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Nukleární receptory - studium nových ligandů a význam genové variability
Carazo Fernández, Alejandro ; Pávek, Petr (advisor) ; Mičuda, Stanislav (referee) ; Vrzal, Radim (referee)
IN ENGLISH LANGUAGE Candidate: Mgr. Alejandro Carazo Fernández Supervisor: Prof. PharmDr. Petr Pávek, PhD. Title of the doctoral thesis: Nuclear receptors - new ligands study and importance of the genetic variability Nuclear receptors (NRs) constitute a superfamily of transcription factors, which regulate the expression of target genes upon the binding of a ligand. These receptors can be classified in steroid receptors, "orphan receptors" and "adopted orphan receptors" depending on the affinity to an endogenous ligand. Nuclear receptors play important roles in physiological processes and are widely distributed in the human body. Thus, adipogenesis, lipolysis, insulin sensitivity, oxidative metabolism, fatty acid homeostasis, cholesterol homeostasis, gluconeogenesis, glycogen homeostasis, triglyceride metabolism among other processes, are regulated by nuclear receptors. During my study, we have tested several sets of drugs, endogenous, natural and synthetic, in several nuclear receptors, focusing mainly on constitutive androstane receptor (CAR) and to a lesser extent on pregnane X receptor (PXR). My main aim was to find a new and reliable ligand or activator for human CAR. In addition, I aimed to study the mechanism of action by which these compounds interact with the receptor and how they trigger...
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DRUG INTERACTION WITH XENOBIOTIC-METABOLIZING ENZYMES
Krasulová, Kristýna ; Hudeček, Jiří (referee) ; Vrzal, Radim (referee)
The aim of this Thesis was to evaluate the interaction of optical isomers of chiral drugs with nine of the most important xenobiotic-metabolizing enzymes, cytochromes P450. A key cause of drug-drug interactions is the inhibition of cytochrome P450 enzymes that are responsible for elimination of many drugs. Screening for inhibition potency of P450 by drugs is an important part of drug research. First part of the work was focused on the ability of chiral drugs to influence enzyme activity of nine most important cytochromes P450 involved in drug metabolism. The inhibition potency of individual enantiomers of one drug was compared. Optical isomers of azole antifungal drugs, known CYP3A4 inhibitors; enantiopure drugs, their excluded enantiomer and racemate; and dihydropyridine calcium channel blockers were studied. Molecular docking was used to verify selected in vitro results. Last aim of this work was to evaluate the effect of enantiomers of model drug, amlodipine, on enzyme activity of CYP2C9 and CYP2C19 alleles corresponding to poor, intermediate and extensive activity. Systematic testing of effect of individual enantiomers on enzyme activities of P450 in human liver microsomes revealed differences in the inhibition potency in most cases. Most interactions were with the most important form, CYP3A4....
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Nukleární receptory - studium nových ligandů a význam genové variability
Carazo Fernández, Alejandro ; Pávek, Petr (advisor) ; Mičuda, Stanislav (referee) ; Vrzal, Radim (referee)
IN ENGLISH LANGUAGE Candidate: Mgr. Alejandro Carazo Fernández Supervisor: Prof. PharmDr. Petr Pávek, PhD. Title of the doctoral thesis: Nuclear receptors - new ligands study and importance of the genetic variability Nuclear receptors (NRs) constitute a superfamily of transcription factors, which regulate the expression of target genes upon the binding of a ligand. These receptors can be classified in steroid receptors, "orphan receptors" and "adopted orphan receptors" depending on the affinity to an endogenous ligand. Nuclear receptors play important roles in physiological processes and are widely distributed in the human body. Thus, adipogenesis, lipolysis, insulin sensitivity, oxidative metabolism, fatty acid homeostasis, cholesterol homeostasis, gluconeogenesis, glycogen homeostasis, triglyceride metabolism among other processes, are regulated by nuclear receptors. During my study, we have tested several sets of drugs, endogenous, natural and synthetic, in several nuclear receptors, focusing mainly on constitutive androstane receptor (CAR) and to a lesser extent on pregnane X receptor (PXR). My main aim was to find a new and reliable ligand or activator for human CAR. In addition, I aimed to study the mechanism of action by which these compounds interact with the receptor and how they trigger...
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Nuclear receptors - new ligands study and importance of the genetic variability
Carazo Fernández, Alejandro José ; Pávek, Petr (advisor) ; Mičuda, Stanislav (referee) ; Vrzal, Radim (referee)
IN ENGLISH LANGUAGE Candidate: Mgr. Alejandro Carazo Fernández Supervisor: Prof. PharmDr. Petr Pávek, PhD. Title of the doctoral thesis: Nuclear receptors - new ligands study and importance of the genetic variability Nuclear receptors (NRs) constitute a superfamily of transcription factors, which regulate the expression of target genes upon the binding of a ligand. These receptors can be classified in steroid receptors, "orphan receptors" and "adopted orphan receptors" depending on the affinity to an endogenous ligand. Nuclear receptors play important roles in physiological processes and are widely distributed in the human body. Thus, adipogenesis, lipolysis, insulin sensitivity, oxidative metabolism, fatty acid homeostasis, cholesterol homeostasis, gluconeogenesis, glycogen homeostasis, triglyceride metabolism among other processes, are regulated by nuclear receptors. During my study, we have tested several sets of drugs, endogenous, natural and synthetic, in several nuclear receptors, focusing mainly on constitutive androstane receptor (CAR) and to a lesser extent on pregnane X receptor (PXR). My main aim was to find a new and reliable ligand or activator for human CAR. In addition, I aimed to study the mechanism of action by which these compounds interact with the receptor and how they trigger...
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