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Gene Review

GPX4  -  glutathione peroxidase 4

Homo sapiens

Synonyms: GPx-4, GSHPx-4, Glutathione peroxidase 4, MCSP, PHGPx, ...
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Disease relevance of GPX4

  • These results confirm a role for selenium in risk of lung cancer and the independent regulation of GPX1 and GPX4 [1].
  • Our results show that two of the glutathione peroxidase family members (GPX1 and GPX4) are highly induced by supplemental selenium in prostate cancer cells but only slightly induced in RWPE-1 cells [2].
  • The Se-deficient diet caused significant decreases in GPx activity and cGPx mRNA expression but no change in PHGPx mRNA, together with significant proteinuria and glucosuria and slight decline in Ccr [3].

High impact information on GPX4


Biological context of GPX4


Anatomical context of GPX4

  • The pivotal link between Se, sperm quality and male fertility is GPX4 since the enzyme is essential to allow the production of the correct architecture of the midpiece of spermatozoa [12].
  • CONCLUSION: In endothelial cells, sulforaphane increases TR-1 but not GPX-1 and GPX-4 and in doing so confers protection against oxidative damage induced by lipid hydroperoxides [13].
  • The aim of this study was to investigate the role of coenzyme Q on the mRNA abundance of PHGPx and the reactive oxygen species (ROS) production in two different cell lines from human prostate, a line of non cancer cells (PNT2) and a line of cancer cells (PC3) [14].

Associations of GPX4 with chemical compounds

  • The biological roles of the essential micronutrient Se are attributed to its presence in a range of 20-30 selenoproteins including the cytosolic and phospholipid hydroperoxide glutathione peroxidases (GPX1 and GPX4) [15].
  • Sulforaphane induced TR-1 expression in selenium-deficient cells (1.83 +/- 0.11 fold, P < 0.001) and selenium-supplemented cells (2.90 +/- 0.17 fold, P < 0.001) but had no inductive effect on GPX-1 or GPX-4 [13].
  • RESULTS: Selenite treatment increased the concentration of TR-1 (1.6 +/- 0.17 fold, P < 0.05), GPX-1 activity (8.2 +/- 1.08 fold, P < 0.001), and GPX-4 activity (3.1 +/- 0.25 fold, P < 0.001) [13].
  • Results showed that malignant cells markedly differ in their response to coenzyme Q compared to non-malignant cells, with no changes in PHGPx expression and greater ROS production [14].

Other interactions of GPX4

  • On the basis of these results, we demonstrate that snPHGPx expression is mediated by the transcription factor CREM-tau, which acts as a cis-acting element localized in the first intron of the PHGPx gene [8].
  • In the familiy of selenium-dependent glutathione peroxidases (GPx) the ranking is GI-GPx > or = PHGPx > cGPx = pGPx [16].
  • OBJECTIVE: To determine the expression and enzymatic activity of glutathione peroxidase (GPX)-1, GPX-4, and glutathione reductase together with glutathione (GSH) concentrations in spermatozoa from fertile and infertile men [17].
  • METHODS: EAhy926 cells were supplemented with 40 nM of selenite and/or sulforaphane (10 muM) for 72 h and the expression of TR-1, GPX-1, and GPX-4 was assessed [13].
  • All of these derive from the same gene and are structurally related with the exception of the snPHGPx (sperm nucleus-specific form), which differs from the others due to the presence of an arginine-rich N-terminus [8].

Analytical, diagnostic and therapeutic context of GPX4

  • Northern blot analysis indicated that the increase in GPX activities was due to increased transcript levels of GPX1 but not GPX4 in both cells [18].
  • Further support derived from site-specific effects observed using (i) a mitochondrial GPX4-overexpressing clone (7G4) of COH-BR1 tumor cells, and (ii) an ALA treatment protocol in which most cellular PpIX is either inside (Pr-1) or outside (Pr-2) mitochondria [19].


