• MeSH
• depresivní poruchy farmakoterapie   komplikace   MeSH
• enzymová indukce MeSH
• fenytoin * farmakokinetika   otrava   škodlivé účinky   MeSH
• komorbidita MeSH
• lékové interakce MeSH
• lékový hypersenzitivní syndrom etiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• monitorování léčiv MeSH
• pokus o sebevraždu MeSH
• úrazy pádem MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Cytochrome P450 family 1 (CYP1) enzymes contribute both to metabolism of xenobiotics and to the control of endogenous levels of ligands of the aryl hydrocarbon receptor (AhR). Their activities, similar to other CYPs, can be altered in tumor tissues. Here, we examined a possible role of proliferative/survival pathways signaling, which is often deregulated in tumor cells, and possible links with p300 histone acetyltransferase (a transcriptional co-activator) in the control of CYP1 expression, focusing particularly on CYP1A1. Using cell models derived from human liver, we observed that the induction of CYP1A1 expression, as well as other CYP1 enzymes, was reduced in exponentially growing cells, as compared with their non-dividing counterparts. The siRNA-mediated inhibition of proliferation/pro-survival signaling pathway effectors (such as β-catenin and/or Hippo pathway effectors YAP/TAZ) increased the AhR ligand-induced CYP1A1 mRNA levels in liver HepaRG cells, and/or in colon carcinoma HCT-116 cells. The activation of proliferative Wnt/β-catenin signaling in HCT-116 cells reduced both the induction of CYP1 enzymes and the binding of p300 to the promoter of CYP1A1 or CYP1B1 genes. These results seem to indicate that aberrant proliferative signaling in tumor cells could suppress induction of CYP1A1 (or other CYP1 enzymes) via competition for p300 binding. This mechanism could be involved in modulation of the metabolism of both endogenous and exogenous substrates of CYP1A1 (and other CYP1 enzymes), with possible further consequences for alterations of the AhR signaling in tumor cells, or additional functional roles of CYP1 enzymes.

• MeSH
• cytochrom P-450 CYP1A1 biosyntéza   genetika   MeSH
• enzymová indukce fyziologie   MeSH
• HCT116 buňky MeSH
• játra patologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory tračníku genetika   patologie   MeSH
• proliferace buněk fyziologie   MeSH
• protein p300 asociovaný s E1A metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• signální dráha Hippo fyziologie   MeSH
• signální dráha Wnt fyziologie   MeSH
• signální transdukce fyziologie   MeSH
• viabilita buněk fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

OBJECTIVE: To receive information about carbamazepine and its active metabolite 10,11-epoxide transport into mature milk and suckling infants. METHODS: In this cohort study, maternal serum, mature milk, and infant serum carbamazepine and epoxide levels were measured between the 6th and 29th postnatal day (carbamazepine in 1990-2017, epoxide in 1997-2017). Paired maternal serum, infant serum and milk levels were used for the assessment of ratios of this levels. The influence of combined treatment with enzyme-inducing antiepileptic drugs and valproic acid was assessed. Relationship between maternal serum, infant serum, and milk levels was also evaluated. RESULTS: Maternal carbamazepine levels were 1.4-10.4 mg/L, milk 0.5-6.7 mg/L and infant 0.5-2.6 mg/L. Maternal 10,11-epoxide levels were 0.3-5.4 mg/L, milk 0.3-3.7 mg/L and infant 0.3-0.6 mg/L. Highly significant correlations were observed exclusively between milk and maternal serum levels of both carbamazepine and 10,11-epoxide. Concomitant administration of enzyme-inducing antiepileptic drugs significantly increased the maternal apparent oral clearance of carbamazepine by approximately 130%. Carbamazepine combined with valproic acid significantly increased epoxide levels in milk and maternal serum but not in breastfed infants. CONCLUSIONS: In breastfed infants, carbamazepine levels did not reach the lower limit of the therapeutic range used for the general epileptic population, and the majority of epoxide levels were less than the lower limit of quantification. Routine monitoring of carbamazepine in these infants is not compulsory. However, observation of breastfed infants is desirable. If signs of potential adverse reactions are evident, infant serum concentrations should be monitor.

