|
Aspects of Gene Regulation of CYP3A4 in Hepatic Tissue.
Krausová, Lucie ; Štaud, František (advisor) ; Mičuda, Stanislav (referee) ; Skálová, Lenka (referee)
1 Summary CYP3A4 is an important enzyme involved in elimination of majority of metabolized xenobiotics. It plays a major role in the detoxification system of the human body, therefore it is responsible for many drug-drug interactions (DDIs). DDI present a complication of current pharmacotherapy, in the extreme they can lead in failure of therapy or in life-threatening toxic effects. DDIs are caused by changes in enzymatic activity of CYP3A4, which is highly variable among individuals. An important mechanism of modulating CAP3A4 activity is the regulation of inducible transcription by nuclear receptors, especially PXR, CAR and GR. The structure of CYP3A4 promoter and mechanisms of transcriptional regulation has been studding intensively for many years, but the research of relationship of nuclear receptors and transcriptional cofactors in CYP3A4 transactivation is still incomplete. Present work contributes to elucidation of some questions concerning the effects of azole antimycotics on CYP3A4 transcription via PXR, potency of valproic acid to activate PXR and CAR or determinants of CYP3A4 expression via GR in placental cells. The experiments were performed with up-to-date molecular biology methods and using in vitromodels of the primary human hepatocytes and hepatoma cell lines. To the aims of the doctoral...
|
| |
| |
| |
|
Local metabolism of glucocorticoids in female Prague hereditary hypertriglyceridemic rats
Klusoňová, Petra ; Pácha, Jiří (advisor) ; Kopecký, Jan (referee) ; Haluzík, Martin (referee)
11-hydroxysteroid dehydrogenase (11HSD1) is an oxidoreductase which catalyzes conversion of inactive 11-oxo steroid derivatives into active 11-hydroxy forms. 11HSD1 elevates intracellular level of active glucocorticoid (GC) hormones: cortisol in human tissues and corticosterone in rodents, therefore local level of active GCs can be set independently from systemic secretion driven by hypothalamo-pituitary-adrenal axis (HPA axis). Chronic systemic excess of GCs results in development of Cushing's syndrome which is characterised by central obesity and other metabolic disturbances. Despite normal serum levels of GCs, the patients with idiopathic obesity also develop metabolic syndrome. It was suggested that GCs could be elevated locally in target tissues due to enhanced 11HSD1 activity. This hypothesis was confirmed in transgenic rodent models. Prague hereditary hypertriglyceridemic (HHTg) rats represent a non-obese model of metabolic syndrome without genetic manipulations or specific mutations. The strain was bred by cross-mating of Wistar rat individuals with elevated serum levels of triglycerides (TGs). The strain exhibit hypertriglyceridemia and hypertension. When kept on high carbohydrate diet HHTg rats exhibit alterations in glucose homeostasis. Since there are no data that would describe...
|
|
Influence of Structure of Ionic Liquids on the Properties of their Mixtures with Water
Rotrekl, Jan
This contribution reports on a part of the results of a project focused on imidazolium-based ILs with a bis{(trifluoromethyl)sulfonyl}imide anion. The choice of the studied ILs is motivated by a study of the influence of the cation structure on the physico-chemical properties of pure ionic liquids and their mixtures with molecular solvents. For this purpose, four isomeric ILs, namely 1-alkyl-3-butylimidazolium bis{(trifluoromethyl) sulfonyl}imides (abbreviated [C4xC5im][Tf2N], alkyl = pentyl, isopentyl, 3-pentyl, or cyclopentyl) were selected. In a previous work, fundamental physico-chemical properties such as density, isobaric heat capacity, viscosity, electrical conductivity were measured.2 In this part of the study, the properties of the studied range of ILs in systems with water were investigated.
Fulltext: content.csg -  PDF
Plný tet: SKMBT_C22015061709371 - PDF
|
|
The comparison of the efficiency of cytochromes P450 expressed in prokaryotic and eukaryotic systems
Kroftová, Natálie ; Stiborová, Marie (advisor) ; Martínková, Markéta (referee)
v anglickém jazyce Cancer disease is a group of clinically diverse diseases characterized by uncontrolled proliferation of cancer cells incapable of differentiation. Tumor therapy consists of a combination of surgery, radiotherapy and chemotherapy utilizing cytostatic agents. The plant alkaloid ellipticine ranks among a group of cytostatic agents. Its mode of action is based on DNA intercalation, inhibition of topoisomerase II and formation of covalent DNA adducts. Ellipticine is oxidized through cytochromes P450 catalysis into detoxication metabolites 9-hydroxyellipticine and 7-hydroxyellipticine, and into activation metabolites 12-hydroxyellipticine, 13-hydroxyellipticine and ellipticine N2 -oxide. The aim of practical part of this work was to compare the efficiency of human cytochromes P450 1A1/2 and 3A4 expressed in prokaryotic and eukaryotic systems in the process of ellipticine oxidation. Ellipticine metabolites were analysed using high performance liquid chromatography. It was found that cytochrome P450 1A1 expressed in the prokaryotic system catalyses predominantly the formation of 9-hydroxyellipticine and 7-hydroxy- ellipticine. The difference is minimal in the production of ellipticine metabolites catalysed by cytochromes P450 1A2 expressed in both cellular systems. The formation of...
|
|
Atomistické simulace uspořádávání v niklových slitinách pod vlivem mechanického napětí
Buršík, Jiří
Systems containing up to six alloing elements typical of advanced Ni-based superalloys were modelled.their ordering was simulated at atomic level using a Monte Carlo approach with púeriodic boundary conditions and Kawasaki dynamics.molecular dynamics routines were embedded into standard kinetic Ising model to account for relaxing of local atomic positions.Straining computer experiments show that elastic parameters and bulk modulus undergo comparatively large changes at the beginning of ordering process.
|
|
The Meat Utilization of Rabbit Breed Czech Solver
PRAVDOVÁ, Lenka
This master's thesis focuses on the utilization of the Czech Solver, a Czech national rabbit breed, which is registered in The National Programme on Conservation of genetic resources of plants, animals and micro-organisms for Food and Agriculture. The Czech Solver was originally invented to be able to confirm or disprove the purebred origin of the tested animal. This feature is useful for breeders so that compensates for low meat performance breed. Fertility monitored breeding is less than the average fertility medium breeds, among that is the Czech Solver sorted, and significantly lower than the fertility of broiler rabbits. Surveyed individuals have achieved monthly weight gain sampler breeds of rabbits, but fattening period to 2.70 kg live weight ranged from an average of 105 days for semi-intensive rearing system in cages to 135 days at a traditional pens housing system farming, which is at least 27 days longer than the period of fattening broiler rabbits. Average growth rates were observed in the amount of 19.7 g in traditional breeding and 20.6 g in semi-intensive farming. Because the rabbits were slaughtered when reaching 2.70 kg live weight, were at abattoir analysis revealed no statistically significant differences between males and females or between traditional and semi-intensive farming. Slaughter analysis confirmed the breed Czech Solver average percentages of the intermediate part, fore and hind parts of the carcass and a higher proportion of kidney fat compared to other breeds of rabbits included in the genetic resources and compared with broiler breeds.
|
| |
guest ::
