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Untersuchung toxischer Effekte nierenkanzerogener Substanzen, sowie deren Wirkungsmechanismen in vitro

Untersuchung toxischer Effekte nierenkanzerogener Substanzen, sowie deren Wirkungsmechanismen in vitro

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Prüfsumme: MD5:378392b19ed713226425ebc98d4f24d9

HULJIC, Susanne Jelena, 2010. Untersuchung toxischer Effekte nierenkanzerogener Substanzen, sowie deren Wirkungsmechanismen in vitro

@phdthesis{Huljic2010Unter-7546, title={Untersuchung toxischer Effekte nierenkanzerogener Substanzen, sowie deren Wirkungsmechanismen in vitro}, year={2010}, author={Huljic, Susanne Jelena}, address={Konstanz}, school={Universität Konstanz} }

Huljic, Susanne Jelena 2011-03-24T17:35:18Z deu Huljic, Susanne Jelena Toxic effects and mechanisms of action of renal cancerogenic substances in vitro Untersuchung toxischer Effekte nierenkanzerogener Substanzen, sowie deren Wirkungsmechanismen in vitro 2010 deposit-license The natural compounds Aristolochic Acid (AA), Ochratoxin A (OTA) and Cycasin are nephrotoxic and carcinogenic in rodents. AA and OTA exposure in humans are known and human exposure to Cycasin is suspected. Despite exposure, toxic effects in humans are only proven for AA. However, the observed effects of the genotoxic substance AA in humans were different to those seen in rodents, suggesting a species-specific mechanism of action. In vitro-models could serve as a powerful tool to evaluate species-specific toxicity. Especially the use of human primary cells could enable characterisation and evaluation of possible human-specific effects.<br />It was postulated, that in vitro-systems, in addition to in vivo-Studies, are a valuable tool to investigate species-specific toxicity of AA, OTA and Cycasin. The aim of the study was to examine the susceptibility of different kidney cortex cell models (continuous cell lines, primary cells) to the toxin in question and therefore their value for studying species-specific effects.<br />In this study, the cytotoxicity of AA, OTA and MAMAc was evaluated and used for a pre-selection of cells (cell line, primary cells) sufficiently susceptible to the toxin in question. Furthermore, effects of the genotoxic compounds AA and MAMAc on the cell cycle and the induction of DNA-strand breaks and DNA-repair were examined. Finally, the effects of AA and OTA on gene-expression were studied.<br />Cytotoxic response was generally higher in primary cells as in the corresponding cells lines, possibly reflecting the higher status of differentiation in primary cells. The observed reduction of cell proliferation and the observed induction of cdkn1a-gene-expression indicate a genotoxic effect of AA in vitro, which seems to reflect sufficient susceptibility of the used cell model. In contrast to this, AA and OTA had only a small effect on gene-expression. However, the low degree of deregulation as well as the small number of deregulated genes could be a result of the low toxin concentrations used. Nevertheless, deregulation of toxin-relevant genes was observed. In this study, species-specific differences in cytotoxicity of AA and MAMAc were shown, with toxicity being highest in kidney cortex cells of porcine origin. These results are in accordance with prior results, showing metabolic activation of AA to be species-dependent, with minipigs having the most effective activation system followed by human and rat. Although cytotoxicity assays can not allow discrimination of distinctive mechanistic responses, it is suspected that the description of constitutive differences in the susceptibility of cells originating of different species can be achieved.<br />From this study, primary kidney cortex cells appear to be a valuable tool to investigate the toxicity of AA, OTA and Cycasin. Furthermore, human primary cells seem to be useful for the evaluation of possible human-specific effects. However, the availability and quality of biopsy material from primary care facilities for the establishment of primary human cell culture is highly variable and commercially available cells are expensive. Given the genetic proximity of human and pigs and the anatomical and physiological similarity of the kidneys, future direction should therefore consider the use of primary porcine cell models as an alternative system. 2011-03-24T17:35:18Z application/pdf

Dateiabrufe seit 01.10.2014 (Informationen über die Zugriffsstatistik)

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