• MeSH
• antikonvulziva metabolismus   farmakokinetika   MeSH
• biotransformace MeSH
• dospělí MeSH
• enzymová indukce účinky léků   MeSH
• epoxidové sloučeniny metabolismus   MeSH
• karbamazepin metabolismus   farmakokinetika   MeSH
• kohortové studie MeSH
• kojení MeSH
• kyselina valproová farmakokinetika   MeSH
• lékové interakce MeSH
• lidé MeSH
• mateřské mléko chemie   metabolismus   MeSH
• mladý dospělý MeSH
• monitorování léčiv MeSH
• novorozenec MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Tuberculosis (TB) remains one of the major health concerns worldwide. Mycobacterium tuberculosis (Mtb), the causative agent of TB, can flexibly change its metabolic processes during different life stages. Regulation of key metabolic enzyme activities by intracellular conditions, allosteric inhibition or feedback control can effectively contribute to Mtb survival under different conditions. Phosphofructokinase (Pfk) is one of the key enzymes regulating glycolysis. Mtb encodes two Pfk isoenzymes, Pfk A/Rv3010c and Pfk B/Rv2029c, which are differently expressed upon transition to the hypoxia-induced non-replicating state of the bacteria. While pfkB gene and protein expression are upregulated under hypoxic conditions, Pfk A levels decrease. Here, we present biochemical characterization of both Pfk isoenzymes, revealing that Pfk A and Pfk B display different kinetic properties. Although the glycolytic activity of Pfk A is higher than that of Pfk B, it is markedly inhibited by an excess of both substrates (fructose-6-phosphate and ATP), reaction products (fructose-1,6-bisphosphate and ADP) and common metabolic allosteric regulators. In contrast, synthesis of fructose-1,6-bisphosphatase catalyzed by Pfk B is not regulated by higher levels of substrates, and metabolites. Importantly, we found that only Pfk B can catalyze the reverse gluconeogenic reaction. Pfk B thus can support glycolysis under conditions inhibiting Pfk A function.

• MeSH
• adenosindifosfát metabolismus   farmakologie   MeSH
• adenosintrifosfát metabolismus   farmakologie   MeSH
• alosterická regulace MeSH
• bakteriální proteiny antagonisté a inhibitory   metabolismus   MeSH
• enzymová indukce MeSH
• fosfofruktokinasy antagonisté a inhibitory   metabolismus   MeSH
• fruktosadifosfáty biosyntéza   farmakologie   MeSH
• fruktosafosfáty metabolismus   farmakologie   MeSH
• glukoneogeneze MeSH
• glykolýza MeSH
• hexosafosfáty metabolismus   MeSH
• izoenzymy antagonisté a inhibitory   metabolismus   MeSH
• katalýza MeSH
• kinetika MeSH
• kyslík farmakologie   MeSH
• L-laktátdehydrogenasa metabolismus   MeSH
• Mycobacterium tuberculosis účinky léků   enzymologie   MeSH
• pyruvátkinasa metabolismus   MeSH
• rekombinantní proteiny metabolismus   MeSH
• substrátová specifita MeSH
• zpětná vazba fyziologická MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH

Mono-methylindoles (MMI) were described as agonists and/or antagonists of the human aryl hydrocarbon receptor (AhR). Here, we investigated the effects of MMI on AhR-CYP1A pathway in human hepatocytes and HepaRG cells derived from human progenitor hepatic cells. All MMI, except of 2-methylindole, strongly induced CYP1A1 and CYP1A2 mRNAs in HepaRG cells. Induction of CYP1A genes was absent in AhR-knock-out HepaRG cells. Consistently, CYP1A1 and CYP1A2 mRNAs and proteins were induced by all MMIs (except 2-methylindole), in human hepatocytes. The enzyme activity of CYP1A1 was inhibited by MMIs in human hepatocytes and LS180 colon cancer cells in a concentration-dependent manner (IC50 values from 1.2 μM to 23.8 μM and from 3.4 μM to 11.4 μM, respectively). Inhibition of CYP1A1 activity by MMI in human liver microsomes was much weaker as compared to that in intact cells. Incubation of parental MMI with human hepatocytes either diminished (4-methylindole, 6-methylindole) or enhanced (7-methylindole) their agonist effects on AhR in AZ-AHR reporter cells. In conclusion, overall effects of MMI on AhR-CYP1A pathway in human cells comprise the induction of CYP1A genes through AhR, the inhibition of CYP1A catalytic activity and possibly the metabolic transformation causing loss or gain of AhR agonist activity of parental compounds.