  1. Effects of selenium supplementation on expression of glutathione peroxidase isoforms in cultured human lung adenocarcinoma cell lines. Romanowska, M., Kikawa, K.D., Fields, J.R., Maciag, A., North, S.L., Shiao, Y.H., Kasprzak, K.S., Anderson, L.M. Lung Cancer (2007) [Pubmed]
  2. Selenoprotein expression is regulated at multiple levels in prostate cells. Rebsch, C.M., Penna, F.J., Copeland, P.R. Cell Res. (2006) [Pubmed]
  3. Effect of selenium-deficient diet on tubular epithelium in normal rats. Fujieda, M., Naruse, K., Hamauzu, T., Miyazaki, E., Hayashi, Y., Enomoto, R., Lee, E., Ohta, K., Yamaguchi, Y., Wakiguchi, H., Enza, H. Pediatr. Nephrol. (2007) [Pubmed]
  4. Levels of major selenoproteins in T cells decrease during HIV infection and low molecular mass selenium compounds increase. Gladyshev, V.N., Stadtman, T.C., Hatfield, D.L., Jeang, K.T. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  5. Biological significance of phospholipid hydroperoxide glutathione peroxidase (PHGPx, GPx4) in mammalian cells. Imai, H., Nakagawa, Y. Free Radic. Biol. Med. (2003) [Pubmed]
  6. Hyperresistance to photosensitized lipid peroxidation and apoptotic killing in 5-aminolevulinate-treated tumor cells overexpressing mitochondrial GPX4. Kriska, T., Korytowski, W., Girotti, A.W. Free Radic. Biol. Med. (2002) [Pubmed]
  7. Phospholipid hydroperoxide glutathione peroxidase activity of human glutathione transferases. Hurst, R., Bao, Y., Jemth, P., Mannervik, B., Williamson, G. Biochem. J. (1998) [Pubmed]
  8. cAMP-response element modulator-tau activates a distinct promoter element for the expression of the phospholipid hydroperoxide/sperm nucleus glutathione peroxidase gene. Tramer, F., Vetere, A., Martinelli, M., Paroni, F., Marsich, E., Boitani, C., Sandri, G., Panfili, E. Biochem. J. (2004) [Pubmed]
  9. Metamorphosis of the selenoprotein PHGPx during spermatogenesis. Flohé, L., Foresta, C., Garolla, A., Maiorino, M., Roveri, A., Ursini, F. Ann. N. Y. Acad. Sci. (2002) [Pubmed]
  10. PHGPx overexpression induces an increase in COX-2 activity in colon carcinoma cells. Barrière, G., Rabinovitch-Chable, H., Cook-Moreau, J., Faucher, K., Rigaud, M., Sturtz, F. Anticancer Res. (2004) [Pubmed]
  11. Determinants of PHGPx expression in a cultured endothelial cell line. Brigelius-Flohé, R., Friedrichs, B., Maurer, S., Streicher, R. Biomed. Environ. Sci. (1997) [Pubmed]
  12. Selenium and endocrine systems. Beckett, G.J., Arthur, J.R. J. Endocrinol. (2005) [Pubmed]
  13. Selenium and sulforaphane modify the expression of selenoenzymes in the human endothelial cell line EAhy926 and protect cells from oxidative damage. Campbell, L., Howie, F., Arthur, J.R., Nicol, F., Beckett, G. Nutrition (Burbank, Los Angeles County, Calif.) (2007) [Pubmed]
  14. Coenzyme Q differentially modulates phospholipid hydroperoxide glutathione peroxidase gene expression and free radicals production in malignant and non-malignant prostate cells. Quiles, J.L., Farquharson, A.J., Ramírez-Tortosa, M.C., Grant, I., Milne, L., Huertas, J.R., Battino, M., Mataix, J., Wahle, K.W. Biofactors (2003) [Pubmed]
  15. A novel single nucleotide polymorphism in the 3' untranslated region of human glutathione peroxidase 4 influences lipoxygenase metabolism. Villette, S., Kyle, J.A., Brown, K.M., Pickard, K., Milne, J.S., Nicol, F., Arthur, J.R., Hesketh, J.E. Blood Cells Mol. Dis. (2002) [Pubmed]
  16. 3'UTRs of glutathione peroxidases differentially affect selenium-dependent mRNA stability and selenocysteine incorporation efficiency. Müller, C., Wingler, K., Brigelius-Flohé, R. Biol. Chem. (2003) [Pubmed]
  17. Relationship among standard semen parameters, glutathione peroxidase/glutathione reductase activity, and mRNA expression and reduced glutathione content in ejaculated spermatozoa from fertile and infertile men. Garrido, N., Meseguer, M., Alvarez, J., Simón, C., Pellicer, A., Remohí, J. Fertil. Steril. (2004) [Pubmed]
  18. Levels of reactive oxygen species and primary antioxidant enzymes in WI38 versus transformed WI38 cells following bleomcyin treatment. Yen, H.C., Chang, H.M., Majima, H.J., Chen, F.Y., Li, S.H. Free Radic. Biol. Med. (2005) [Pubmed]
  19. Role of mitochondrial cardiolipin peroxidation in apoptotic photokilling of 5-aminolevulinate-treated tumor cells. Kriska, T., Korytowski, W., Girotti, A.W. Arch. Biochem. Biophys. (2005) [Pubmed]
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