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Asymmetric biotransformation of certain tetralones to tetralols
Andrejch, Jan ; Poljaková, Jitka (advisor) ; Martínek, Václav (referee)
Preparation of pure enantiomers is very important part of chemical synthesis of industrially and pharmaceutically useful compounds. In recent years traditional chemical synthesis is replaced by biotransformations. Biotransformation means the use of isolated enzymes, enzymatic systems or whole cells in catalysis of chemical reactions. In comparison with chemical synthesis it has certain advantages. In this work the activity of yeast strains Saccharomyces uvarum K8, Saccharomyces cerevisiae K12, Torulopsis azyma K43, Torulopsis sphaerica K46 and Candida tropicalis K49, K51 a K52 in catalysis of reduction 6- bromo-2-tetralone, 7-hydroxy-2-tetralone and 7-methoxy-2-tetralone was studied. Products of these reductions are used in preparation of pharmaceutical drugs. Suitable conditions for biotransformations were found and it was proved that the yeast strains Saccharomyces uvarum K8 and Candida tropicalis K52 are able to produce 2- tetralones with ee greater than 90% with conversion 100% after four-hour biotransformation. This thesis is written in Czech.
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Technologické možnosti využití pivovarských kvasinek
Bergová, Sabina
This Bachelor thesis is focused on technological options on how to utilize brewer's yeast. It describes and concerns primary and secondary yeast cell and the usage of brewer's yeast. The primarily usage of brewer's yeast includes the production of beer, alcohol and last but not least bread. The usefulness of secondary yeast is focused on creation of SCP (Single cell protein), furthermore on how to gain medication and food supplements, cosmetics, feed, ephedrine, biofuel, fertilizer, condiment but also the ability of yeast bio sorption.
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Metabolismus kofeinu v lidském organismu, stanovení vybraných metabolitů metodou HPLC
LÁVIČKOVÁ, Kateřina
This bachelor thesis deals with description of caffeine metabolism in human body and the development, optimization and validation of the analytical method for the determination of selected caffeine metabolites in urine using HPLC. The first part was devoted to the description of caffeine metabolism, sources of caffeine and its influence on human body. Experimental part was focused on the development, optimization and validation of the analytical method to determine four caffeine metabolites and caffeine itself. This method was designed to be used by grammar student's laboratory. The work includes laboratory manual.
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Effect of rat enzymes on the metabolism of tyrosine kinase inhibitors in vitro and in vivo
Škriabová, Simona ; Indra, Radek (advisor) ; Ptáčková, Renata (referee)
Tyrosine kinase inhibitors are small molecules, orally available, well-tolerated and globally approved drugs for the treatment of several types of tumors. These drugs include vandetanib, cabozantinib, and lenvatinib, which are used to treat thyroid cancer. Vandetanib and cabozantinib are drugs approved for the treatment of medullary thyroid cancer, and lenvatinib is approved for the treatment of differentiated thyroid cancer. In the presented diploma thesis, the in vitro and in vivo metabolism of vandetanib, cabozantinib and lenvatinib was studied. Microsomes isolated from the liver of rats premedicated with pregnenolone carbonitrile were used to study in vitro metabolism. Plasma and urine samples of rats premedicated with individual tyrosine kinase inhibitors were used to study in vivo metabolism. The resulting metabolites were analyzed by high-performance liquid chromatography and subsequently identified using the mass spectrometry method. In the study of in vitro metabolism, when NADPH and cofactors (glucuronic acid and glutathione) were added to the samples, it was found that the most metabolites appeared for all three drugs during a longer incubation periods, and at the same time, it was found that glucuronic acid and glutathione can influence the structure, properties and functions of the...
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LC-MS/MS study of phase one in vitro biotransformation of potential drugs against Alzheimer's disease
Kuřátková, Aneta ; Kučera, Radim (advisor) ; Váňová, Nela (referee)
No treatment that would completely stop the progression of Alzheimer's disease has not been found yet. Recently used tacrine showed good results in the treatment of Alzheimer's disease, however long-term use led to chronic hepatotoxicity due to its metabolites. This master thesis deals with the compound 7-phenoxytacrine, one of the promising tacrine derivatives, which is one of the candidates for potential use in the therapy of Alzheimer's disease. Due to the formation of hepatotoxic metabolites of tacrine after the biotransformation in human liver, it appears necessary to identify the emerging metabolites of 7-phenoxytacrine molecule. Within this master's thesis in vitro biotransformation study of 7-phenoxytacrine using human liver microsomes was performed. High performance liquid chromatography with tandem mass spectrometry was used to determine the parent substance and the seventeen 7-phenoxytacrine metabolites. The analytical method showed the formation of six monohydroxylated and eleven dehydroxylated metabolites of 7-phenoxytacrine. Thus, we concluded that hydroxylation is the major metabolic reaction after in vitro microsomal biotransformation. In addition to the identification of metabolites, a quantification and microsomal stability study, including the determination of the amount of...