• MeSH
• cytochrom P-450 CYP1A1 antagonisté a inhibitory   biosyntéza   genetika   MeSH
• enzymová indukce MeSH
• hepatocyty účinky léků   enzymologie   MeSH
• indoly farmakologie   MeSH
• induktory cytochromu P450 farmakologie   MeSH
• inhibitory cytochromu P450 farmakologie   MeSH
• jaterní mikrozomy účinky léků   enzymologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• nádorové buněčné linie MeSH
• nádory tračníku enzymologie   MeSH
• receptory aromatických uhlovodíků agonisté   genetika   metabolismus   MeSH
• senioři MeSH
• transkripční faktory bHLH agonisté   genetika   metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

After cold shock, the Bacillus subtilis desaturase Des introduces double bonds into the fatty acids of existing membrane phospholipids. The synthesis of Des is regulated exclusively by the two-component system DesK/DesR; DesK serves as a sensor of the state of the membrane and triggers Des synthesis after a decrease in membrane fluidity. The aim of our work is to investigate the biophysical changes in the membrane that are able to affect the DesK signalling state. Using linear alcohols (ethanol, propanol, butanol, hexanol, octanol) and benzyl alcohol, we were able to suppress Des synthesis after a temperature downshift. The changes in the biophysical properties of the membrane caused by alcohol addition were followed using membrane fluorescent probes and differential scanning calorimetry. We found that the membrane fluidization induced by alcohols was reflected in an increased hydration at the lipid-water interface. This is associated with a decrease in DesK activity. The addition of alcohol mimics a temperature increase, which can be measured isothermically by fluorescence anisotropy. The effect of alcohols on the membrane periphery is in line with the concept of the mechanism by which two hydrophilic motifs located at opposite ends of the transmembrane region of DesK, which work as a molecular caliper, sense temperature-dependent variations in membrane properties.

• MeSH
• alkoholy farmakologie   MeSH
• aminokyselinové motivy MeSH
• Bacillus subtilis metabolismus   MeSH
• bakteriální proteiny metabolismus   MeSH
• buněčná membrána účinky léků   fyziologie   MeSH
• desaturasy mastných kyselin biosyntéza   genetika   MeSH
• diferenciální skenovací kalorimetrie MeSH
• enzymová indukce účinky léků   MeSH
• fluidita membrány účinky léků   MeSH
• fluorescenční polarizace MeSH
• fosforylace MeSH
• hydrofobní a hydrofilní interakce MeSH
• mastné kyseliny metabolismus   MeSH
• nízká teplota MeSH
• posttranslační úpravy proteinů * MeSH
• proteinkinasy metabolismus   MeSH
• regulace genové exprese u bakterií účinky léků   MeSH
• rekombinantní fúzní proteiny metabolismus   MeSH
• reportérové geny MeSH
• signální transdukce účinky léků   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie 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

Heat Shock Protein 90 (HSP90) is a fertility-associated protein, the expression of which positively correlates with sperm quality in many species. Geranylgeranylacetone (GGA) is reported to induce expression of HSP90. The present study aimed to investigate whether GGA induced expression of HSP90 in Acipenser sinensis sperm to exert a cryoprotective effect. Sperm from five male A. sinensis was combined with extender containing 20 mmol/L tris pH = 8.1, 10% v/v methanol, 2-5 mmol/L KCl, 15 mmol/L lactose, and 15 mmol/L trehalose, with GGA at 0, 14, 67, 135, 673, 1346, or 6731 μmol/L. After cryopreservation and thawing, the percentage of motile spermatozoa, spermatozoon curvilinear velocity (VCL), straight-line velocity (VSL), average path velocity (VAP), acrosome integrity, and membrane integrity, as well as fertility were evaluated. Sperm quality increased with the increase of GGA to 673 μmol/L, but decreased at higher concentrations. Expression levels of HSP90α were detected by Western blot in sperm frozen with GGA at 673 μmol/L (highest obtained sperm quality), 6731 μmol/L (highest GGA concentration), and a control without GGA. The expression of HSP90α increased with the increase in GGA, with lowest expression observed in the control. GGA was found to induce increase of HSP90α, and this increase was associated with higher quality cryopreserved sperm at concentrations ≤673 μmol/L. This research suggests a viable technique to increase the quality of cryopreserved A. sinensis sperm by adding GGA to induce expression of HSP90α.

