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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...
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Factors Affecting Metabolism of Anthelmintics
Forstová, Veronika ; Skálová, Lenka (advisor) ; Machala, Miroslav (referee) ; Chládek, Jaroslav (referee)
Nowadays, anthelmintic therapy is the main method in the fight with parasitic worms. Anthelmintics, as well as other xenobiotics, undergo structural changes by effect of biotransformation enzymes, when lipophilic substances are transformed to polar substances more easily eliminable from the organism. Generally, biological effects of metabolites and parent compound are different. Activity of biotransformation enzymes is thus the fundamental factor influencing velocity of detoxification and elimination of the compound from the body and duration of drug effect as well. Modulation of biotransformation enzymes' activities can lead to changes in pharmacokinetic parameters of drug itself as well as other xenobiotics and thus to the risk of decrease in desired effect and/or increase in adverse effects with corresponding impact on the quality of drug therapy. In addition, possible risk of drug residues' presence in animal products has to be considered in farm animals. Biotransformation of xenobiotics is affected by many physiological as well as pathological factors. These factors can be divided into inter-individual (species, gender, genetic polymorphism) and intra-individual (age, diet, medication, disease, etc.). All these factors cause wide variability in occurrence and activity of biotransformation...
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Effect of selected compounds on the reduction and toxicity of doxorubicine in the tumorous cellular line
Vildová, Lenka ; Skálová, Lenka (advisor) ; Szotáková, Barbora (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Title, Name, Surname of candidate: Mgr. Lenka Vildová Title, Name, Surname of tutor: Doc. RNDr. Lenka Skálová, Ph.D. Title, Name, Surname of tutor-specialist: Mgr. Martina Gavelová, Ph.D. Title of a diploma work: The effect of selected compounds on reduction and toxicity of doxorubicin in cancer cell line. The anthracycline antibiotic doxorubicin is widely used in the treatment of solid and haematologic malignancies, including breast cancer. The major metabolite of doxorubicin is 13-doxorubicinol that has a significantly lower antineoplastic potency compared to the parent drug and has been implicated as a potential mediator of chronic cardiotoxicity. The aim of the present study was to evaluate the effect of inhibitors of carbonyl reductase 1 (CBR1), such as quercitrin, rutin, and menadion, and prospective anticancer agent oracin on reduction and toxicity of doxorubicin in human breast cancer MCF-7 cells. Experiment performed with menadion revealed that CBR1 plays a important role in reduction of doxorubicin in cytosol of MCF-7 cells. The formation of 13-doxorubicinol was inhibited by oracin that acts as a competitive inhibitor of CBR1. The cytotoxic effect of doxorubicin was examined by the...
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The metabolism of anthelmintics for helminth
Cvilink, Viktor ; Skálová, Lenka (advisor) ; Holčapek, Michal (referee) ; Machala, Miroslav (referee)
Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Mgr. Viktor Cvilink Supervisor: Doc. RNDr. Lenka Skálová, Ph.D. Title of Doctoral Thesis: METABOLISM OF ANTHELMINTICS IN HELMINTHS Anthelminthic drugs are presently the principal method for the control of helminth diseases. Knowledge of detoxification mechanisms that helminths possess is important for understanding the processes that affect the drug concentration within a helminth organism and may be crucial in the treatment efficacy. When the drug concentration in a target organism does not reach the therapeutic level, it results in a decreased efficacy of pharmacotherapy which may further lead to the induction of helminth biotransformation enzymes and eventually issue in resistance development to the administered drug. Present knowledge of helminth biotransformation enzymes is insufficient. Often it is not known whether a given individual helminth species possesses such enzymes or whether it is capable of employing them in treatment evasion. In the presented thesis, the objective was to investigate the biotransformation pathways of selected anthelminthics in model helminth species, identify the formed metabolites and characterize biotransformation enzymes of the studied parasites. Our...
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