Nitric oxide storage and transport in cells are mediated by glutathione S-transferase P1-1 and multidrug resistance protein 1 via dinitrosyl iron complexes

Hiu Chuen Lok, Yohan Suryo Rahmanto, Clare L. Hawkins, Danuta S. Kalinowski, Charles S. Morrow, Alan J. Townsend, Prem Ponka, Des R. Richardson

Research output: Contribution to journalArticle

Abstract

Nitrogen monoxide (NO) plays a role in the cytotoxic mechanisms of activated macrophages against tumor cells by inducing iron release. We showed that NO-mediated iron efflux from cells required glutathione (GSH) (Watts, R. N., and Richardson, D. R. (2001) J. Biol. Chem. 276, 4724-4732) and that the GSH-conjugate transporter, multidrug resistance-associated protein 1 (MRP1), mediates this release potentially as a dinitrosyl-dithiol iron complex (DNIC; Watts, R. N., Hawkins, C., Ponka, P., and Richardson, D. R. (2006) Proc. Natl. Acad. Sci. U.S.A. 103, 7670-7675). Recently, glutathione S-transferase P1-1 (GST P1-1) was shown to bind DNICs as dinitrosyl-diglutathionyl iron complexes. Considering this and that GSTs and MRP1 form an integrated detoxification unit with chemotherapeutics, we assessed whether these proteins coordinately regulate storage and transport of DNICs as long lived NO intermediates. Cells transfected with GSTP1 (but not GSTA1 or GSTM1) significantly decreased NO-mediated 59Fe release from cells. This NO-mediated 59Fe efflux and the effect of GST P1-1 on preventing this were observed with NO-generating agents and also in cells transfected with inducible nitric oxide synthase. Notably, 59Fe accumulated in cells within GST P1-1-containing fractions, indicating an alteration in intracellular 59Fe distribution. Furthermore, electron paramagnetic resonance studies showed that MCF7-VP cells transfected with GSTP1 contain significantly greater levels of a unique DNIC signal. These investigations indicate that GST P1-1 acts to sequester NO as DNICs, reducing their transport out of the cell by MRP1. Cell proliferation studies demonstrated the importance of the combined effect of GST P1-1 and MRP1 in protecting cells from the cytotoxic effects of NO. Thus, the DNIC storage function of GST P1-1 and ability of MRP1 to efflux DNICs are vital in protection against NO cytotoxicity.

Original languageEnglish (US)
Pages (from-to)607-618
Number of pages12
JournalJournal of Biological Chemistry
Volume287
Issue number1
DOIs
StatePublished - Jan 2 2012
Externally publishedYes

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Glutathione S-Transferase pi
P-Glycoprotein
Glutathione Transferase
Nitric Oxide
Iron
dinitrosyl iron complex
Detoxification
Macrophages
MCF-7 Cells
Electron Spin Resonance Spectroscopy
Cell proliferation
Nitric Oxide Synthase Type II
Cytotoxicity
Glutathione
Paramagnetic resonance
Tumors
Cells
Cell Proliferation
multidrug resistance-associated protein 1

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Lok, H. C., Suryo Rahmanto, Y., Hawkins, C. L., Kalinowski, D. S., Morrow, C. S., Townsend, A. J., ... Richardson, D. R. (2012). Nitric oxide storage and transport in cells are mediated by glutathione S-transferase P1-1 and multidrug resistance protein 1 via dinitrosyl iron complexes. Journal of Biological Chemistry, 287(1), 607-618. https://doi.org/10.1074/jbc.M111.310987

Nitric oxide storage and transport in cells are mediated by glutathione S-transferase P1-1 and multidrug resistance protein 1 via dinitrosyl iron complexes. / Lok, Hiu Chuen; Suryo Rahmanto, Yohan; Hawkins, Clare L.; Kalinowski, Danuta S.; Morrow, Charles S.; Townsend, Alan J.; Ponka, Prem; Richardson, Des R.

In: Journal of Biological Chemistry, Vol. 287, No. 1, 02.01.2012, p. 607-618.

Research output: Contribution to journalArticle

Lok, HC, Suryo Rahmanto, Y, Hawkins, CL, Kalinowski, DS, Morrow, CS, Townsend, AJ, Ponka, P & Richardson, DR 2012, 'Nitric oxide storage and transport in cells are mediated by glutathione S-transferase P1-1 and multidrug resistance protein 1 via dinitrosyl iron complexes', Journal of Biological Chemistry, vol. 287, no. 1, pp. 607-618. https://doi.org/10.1074/jbc.M111.310987
Lok, Hiu Chuen ; Suryo Rahmanto, Yohan ; Hawkins, Clare L. ; Kalinowski, Danuta S. ; Morrow, Charles S. ; Townsend, Alan J. ; Ponka, Prem ; Richardson, Des R. / Nitric oxide storage and transport in cells are mediated by glutathione S-transferase P1-1 and multidrug resistance protein 1 via dinitrosyl iron complexes. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 1. pp. 607-618.
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