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ToxSci Advance Access published online on May 4, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp090
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Ochratoxin A-mediated DNA and protein damage: roles of nitrosative and oxidative stresses

C. Cavin#, T. Delatour#, M. Marin-Kuan, F. Fenaille*, D. Holzhäuser, G. Guignard, C. Bezençon, D. Piguet, V. Parisod, J. Richoz-Payot and B. Schilter

Quality and Safety Department, Nestlé Research Center, PO Box 44, Vers-chez-les-Blanc, CH-1000 Lausanne 26, Switzerland * Laboratoire d'Etude du Métabolisme des Médicaments, DSV/iBiTec-S/SPI, CEA/Saclay, 91191 Gif-sur-Yvette Cedex, France

Corresponding author: Christophe Cavin, Ph D. Nestle Research Center, P.O. Box 44, Vers-chez-les Blanc, CH-1000 Lausanne 26, Switzerland, Tel. +41 21 785 80 99, Fax +41 21 785 85 53, e-mail: Christophe.Cavin{at}rdls.nestle.com

Received January 8, 2009; revision received March 11, 2009; accepted April 27, 2009


  Abstract

Ochratoxin A (OTA) is a mycotoxin occurring in a variety of foods. OTA is nephrotoxic and neprocarcinogenic in rodents. An OTA-mediated increase of the inducible nitric oxide (iNOS) expression was observed in NRK renal cell line and in rat hepatocyte cultures suggesting the induction of nitrosative stress. This was associated with an increased NF-{kappa}B activity. The potential consequences of iNOS induction were further investigated. A significant increase in the levels of protein nitrotyrosine residues was observed with OTA. In addition, OTA was found to increase the level of DNA abasic sites in both cell cultures system. This endpoints was used as an indirect measure of 8-nitroguanine formation. Treatment of the cells with L-NIL, a specific inhibitor of iNOS activity, inhibited the OTA-mediated overnitration of proteins but did not reduce the level of DNA abasic sites. It was found previously that Nrf2 activators were able to restore the cellular defense against oxidative stress and could prevent DNA abasic sites in cell cultures. In the present study, pretreatement of the cells with activators of Nrf2 prevented OTA-mediated increase in lipid peroxidation, confirming the potential of Nrf2 activators to confer protection against OTA-mediated oxidative stress. In addition it was found that Nrf2 activators could also prevent OTA-induced protein nitration and cytotoxicity. In conclusion, the present data further confirm oxidative stress as a key source of OTA-induced DNA damage and provide additional evidence for a role of this mechanism in OTA carcinogenicity. The exact role of nitrosative stress still remains to be established.

Key Words: Mycotoxin, Ochratoxin A, inducible Nitric Oxide Synthase (iNOS); nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), oxidative and nitrosative stress, nephrotoxicity, carcinogenicity.

# Both authors contributed equally to this work


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