ToxSci Advance Access originally published online on November 16, 2006
Toxicological Sciences 2007 96(1):30-39; doi:10.1093/toxsci/kfl169
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Reduction in Antioxidant Defenses may Contribute to Ochratoxin A Toxicity and Carcinogenicity
* Quality and Safety Department, Nestlé Research Center, CH-1000 Lausanne 26, Switzerland
Biomedical Research Centre, University of Dundee, Dundee DD1 9SY, United Kingdom
Nephro-Urology Unit, Institute of Child Health, University College London, London WC1E 1EH, United Kingdom
Department of Environmental Science and Technology, Imperial College London, London SW7 2AZ, United Kingdom
1 To whom correspondence should be addressed at Quality and Safety Department, Nestle Research Center, P.O. Box 44, Vers-chez-les Blanc, CH-1000 Lausanne 26, Switzerland. Fax: +41 21-785-85-53. E-mail: christophe.cavin{at}rdls.nestle.com.
Received July 26, 2006; accepted November 14, 2006
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Abstract |
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Ochratoxin A (OTA) is a renal carcinogen in rodents. Its human health significance is unclear. It likely depends upon the mechanism of carcinogenesis. In a previous microarray study a reduction in nuclear factor-erythroid 2 p45-related factor 2 (Nrf2)–dependent gene expression was observed in the kidney but not in the liver of rats fed OTA up to 12 months. Nrf2 regulates detoxification and antioxidant gene expression. The present report shows that OTA decreased the protein expression of several markers of the Nrf2-regulated gene battery in kidney in vivo indicating that the effects observed at mRNA level may be of biological significance. The OTA-mediated Nrf2 response could be reproduced in an NRK renal cell line and in primary hepatocyte cultures. In in vitro systems, an OTA-mediated inhibition of Nrf2 activity was demonstrated by electrophoretic mobility shift and Antioxidant Regulatory Element–driven luciferase reporter assays. The reduction of Nrf2-regulated gene expression resulted in oxidative DNA damage as evidenced by formation of abasic sites in vitro and confirmed in kidney in vivo. All OTA-mediated effects observed were prevented by pretreatment of cell cultures with inducers of Nrf2 activity. Our data suggest that reduction of cellular defense against oxidative stress by Nrf2 inhibition may be a plausible mechanism of OTA nephrotoxicity and carcinogenicity.
Key Words: mycotoxin; ochratoxin A; nuclear factor-erythroid 2 p45-related factor 2 (Nrf2); oxidative stress; nephrotoxicity; carcinogenicity.
This work was supported by the EU-Grant#QLK1-CT-2001-011614.
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