Service Communautaire d'Information sur la Recherche et le Développement - CORDIS

Role of oxidative stress in ochratoxin A-toxicity in vivo and mechanism of ochratoxin A toxicity in vitro

Biomarkers of oxidative stress have been analysed. The stress response was inconsistent regarding the different parameters however, a striking effect on the inducible nitric oxide synthase (iNOS) was observed in cell cultures correlated with a significant increase in protein nitration (3-nytrotyrosine). In addition, a major effect of OTA was observed in vitro cultures on the basal expression of several genes (GST, UDP-GT, GCLC, GCLM) regulated by the transcription factor Nrf2. Nrf2 is known to interact with the Antioxidant Response Element (ARE)-promoter controlling the expression of many genes involved in the cellular antioxidant defence.

Using rats treated chronically with 300mg OTA/ kg bw/day for 7 days up to 12 months, no confirmation of the effect of OTA on iNOS expression and 3-nytrotyrosine formation could be found in the kidney. In contrast, a significant inhibition of several detoxifying enzymes (e.g. glutathione S-transferases, UDP-glucuronosyltransferase) and enzymes involved in the production of the strong antioxidant glutathione was found at the mRNA and protein levels in the kidney but not in the liver of OTA treated rats.

Interestingly, further investigation in in vitro systems showed that OTA-mediated cytotoxicity (LDH release), inhibition of protein synthesis and DNA damage were prevented by pre-treatment of the cells with agents (e.g. coumarin) known to activate Nrf2. Our data suggest that a reduction of the cellular defence against oxidative stress may be a plausible mechanism of OTA nephrocarcinogenicity.

More information on the project can be found at:

Informations connexes

Reported by

Nestle Research Center
Nestle Research Center
1000 Lausanne 26