• MeSH
• cytoprotekce * účinky léků   genetika   MeSH
• diterpeny farmakologie   MeSH
• enzymová indukce účinky léků   MeSH
• kryoprezervace veterinární   MeSH
• kryoprotektivní látky metabolismus   farmakologie   MeSH
• motilita spermií genetika   MeSH
• proteiny tepelného šoku HSP90 genetika   metabolismus   MeSH
• ryby * genetika   metabolismus   MeSH
• spermie MeSH
• uchování spermatu * veterinární   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Polycyclic aromatic hydrocarbons such as benzo[a]pyrene (BaP) can induce cytochrome P450 1A1 (CYP1A1) via a p53-dependent mechanism. The effect of different p53-activating chemotherapeutic drugs on CYP1A1 expression, and the resultant effect on BaP metabolism, was investigated in a panel of isogenic human colorectal HCT116 cells with differing TP53 status. Cells that were TP53(+/+), TP53(+/-) or TP53(-/-) were treated for up to 48 h with 60 μM cisplatin, 50 μM etoposide or 5 μM ellipticine, each of which caused high p53 induction at moderate cytotoxicity (60-80% cell viability). We found that etoposide and ellipticine induced CYP1A1 in TP53(+/+) cells but not in TP53(-/-) cells, demonstrating that the mechanism of CYP1A1 induction is p53-dependent; cisplatin had no such effect. Co-incubation experiments with the drugs and 2.5 μM BaP showed that: (i) etoposide increased CYP1A1 expression in TP53(+/+) cells, and to a lesser extent in TP53(-/-) cells, compared to cells treated with BaP alone; (ii) ellipticine decreased CYP1A1 expression in TP53(+/+) cells in BaP co-incubations; and (iii) cisplatin did not affect BaP-mediated CYP1A1 expression. Further, whereas cisplatin and etoposide had virtually no influence on CYP1A1-catalysed BaP metabolism, ellipticine treatment strongly inhibited BaP bioactivation. Our results indicate that the underlying mechanisms whereby etoposide and ellipticine regulate CYP1A1 expression must be different and may not be linked to p53 activation alone. These results could be relevant for smokers, who are exposed to increased levels of BaP, when prescribing chemotherapeutic drugs. Beside gene-environment interactions, more considerations should be given to potential drug-environment interactions during chemotherapy.

• MeSH
• adukty DNA metabolismus   MeSH
• benzopyren farmakokinetika   farmakologie   MeSH
• cisplatina farmakologie   MeSH
• cytochrom P-450 CYP1A1 biosyntéza   metabolismus   MeSH
• cytochrom P-450 CYP3A biosyntéza   metabolismus   MeSH
• elipticiny farmakokinetika   farmakologie   MeSH
• enzymová indukce účinky léků   MeSH
• etoposid farmakologie   MeSH
• geny p53 MeSH
• HCT116 buňky MeSH
• karcinogeny farmakokinetika   farmakologie   MeSH
• kolorektální nádory farmakoterapie   genetika   metabolismus   patologie   MeSH
• lidé MeSH
• metabolická aktivace MeSH
• nádorový supresorový protein p53 nedostatek   genetika   metabolismus   MeSH
• poškození DNA MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Quercetin, the active substance of tea, fruits and vegetables, exerts a broad spectrum of pharmacological activities and is considered to have potential therapeutic application. The present study was designed to investigate the beneficial effect of quercetin against experimental ischemia- reperfusion (IR) injury of the small intestine in rats. Quercetin was administrated intraperitoneally 30min before 1h ischemia of superior mesenteric artery with following reperfusion periods lasting 1, 4 and 24h. The male specific pathogen-free Charles River Wistar rats were used (n=45). In acute phase, 4h after start of reperfusion, the quercetin induced a significant decrease in mucosal injury index (p<0.05) accompanied by a significant decrease in cyclooxygenase-2 (COX-2) expression in the epithelial lining of the intestinal villi in comparison with the control group (p<0.01). In the epithelium of the intestinal glands, COX-2 expression resulting from IR injury significantly increased regardless quercetin application (in control group p<0.001; in quercetin group p<0.05), but in quercetin group, significant decrease in it during 24h of reperfusion in a late phase of IR injury was detected (p<0.001). Based on morphology of COX-2 positive cells, the COX-2 positivity was found particularly in goblet cells of the intestinal villi epithelium and enteroendocrine cells respectively, in the glandular epithelium. We concluded that quercetin application attenuated mucosal damage from IR injury by inhibiting neutrophil infiltration which was demonstrated by a lower number of myeloperoxidase positive cells in the lamina propria during both phases of IR injury and the significant decrease in that in a late phase after 24h of reperfusion (p<0.05).

• MeSH
• cyklooxygenasa 2 biosyntéza   MeSH
• enzymová indukce MeSH
• epitelové buňky účinky léků   enzymologie   MeSH
• peroxidasa biosyntéza   MeSH
• potkani Wistar MeSH
• quercetin farmakologie   terapeutické užití   MeSH
• reperfuzní poškození farmakoterapie   enzymologie   MeSH
• střevní sliznice účinky léků   enzymologie   zranění   patologie   MeSH
• tenké střevo patologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH