PMID- 17110534
OWN - NLM
STAT- MEDLINE
DCOM- 20070330
LR  - 20131121
IS  - 1096-6080 (Print)
IS  - 1096-0929 (Linking)
VI  - 96
IP  - 1
DP  - 2007 Mar
TI  - Reduction in antioxidant defenses may contribute to ochratoxin A toxicity and 
      carcinogenicity.
PG  - 30-9
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.
FAU - Cavin, Christophe
AU  - Cavin C
AD  - Quality and Safety Department, Nestle Research Center, CH-1000 Lausanne 26, 
      Switzerland. christophe.cavin@rdls.nestle.com
FAU - Delatour, Thierry
AU  - Delatour T
FAU - Marin-Kuan, Maricel
AU  - Marin-Kuan M
FAU - Holzhauser, Daisy
AU  - Holzhauser D
FAU - Higgins, Larry
AU  - Higgins L
FAU - Bezencon, Claudine
AU  - Bezencon C
FAU - Guignard, Gabriela
AU  - Guignard G
FAU - Junod, Sylviane
AU  - Junod S
FAU - Richoz-Payot, Janique
AU  - Richoz-Payot J
FAU - Gremaud, Eric
AU  - Gremaud E
FAU - Hayes, John D
AU  - Hayes JD
FAU - Nestler, Sandra
AU  - Nestler S
FAU - Mantle, Peter
AU  - Mantle P
FAU - Schilter, Benoit
AU  - Schilter B
LA  - eng
PT  - Journal Article
DEP - 20061116
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (Carcinogens)
RN  - 0 (Diterpenes)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Nfe2l2 protein, rat)
RN  - 0 (Ochratoxins)
RN  - 0 (RNA, Messenger)
RN  - 1779SX6LUY (ochratoxin A)
RN  - 9007-49-2 (DNA)
RN  - EC 2.5.1.18 (Glutathione Transferase)
RN  - EC 6.3.2.2 (Glutamate-Cysteine Ligase)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
MH  - Animals
MH  - Carcinogens/*toxicity
MH  - Cell Line
MH  - DNA/metabolism
MH  - DNA Damage
MH  - Diterpenes/pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Down-Regulation/*drug effects
MH  - Glutamate-Cysteine Ligase/metabolism
MH  - Glutathione/metabolism
MH  - Glutathione Transferase/metabolism
MH  - Hepatocytes/drug effects/metabolism
MH  - Kidney/*drug effects/metabolism
MH  - Male
MH  - NF-E2-Related Factor 2/*metabolism
MH  - Ochratoxins/*toxicity
MH  - Oxidative Stress/*drug effects
MH  - RNA, Messenger/metabolism
MH  - Rats
MH  - Rats, Inbred F344
MH  - Rats, Sprague-Dawley
MH  - Reproducibility of Results
MH  - Response Elements/drug effects
MH  - Risk Assessment
MH  - Time Factors
MH  - Transcription, Genetic/drug effects
MH  - Transfection
EDAT- 2006/11/18 09:00
MHDA- 2007/03/31 09:00
CRDT- 2006/11/18 09:00
PHST- 2006/11/18 09:00 [pubmed]
PHST- 2007/03/31 09:00 [medline]
PHST- 2006/11/18 09:00 [entrez]
AID - kfl169 [pii]
AID - 10.1093/toxsci/kfl169 [doi]
PST - ppublish
SO  - Toxicol Sci. 2007 Mar;96(1):30-9. doi: 10.1093/toxsci/kfl169. Epub 2006 Nov 16.