Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 30-9 |
| Number of pages | 10 |
| Journal | Toxicological Sciences |
| Volume | 96 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2007 |
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Reduction in antioxidant defenses may contribute to ochratoxin A toxicity and carcinogenicity. / Cavin, Christophe; Delatour, Thierry; Marin-Kuan, Maricel; Holzhäuser, Daisy; Higgins, Larry; Bezençon, Claudine; Guignard, Gabriela; Junod, Sylviane; Richoz-Payot, Janique; Gremaud, Eric; Hayes, John D.; Nestler, Sandra; Mantle, Peter; Schilter, Benoît.
In: Toxicological Sciences, Vol. 96, No. 1, 2007, p. 30-9.Research output: Contribution to journal › Article
TY - JOUR
T1 - Reduction in antioxidant defenses may contribute to ochratoxin A toxicity and carcinogenicity
AU - Cavin, Christophe
AU - Delatour, Thierry
AU - Marin-Kuan, Maricel
AU - Holzhäuser, Daisy
AU - Higgins, Larry
AU - Bezençon, Claudine
AU - Guignard, Gabriela
AU - Junod, Sylviane
AU - Richoz-Payot, Janique
AU - Gremaud, Eric
AU - Hayes, John D.
AU - Nestler, Sandra
AU - Mantle, Peter
AU - Schilter, Benoît
PY - 2007
Y1 - 2007
N2 - 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.
AB - 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.
U2 - 10.1093/toxsci/kfl169
DO - 10.1093/toxsci/kfl169
M3 - Article
VL - 96
SP - 30
EP - 39
JO - Toxicological Sciences
JF - Toxicological Sciences
SN - 1096-6080
IS - 1
ER -