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Function of Biotransformation Enzymes in Development of Nephropathies Caused by Aristolochic Acid
Bárta, František ; Stiborová, Marie (advisor) ; Koblihová, Jitka (referee) ; Eckschlager, Tomáš (referee)
- 6 - ABSTRACT Plant alkaloid aristolochic acid (AA) is a proven human carcinogen which causes two serious diseases: Aristolochic Acid Nephropathy (AAN) and Balkan Endemic Nephropathy (BEN). One of the characteristic features of both AAN and BEN is their close association with the development of upper urothelial carcinoma (UUC) in the renal tissue of patients. Although both nephropathies are mediated by the same compound (i.e. AA), their development differs slightly. The differences might be explained by a different exposure schedule of patients or interindividual differences in expression levels and activities of the enzymes metabolising AA in organisms. Detailed knowledge of these enzymes can contribute to the elucidation of the interindividual susceptibility to AA. In this thesis, enzymes participating in both oxidative detoxification of AAI, a major component of natural mixture of AA, and its reductive activation leading to the formation of AA-DNA adducts were studied. In a rat experimental model (Rattus norvegicus), NAD(P)H:quinone oxidoreductase 1 (NQO1) and its role in reductive bio-activation of AAI in vivo were examined utilising a specific inhibitor of this enzyme, dicoumarol. Oxidative detoxification of AAI resulting in formation of a demethylated derivative AAIa (8-hydroxyaristolochic...
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Inhibitors of tyrosine kinases as anticancer drugs of a new generation
Hromek, Vlastimil ; Stiborová, Marie (advisor) ; Bárta, František (referee)
At the present time many types of treatment are used for curing of different cancer diseases. Among the most common types of such treatment belong a surgery, radiotherapy, chemotherapy, and immunotherapy. In the case of chemotherapy, there is used a wide (broad) spectrum of chemotherapeutics such as alkylating agents, platinum compounds, antimetabolites, anthracyclines and, at the present time, also inhibitors of tyrosine kinases. The bachelor thesis describes different types of tyrosine kinase inhibitors and their use in treatment of several cancers. They become popular because of their high specifity and minimal side efects. The first successful use of a tyrosine kinase inhibitor was treatment of the patients suffering from chronic myelogenous leukemia (CML) with imatinib. Vandetanib is another inhibitor of tyrosine kinases that is now used for treatment of another cancer, the medullary thyroid cancer. During treatment, vandetanib is biotransformed with cytochromes P450, which are the terminal oxidases of a mixed function oxidase (MFO) system, into the less efficient metabolites. In the practical part of the bachelor thesis we isolated enzymes, which metabolize xenobiotics, including vandetanib. Rat liver tissue was used for isolation of NADPH:cytochrome P450 reductase, which was isolated as a...
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Mechanism of carcinogenicity and nephrotoxicity of aristolochic acids
Bárta, František
Aristolochic acids (AA) are human carcinogens which have also very strong nephrotoxic properties. A mixture of AA is present in Aristolochiacae plant species. These plants were and still are used in traditional medicine in some countries, particularly in Asia. Aristolochic acids participate in development of two types of nephropathies. The first disease is designated as Aristolochic Acid Nephropathy (AAN), the second one is Balkan Endemic Nephropathy (BEN). Both nephropathies are associated with urothelial malignancies, which are caused by AA. One of the common features of ANN and BEN is that not all individuals exposed to AA suffer from nephropathy and tumour development. One cause for these different responses may be individual differences in the activities and expression levels of the enzymes catalyzing the biotransformation of AAI, the major toxic component of AA contained in Aristolochia species. Detailed knowledge of enzymes which participate in metabolism of AAI may contribute to elucidation of inter-individual susceptibility to AAN, BEN and later urothelial malignancies. Aristolochic acid I is either oxidative detoxicated or reductive activated by biotransformation enzymes. Reductive bioactiovation of AAI leads to formation of covalent AA-DNA adducts in organism which result in producing of...
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Study on the induction of intestinal conjugation enzymes by food supplements
Hrdinová, Johana ; Hodek, Petr (advisor) ; Bárta, František (referee)
Cytochrome P450s (CYP) are enzymes, that play an important role in the metabolism of foreign compounds (e.g. drugs, carcinogens, pollutants) and they also participate in the metabolism of hydrophobic endogenic substrates (e.g. sterols, fatty acids, prostaglandins). Cytochromes of subfamily CYP1A are involved in activation of precarcinogens. Whereas the consumption of dietary supplements containing chemopreventive substances (e.g. flavonoids) that can prevent the process of carcinogenesis is significantly increasing in recent years, although these substances may also have a negative effect on the organism. That because these substances can induce the cytochrome P450s and thus increase the risk of activation precarcinogens. In this study had been investigated the inductive effect of some flavonoids compounds - β-naphthoflavone, myricetin, dihydromyricetin and a drug containing an extract of red vine leafs - Antistax®.
