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Nephropathy and tumour development caused by plant alkaloids aristolochic acid
Bárta, František ; Stiborová, Marie (advisor) ; Šácha, Pavel (referee)
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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Molecular mechanism of carcinogenicity of aristolochic acid
Levová, Kateřina ; Stiborová, Marie (advisor) ; Ryšlavá, Helena (referee) ; Souček, Pavel (referee)
Aristolochic acids (AA) are carcinogenic and nephrotoxic alkaloids from Aristolochia species. Aristolochic acid I (AAI), the major component of AA, causes the development of Aristolochic acid nephropathy (AAN) and Balkan endemic nephropathy (BEN). These two diseases cause total renal failure and urothelial malignancies. The fact that these diseases have not been developed in all persons, who have been exposed to their action, might be causd by different activities and protein levels of the enzymes metabolizing AAI. Thus, the identification of enzymes involved in the metabolism, and detailed knowledge of their expression and catalytic specifities is a major importance. Aristolochic acid I (AAI) can be metabolized by several types of reactions. Like most nitroaromatics, the main activation pathway of AAI is reduction of its nitro group to form a cyclic acylnitrenium ion, which can bind to the purine bases, thereby forming AAI-DNA adducts. The detoxication pathway of AAI is its oxidative demethylation by cytochromes P450 forming detoxication metabolite 8-hydroxyaristolochic acid Ia (AAIa). In the present thesis, using rat and human enzymes and as well as several mice models, the metabolism of AAI in vitro and in vivo was investigated. The first model has deleted gene for NADPH:cytochrome P450...
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Effect of cytochrome b5 on activity of cytochromes P450
Ličko, Vojtech ; Indra, Radek (advisor) ; Feglarová, Tereza (referee)
ABSTRACT Cytochrome b5 (CYB5) is heme protein capable of reduction of cytochromes P450 (CYP) or some other enzymes. However, his regulative capability was also observed by his apo form, i.e. in absence of heme prosthetic group in the active center. CYB5 can accept electron from cytochrome b5 reductase (CYB5R) or from cytochrome P450 reductase (CYPOR). CYPOR by itself is reduced by NADPH and is also able to forward electron to CYP independently of CYB5. CYB5R on the other hand is reduced by NADH. Efficiency of CYB5 to accept and forward an electron was studied in vitro with five different substrates - testosterone, Sudan I, aristolochic acid I (AAI), ellipticine and vandetanib. These substrates were chosen considering their characteristic reactions, which are catalyzed by their respective isoforms of CYP. The experiments with these substrates were carried out in the medium with recombinant CYPs prepared in insect cells or E. coli or in the medium with hepatic microsomes isolated from different organisms. Rats, from which the majority of these microsomes was isolated, were premedicated by different CYP inducers. The experiments were carried out in medium with NADH or NADPH in order to assess the capability of CYB5 to reduce CYP independently of CYPOR. The capability of CYB5 and CYB5R to act as a...
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Molecular mechanism of carcinogenicity of aristolochic acid
Levová, Kateřina ; Stiborová, Marie (advisor) ; Ryšlavá, Helena (referee) ; Souček, Pavel (referee)
Aristolochic acids (AA) are carcinogenic and nephrotoxic alkaloids from Aristolochia species. Aristolochic acid I (AAI), the major component of AA, causes the development of Aristolochic acid nephropathy (AAN) and Balkan endemic nephropathy (BEN). These two diseases cause total renal failure and urothelial malignancies. The fact that these diseases have not been developed in all persons, who have been exposed to their action, might be causd by different activities and protein levels of the enzymes metabolizing AAI. Thus, the identification of enzymes involved in the metabolism, and detailed knowledge of their expression and catalytic specifities is a major importance. Aristolochic acid I (AAI) can be metabolized by several types of reactions. Like most nitroaromatics, the main activation pathway of AAI is reduction of its nitro group to form a cyclic acylnitrenium ion, which can bind to the purine bases, thereby forming AAI-DNA adducts. The detoxication pathway of AAI is its oxidative demethylation by cytochromes P450 forming detoxication metabolite 8-hydroxyaristolochic acid Ia (AAIa). In the present thesis, using rat and human enzymes and as well as several mice models, the metabolism of AAI in vitro and in vivo was investigated. The first model has deleted gene for NADPH:cytochrome P450...
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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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