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Carcinogenesis Advance Access published online on January 19, 2008
Carcinogenesis, doi:10.1093/carcin/bgn013
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Expression of MRP1 and GSTP1-1 modulate the acute cellular response to treatment with the chemopreventive isothiocyanate, sulforaphane

Mebrahtu B. Sibhatu, Pamela K. Smitherman, Alan J. Townsend and Charles S. Morrow*

Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157

* To whom correspondence should be addressed at: Department of Biochemistry, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157. Telephone: 336-713-7218. Fax: 336-716-7161. Email: cmorrow{at}wfubmc.edu

A major component of the anti-carcinogenic activity of the dietary chemopreventive agent sulforaphane (SFN) is attributed to its ability to induce expression of phase II detoxification genes containing the antioxidant response element (ARE) within their promoters. Because SFN is a reactive electrophile––readily forming conjugates with glutathione––we asked whether expression of glutathione S-transferase (GST) P1-1 and the glutathione conjugate efflux pump, MRP1, would significantly modify the cellular response to SFN exposure. This was investigated using GST- and MRP1-poor parental MCF7 cells and transgenic derivatives expressing GSTP1-1 and/or MRP1. Compared with parental cells, expression of GSTP1-1 alone enhanced the rate of intracellular accumulation of SFN and its glutathione conjugate, SFN-SG––an effect that was associated with increased ARE-containing reporter gene induction. Expression of MRP1 greatly reduced SFN/SFN-SG accumulation and resulted in significant attenuation of SFN-mediated induction of ARE-containing reporter and endogenous gene expression. Co-expression of GSTP1-1 with MRP1 further reduced the level of induction. Depletion of glutathione prior to SFN treatment or the substitution of tBHQ for SFN abolished the effects of MRP1/GSTP1-1 on ARE-containing gene induction––indicating that these effects are glutathione-dependent. Lastly, analysis of Nrf2––a transcription factor operating via binding to the ARE––showed that the increased levels of Nrf2 following SFN treatment were considerably less sustained in MRP1-expressing, especially those co-expressing GSTP1-1, than in MRP1-poor cells. These results suggest that the regulating effects of MRP1 and GSTP1-1 expression on SFN-dependent induction of phase II genes are ultimately mediated by altering nuclear Nrf2 levels.


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