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LC-MS/MS study of phase one in vitro biotransformation of potential drugs against Alzheimer's disease
Kuřátková, Aneta ; Kučera, Radim (advisor) ; Váňová, Nela (referee)
No treatment that would completely stop the progression of Alzheimer's disease has not been found yet. Recently used tacrine showed good results in the treatment of Alzheimer's disease, however long-term use led to chronic hepatotoxicity due to its metabolites. This master thesis deals with the compound 7-phenoxytacrine, one of the promising tacrine derivatives, which is one of the candidates for potential use in the therapy of Alzheimer's disease. Due to the formation of hepatotoxic metabolites of tacrine after the biotransformation in human liver, it appears necessary to identify the emerging metabolites of 7-phenoxytacrine molecule. Within this master's thesis in vitro biotransformation study of 7-phenoxytacrine using human liver microsomes was performed. High performance liquid chromatography with tandem mass spectrometry was used to determine the parent substance and the seventeen 7-phenoxytacrine metabolites. The analytical method showed the formation of six monohydroxylated and eleven dehydroxylated metabolites of 7-phenoxytacrine. Thus, we concluded that hydroxylation is the major metabolic reaction after in vitro microsomal biotransformation. In addition to the identification of metabolites, a quantification and microsomal stability study, including the determination of the amount of...
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The influence of xenobiotic metabolizing enzymes and transporters on the incidence of colorectal cancer and chemotherapy outcome
Krus, Ivona ; Souček, Pavel (advisor) ; Králíčková, Milena (referee) ; Hodis, Jiří (referee)
Introduction: Colorectal cancer (CRC) is one of the most frequent malignancies and affects approximately 5% of worldwide population. More than 75% of CRC cases represent sporadic forms. Susceptibility to nonhereditary CRC is significantly influenced by polymorphisms and mutations in low-penetrance genes. Variations in biotransformation and DNA repair genes may result in acumulation of toxins and DNA damage in cells leading to the development of cancer. Furthermore, different gene expression profiles of membrane transporters affecting the accumulation of anticancer drugs in tumour cells, e.g. ABC drug transporters, may largely influence inter-individual variability in drug response and chemotherapy outcome. The aim of this study was to evaluate the role of genetic and lifestyle factors in the risk of onset and progression of colorectal cancer. This study followed selected genetic alterations in xenobiotic-metabolizing enzymes (CYP1B1, GSTM1, GSTT1, GSTP1, NQO1 and EPHX1) and genes involved in response to DNA damage (CHEK2 and NBN), as potential CRC susceptibility factors. Another aim of this study was to investigate expression profile of all human ABC transporter genes to follow their prognostic and predictive potential in colorectal carcinoma. Materials and methods: The polymorphisms and other...
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Study of genetic factors modifying the risk of onset and progression of colorectal and pancreatic cancer
Mohelníková Duchoňová, Beatrice ; Souček, Pavel (advisor) ; Skálová, Lenka (referee) ; Macek, Milan (referee)
Introduction: The aim of this study was to evaluate the role of genetic and lifestyle factors in the risk of onset and progression of colorectal and pancreatic cancer. The first part deals with the etiological factors and the importance of polymorphisms in biotransformation enzymes and genetic alterations in the gene CHEK2 in the origin of these malignancies. In the second part, the ABC transporter genes were analyzed as potential prognostic and predictive markers of a treatment's outcome. Materials and methods: The polymorphisms and other genetic alterations were detected using real-time PCR, allelespecific PCR and PCR-RFLP methods in DNA which was extracted from the blood of patients. The frequency of polymorphisms was evaluated and their importance was assessed with regard to the available epidemiological data. Gene expressions were determined by qPCR in paired samples of tumor tissue and adjacent non-tumorous parenchyma. Results: A majority of the observed polymorphisms failed to show a relationship between their presence and the risk of any of these malignancies. CYP2A13 variant allele*7 coding inactive enzyme was found in 7 of 265 controls and in none of 235 pancreatic carcinoma patients. In contrast, GSTP1-codon 105 Val variant allele and GSTT1-null genotype were associated with an elevated...
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Study of interaction of dihydromyricetin and alcohol in vivo
Vargová, Silvia ; Hodek, Petr (advisor) ; Kubíčková, Božena (referee)
- Abstrakt Dihydromyricetin (DHM), also known as ampelopsin, is a natural antioxidant found in the plant Ampelopsis grossedentata, traditionally used in Chinese medicine. Dihydromyricetin exhibits health-benefiting activities. Besides its antioxidative, anti-inflammatory, anticancer, and antimicrobial effects, it is said to suppress intoxication by alcohol and mitigate the symptoms of hangover and abstention. The mechanism of the activity of DHM on the metabolism of ethanol has not been fully explored. Thus, the focal point of the presented thesis was to explore the effect of DHM on the expression of CYP2E1, one of the major enzymes participating in the metabolism of ethanol in organisms. Male rats were administered with ethanol (EtOH) or ethanol in combination with DHM, and the EtOH concentration of the blood was determined. The amount of EtOH and acetaldehyde in the blood of individuals indicates that DHM does not affect the rate of EtOH metabolism. Subsequently, the effect of DHM on repeated premedication of EtOH was monitored. The group of rats treated with DHM showed a slower metabolism of EtOH than the group solely premedicated with EtOH. Ultimately, the effect of DHM on CYP2E1 expression was studied. Microsomal fractions were prepared from the rat livers. By use of Western blotting with a...
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