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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 of metabolism carcinogenic and nephrotoxic natural compound aristolochic acid II
Martináková, Lenka ; Stiborová, Marie (advisor) ; Moserová, Michaela (referee)
Aristolochic acids (AA) have been considered as toxicants of plants which were found in plants of the family Aristolochiaceae. The most abundant acids in mentioned plants are aristolochic acid I (AAI) and aristolochic acid II (AAII). AA have been considered as causes kidney disease called Aristolochic acid nephropathy (AAN). AAN was initially discovered in patients of one Belgian clinic in Brussels specialized on treatment of patients leading to a decrease in their body weight. The first name of this disease was Chinese herb nephropathy (CHN). Later, it was discovered that one component of herbal preparation was changed by a mistake with the Aristolochiaceae plant. The second type of renal disease caused by AA was discovered in populations of countries along the Danube river, called as Balkan endemic nephropathy (BEN), which was probably caused by the contamination of grains with plants containing AA. These renal diseases (AAN and BEN) are often associated with development of upper urothelial cancer (UUC). AA (AAI + AAII) in organisms are subject to biotransformation leading to its reductive activation or oxidative detoxification. Both cytosolic enzymes [NAD(P)H:quinone oxidoreductase] and microsomal enzymes [cytochromes P450, NADPH:cytochrome P450 reductase] participate in their reduction. The...
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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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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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Plant alkaloids and their effects on enzymes metabolizing xenobiotics
Višněvská, Kateřina ; Stiborová, Marie (advisor) ; Černá, Věra (referee)
Sanguinarine and chelerythrine are quaternary benzo[c]phenanthridine alkaloids. The first step in sanguinarine metabolism is its reduction to dihydrosanguinarin. Antimicrobial and anti-inflammatory activities of these alkaloids are used in dentistry and as feed additives. Sanguinarine and chelerythrine induce apoptosis of cells. Fluorescence of these alkaloids and intercalation into DNA could be utilized to use the alkaloids as supravital DNA probe. Negative effect of sanguinarine and chelerythrine is their genotoxicity. Cytochrome P450 and peroxidase oxidize ellipticine to detoxication and activation metabolites. Ellipticine is a potent antineoplastic agent exhibiting the multimodal mechanism of its action. Ellipticine intercalates into DNA and inhibits topoisomerase II. Covalent DNA aducts are mediated by CYP or peroxidase oxidation of ellipticine. The anti-tumor activity of ellipticine and its derivatives is caused by a combination mechanism of cell cycle arrest and induction of the apoptotic pathway. Pharmacological efficiencies and geneotoxic side effects of ellipticine is dependent on levels and activities of cytochrome P450 or peroxidase in target tissues. Aristolactams are the major metabolites of biotransformation of aristolochic acid. Nitroreduction is the crucial step in formation of an...
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