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.

• 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

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.

• 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

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.

• 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
• primární buněčná kultura MeSH
• reportérové geny MeSH
• steroidní receptory účinky léků   metabolismus   MeSH
• střeva účinky léků   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články 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.

• 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
• 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

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.

• 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

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.

• 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