-reported non-smokers. RESULTS AND DISCUSSION: Except for rs3733829, association with tobacco dependence was confirmed for all other genetic variants. In agreement with previous studies, the strongest determinant of tobacco dependence was rs16969968 with OR (95%CI) 1.32 (1.08-1.62) for A allele carriers vs. GG comparison (P=0.003). In contrast, none of the analysed variants reached significance with respect to a 1-year course of successful tobacco dependence treatment (all P over 0.18) in a subset of 525 patients. CONCLUSION: We confirmed the association between variants within genes that code nicotinic-acetylcholine receptors (-A3, -A5 and -B3), CYP2A6/B6 and tobacco dependence development in the Czech population. The success of the tobacco dependence treatment was not influenced by the analysed SNPs.

• Klíčová slova
• CYP2A6/B6, Czechs, EGLN2, Nicotine-acetylcholine receptors, Smoking cessation, Tobacco dependence,
• MeSH
• celogenomová asociační studie MeSH
• cytochrom P450 CYP2A6 MeSH
• cytochrom P450 CYP2B6 genetika   MeSH
• dospělí MeSH
• genetická predispozice k nemoci * MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé MeSH
• nikotinové receptory genetika   MeSH
• poruchy vyvolané užíváním tabáku genetika   terapie   MeSH
• proteiny nervové tkáně MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Československo MeSH
• Názvy látek
• CHRNA5 protein, human MeSH Prohlížeč
• CYP2A6 protein, human MeSH Prohlížeč
• cytochrom P450 CYP2A6 MeSH
• cytochrom P450 CYP2B6 MeSH
• nikotinové receptory MeSH
• proteiny nervové tkáně MeSH

The Pregnane X (PXR), Vitamin D (VDR) and Farnesoid X (FXR) nuclear receptors have been shown to be receptors of bile acids controlling their detoxification or synthesis. Chenodeoxycholic (CDCA) and lithocholic (LCA) acids are ligands of FXR and VDR, respectively, whereas 3-keto and acetylated derivates of LCA have been described as ligands for all three receptors. In this study, we hypothesized that oxidation or acetylation at position 3, 7 and 12 of bile acids DCA (deoxycholic acid), LCA, CA (cholic acid), and CDCA by detoxification enzymes or microbiome may have an effect on the interactions with bile acid nuclear receptors. We employed reporter gene assays in HepG2 cells, the TR-FRET assay with recombinant PXR and RT-PCR to study the effects of acetylated and keto bile acids on the nuclear receptors activation and their target gene expression in differentiated hepatic HepaRG cells. We demonstrate that the DCA 3,12-diacetate and CA 3,7,12-triacetate derivatives are ligands of PXR and DCA 3,12-diacetate induces PXR target genes such as CYP3A4, CYP2B6 and ABCB1/MDR1. In conclusion, we found that acetylated DCA and CA are potent ligands of PXR. Whether the acetylated bile acid derivatives are novel endogenous ligands of PXR with detoxification or physiological functions should be further studied in ongoing experiments.

• Klíčová slova
• Bile acids, FXR, Metabolism, Nuclear receptors, PXR,
• MeSH
• acetylace MeSH
• buněčné kultury MeSH
• buňky Hep G2 MeSH
• cytochrom P-450 CYP3A genetika   MeSH
• cytochrom P450 CYP2B6 genetika   MeSH
• hepatocyty účinky léků   enzymologie   metabolismus   MeSH
• kyselina cholová chemie   metabolismus   farmakologie   MeSH
• kyselina deoxycholová chemie   metabolismus   farmakologie   MeSH
• lidé MeSH
• ligandy MeSH
• myši MeSH
• oxidace-redukce MeSH
• P-glykoprotein genetika   MeSH
• plazmidy MeSH
• pregnanový X receptor MeSH
• receptory cytoplazmatické a nukleární chemie   genetika   metabolismus   MeSH
• receptory kalcitriolu chemie   genetika   metabolismus   MeSH
• reportérové geny MeSH
• simulace molekulového dockingu MeSH
• steroidní receptory chemie   genetika   metabolismus   MeSH
• techniky dvojhybridového systému MeSH
• transfekce MeSH
• vazba proteinů MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cytochrom P-450 CYP3A MeSH
• cytochrom P450 CYP2B6 MeSH
• farnesoid X-activated receptor MeSH Prohlížeč
• kyselina cholová MeSH
• kyselina deoxycholová MeSH
• ligandy MeSH
• P-glykoprotein MeSH
• pregnanový X receptor MeSH
• receptory cytoplazmatické a nukleární MeSH
• receptory kalcitriolu MeSH
• steroidní receptory MeSH

Olomoucine II is a cyclin-dependent kinase inhibitor and a potential antineoplastic agent because it can arrest animal cell cycles. This study examines its interactions with human liver microsomal cytochrome P450 (P450) enzymes. Spectroscopic and high-performance liquid chromatography (HPLC) methods were used to estimate the degree of olomoucine II-mediated inhibition of enzymatic activities of eight drug-metabolizing P450s in vitro. In addition, mass spectrometry coupled with HPLC was used to identify an olomoucine II metabolite (2,5-dihydroxyroscovitine) formed in the reaction mixtures, and CYP3A4 was found to be responsible for the hydroxylation of the N(6)-benzyl ring at position 5, leading to this compound. Olomoucine II significantly inhibited the enzymatic activities of CYP1A2, CYP2C9, and (to a lesser degree) CYP3A4. The results indicate that use of olomoucine II as a drug could affect the activities of CYP3A4, CYP1A2, and CYP2C9 in vivo. Hence, the clinical relevance of these interactions should be carefully evaluated.

• MeSH
• aromatické hydroxylasy antagonisté a inhibitory   MeSH
• cytochrom P-450 CYP3A MeSH
• cytochrom P450 CYP2B6 MeSH
• cytochrom P450 CYP2C9 MeSH
• inhibiční proteiny cyklin-dependentních kinas farmakologie   MeSH
• inhibitory cytochromu P450 CYP1A2 MeSH
• inhibitory cytochromu P450 CYP3A * MeSH
• inhibitory cytochromu P450 MeSH
• jaterní mikrozomy účinky léků   enzymologie   MeSH
• játra cytologie   enzymologie   MeSH
• lékové interakce MeSH
• lidé MeSH
• N-demethylasy MeSH
• protinádorové látky farmakologie   MeSH
• puriny farmakologie   MeSH
• substrátová specifita MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aromatické hydroxylasy MeSH
• CYP2B6 protein, human MeSH Prohlížeč
• CYP2C9 protein, human MeSH Prohlížeč
• CYP3A4 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP3A MeSH
• cytochrom P450 CYP2B6 MeSH
• cytochrom P450 CYP2C9 MeSH
• inhibiční proteiny cyklin-dependentních kinas MeSH
• inhibitory cytochromu P450 CYP1A2 MeSH
• inhibitory cytochromu P450 CYP3A * MeSH
• inhibitory cytochromu P450 MeSH
• N-demethylasy MeSH
• olomoucine II MeSH Prohlížeč
• protinádorové látky MeSH
• puriny MeSH