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Mechanisms of action of tumorigenesis by ochratoxin A

Accelerator mass spectrometry (AC/MS) studies on DNA-binding did not show a covalent binding of 14C from ochratoxin A to liver and kidney DNA from rats treated in vivo. In addition, mechanistic investigations did not give evidence for formation of DNA-adducts from OTA. Moreover, analysis of possible DNA-modifications induced by OTA by post labelling did not indicate adduct formation in the project lab or in an external laboratory even in samples from animal treated with high OTA-doses for 2 weeks. In samples from ochratoxin A treated animals, conceivable metabolites of OTA were not detected.

Both ochratoxin A and ochratoxin B induced cell proliferation in the kidney, but only limited nephrotoxicity and some DNA-damage. OTB was much less toxic than OTA due to rapid bio transformation. Repeated ochratoxin A administration to rats resulted in high OTA-concentrations in the target organ kidney, but also in the non-target organ liver and induced some DNA-damage both in liver and kidney. Toxicity was, however, restricted to the kidney. Both OTA and OTB caused minor DNA-damage in the non-target organ liver and in the target organ kidney. The spectrum of effects of OTA on the kidney in rats is unusual and not consistent with necrosis as expected from generation of reactive metabolites and their covalent binding.

In summary, the results suggest a specific mode of action of OTA on the kidney in rats, which is not due to genotoxicity due to the absence of DNA-binding and absence of biotransformation-dependent mutagenicity of OTA. The kidney specific response represents a modulation of cell-adhesion and cell-cell communication involved in tumor formation.

One partner analysed biomarkers of oxidative stress and showed an induction of the inducible nitric oxide synthase (INOS). However, the stress-response was inconsistent with regard to the different parameters determined and a possible delay in the response in vivo is indicated. The liver of animals treated for 7 and 12 months with OTA showed a significant induction of 4-HNE adduct formation. However, this effect was not confirmed in rat kidney.

OTA administration to rats rapidly (after 21 days) decreased the expression of several detoxifying enzymes (GST, UDP-GT etc.) in the kidney but not in the liver. These data strongly suggest that OTA may repress the Nrf2 pathway, which has been reported to be responsible for the activation of several detoxifying phase II enzymes and antioxidant proteins. Data from the DNA microarray experiment (Affymetrix) strongly support an ambition of the Nrf2 pathway specifically in the kidney of rat treated chronically with OTA, resulting in a marked inhibition of the defence mechanism of the kidney cells against oxidative stress.

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