ToxSci Advance Access published online on April 13, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi171
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1 Department of Nutritional Toxicology, Institute for Nutritional Sciences, Friedrich Schiller University, Dornburger Straße 25, D-07743 Jena, Germany
* To whom correspondence should be addressed. The cellular production of 4-hydroxy-2-nonenal (HNE), a product of endogenous lipid peroxidation, constitutes a genotoxic risk factor for carcinogenesis. Our previous studies have shown that human HT29 colon cells developed resistance toward HNE injury after treatment with butyrate, a dietary-associated gut fermentation product. This resistance was attributed to the induction of certain glutathione S-transferases (hGSTP1-1, hGSTM2-2, and hGSTA1-1) and also for the tripeptide glutathione (GSH) synthesizing enzymes. In the present study, we have investigated in HT29 cells whether hGSTA4-4, which has a high substrate-specificity for HNE, was also inducible by butyrate, and thus could contribute to the previously observed chemoresistance. In addition, we investigated if cellular depletion of GSH by L-buthionine-S,R-sulfoximine (BSO) enhances chemosensitivity to HNE injury in HT29 cells. Incubation of HT29 cells with butyrate (2-4 mM) significantly elicited a 1.8 to 3-fold upregulation of steady state hGSTA4 mRNA over 8-24 hours after treatment. Moreover, 4 mM butyrate tended to increase hGSTA4-4 protein concentrations. Incubation with 100 µM BSO decreased cellular GSH levels by 77 % without significant changes in cell viability. Associated with this was a 2-fold higher level of HNE-induced DNA damage as measured by the comet assay. Collectively, the results of this study and our previous work indicate that the genotoxicity of HNE is highly dependent on cellular GSH status and those GSTs that contribute toward HNE conjugation, including hGSTA4-4. Since HNE contributes to colon carcinogenesis, the favourable modulation of the GSH/GST system by butyrate may contribute to chemoprevention and reduction of the risks.
Received November 8, 2004
Accepted April 4, 2005
Biotransformation and Toxicokinetics
GENOTOXICITY OF 4-HYDROXY-2-NONENAL IN HUMAN COLON TUMOUR CELLS IS ASSOCIATED WITH CELLULAR LEVELS OF GLUTATHIONE AND THE MODULATION OF GLUTATHIONE S-TRANSFERASE A4 EXPRESSION BY BUTYRATE
2 Department Environmental and Occupational Health Sciences, University of Washington, 4225 Roosevelt Way NE, Suite 100, Seattle Washington, USA 98105
Beatrice L. Pool-Zobel, E-mail: b8pobe{at}uni-jena.de
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