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Laboratory Diagnosis of Primary Aldosteronism
Hulová, Dagmar ; Martínková, Markéta (advisor) ; Bárta, František (referee)
Primary aldosteronism is a common form of endocrine hypertension, characterized by inappropriate production of aldosterone by the adrenal cortex, usually because of the unilateral adenoma (APA) or bilateral hyperplasia (IHA). The aim of this study was answer the question, if it is possible to distinguish APA from IHA with the use of the postural or the confirmatory test. From the laboratory results of the postural test, it was found that for the differentiation between the two most common forms of primary hyperaldosteronism APA and IHA is the postural test unusable in most cases. By the confirmation test was confirmed that there is not suppression of aldosterone after the administration of the saline solution to patients with primary aldosteronism below 100 ng∙l-1 in most cases (for APA in 85 %, for IHA in 65 %), in the remaining cases the value of the aldosterone do not decrease below 50 ng∙l-1 A higher value of the aldosterone in APA after the administration of the saline solution in the confirmation test could be considered a laboratory indicator of overproduction in APA.
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Mechanism of carcinogenicity and nephrotoxicity of aristolochic acids
Bárta, František ; Stiborová, Marie (advisor) ; Dračínská, Helena (referee)
Aristolochic acids (AA) are human carcinogens which have also very strong nephrotoxic properties. A mixture of AA is present in Aristolochiacae plant species. These plants were and still are used in traditional medicine in some countries, particularly in Asia. Aristolochic acids participate in development of two types of nephropathies. The first disease is designated as Aristolochic Acid Nephropathy (AAN), the second one is Balkan Endemic Nephropathy (BEN). Both nephropathies are associated with urothelial malignancies, which are caused by AA. One of the common features of ANN and BEN is that not all individuals exposed to AA suffer from nephropathy and tumour development. One cause for these different responses may be individual differences in the activities and expression levels of the enzymes catalyzing the biotransformation of AAI, the major toxic component of AA contained in Aristolochia species. Detailed knowledge of enzymes which participate in metabolism of AAI may contribute to elucidation of inter-individual susceptibility to AAN, BEN and later urothelial malignancies. Aristolochic acid I is either oxidative detoxicated or reductive activated by biotransformation enzymes. Reductive bioactiovation of AAI leads to formation of covalent AA-DNA adducts in organism which result in producing of...
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Nephropathy and tumour development caused by plant alkaloids aristolochic acid
Bárta, František ; Šácha, Pavel (referee) ; Stiborová, Marie (advisor)
Aristolochic acids (AA) are alkaloids contained in plant species of the family Aristolochiaceae. These plants are used since antiquity in traditional medicine to treatment of many varied diseases. There are known anti-inflammatory effects of these compounds, however these alkaloids exhibit mutagenic and carcinogenic properties. Despite of this fact, plant extracts AA are still used in traditional medicine, e.g. in China, India, Taiwan. Aristolochic acids are proven to be the cause of disease designated Aristolochic Acid Nephropathy (AAN, theretofore known as Chinese Herbs Nephropathy (CHN). This unusual nephropathy leads to a total renal failure. The late complication of this disease is the development of tumours in urothelial tissue of patients. AA can form persistent stable covalent DNA adducts. Formation of these DNA adducts lead to AT→TA transversion, the unique mutation in tumour suppressor gene p53 responsible for tumour formation. Balkan Endemic Nephropathy (BEN) is associated with AA, too. In this instance is supported also influence of another factors, e.g. mycotoxins (ochratoxin A). However, in all probability AA contribute to a development of this disease particularly. This hypothesis is supported by finding of AA-DNA adducts in tissues of patients suffering from AAN and BEN and that of...
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Driving of a syringe pump stepper
Bárta, František ; Rampl, Ivan (referee) ; Chmelař, Milan (advisor)
The thesis is focused on the topic of a stepper motor control of injection dosing. At the beginning of the work are discussed properties , types, characteristics and possibilities of control of stepper motors. The thesis deals with the infusion dosing, their properties and parameters. They are shown both domestic and foreign manufacturers and their products. At the conclusion of the work is described by the theoretical design control circuit for stepper motor according to the selected engine.
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