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Gene Review

Gpx4  -  glutathione peroxidase 4

Rattus norvegicus

Synonyms: Gshpx-4, Phgpx, gpx-4, snGpx
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Disease relevance of Gpx4

  • Overexpression of PHGPx and HSP60/10 protects against ischemia/reoxygenation injury [1].
  • The mRNA levels of PHGPx in the cultured cells such as hepatomas, neuronal cells, nephroblastoma, and mammary myo-epithelial cells were higher than those of the tissues [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].
  • In this work we focused on the cytoprotective antiperoxidant effects of GPX4, using a breast tumor epithelial cell line that over-expresses the enzyme [4].
  • An In situ hybridization study showed that PHGPx mRNA in the brain is expressed mainly in the white matter of the cerebral hemisphere and in the Purkinje cells of the cerebellar hemispheres; these sites are known to be the vulnerable to lead toxicity [5].

High impact information on Gpx4


Biological context of Gpx4

  • A nuclear variant of phospholipid-hydroperoxide glutathione peroxidase (PHGPx, GPx-4) was considered to be derived from alternative pre-mRNA splicing in testis and to regulate sperm maturation [8].
  • This observation points to a general role of the nuclear PHGPx variant in regulating cell division [8].
  • These results suggest that mitochondria might be a target for intracellular and extracellular oxidative stress and that mitochondrial PHGPx, as distinct form non-mitochondrial PHGPx, might play a primary role in protecting cells from oxidative stress [9].
  • Mitochondrial PHGPx might prevent changes in mitochondrial functions and cell death by reducing intracellular hydroperoxides [9].
  • Mitochondrial PHGPx failed to protect M15 cells from mitochondrial injury by carbonyl cyanide m-chlorophenylhydrazone, which directly reduces membrane potential without the generation of hydroperoxides [9].

Anatomical context of Gpx4

  • The expression of PHGPX in testes is consistent with the previously described specific requirement for selenium for synthesis of a 15-20-kDa selenoprotein which is related to the production of functional spermatozoa [10].
  • Specific immunostaining of testes by antiserum against PHGPX appears as a fine granular brown pattern localized throughout the cytoplasm in more immature cells but is confined to the peripheral part of the cytoplasm, the nuclear membrane, and mitochondria in maturating spermatogenic cells [10].
  • A construct encoding the leader sequence of PHGPx tagged with green fluorescent protein was used to transfect RBL-2H3 cells, and the fusion protein was transported to mitochondria [9].
  • Flow cytometric analysis showed that mitochondrial PHGPx suppressed the generation of hydroperoxide, the loss of mitochondrial membrane potential, and the loss of plasma membrane integrity that are induced by KCN [9].
  • In early pachytene spermatids, PHGPx signals were noted in the nuclear material exhibiting a very similar density to chromatoid bodies and in the intermitochondrial cement, supporting the previous proposal that chromatoid bodies originate from the nucleus and intermitochondrial cement [11].

Associations of Gpx4 with chemical compounds


Physical interactions of Gpx4

  • Western blotting and immunocytochemical analysis by means of anti-PHGPx antibodies show the different distribution and the strong binding of PHGPx in the testes and sperm cell subcellular compartments (nucleus, acrosome, mitochondria and residual bodies) of rats of different age [16].

Regulatory relationships of Gpx4

  • Similarly, after efferent duct ligation, the 0.9 kb SOD and PHGPX mRNA transcript levels also decreased compared to control testes (p < 0.05) [17].
  • Aminoguanidine (AG) treatment of diabetic rats returned the testis PHGPx activity (136.5 +/- 24.9) to the control level but did not change the value of GPx activity (69.2 +/- 17.4) compared with diabetic group [18].
  • PHGPx apparently inactivated the 5-lipoxygenase that catalyzed the conversion of arachidonic acid to 5-hydroperoxyeicosatetraenoic acid (5-HPETE) since 5-HPETE is a common precursor of 5-HETE, LTC4, and LTB4 [19].

Other interactions of Gpx4

  • Growth, and mRNA levels for selenoprotein P, 5'-deiodinase, and GPX4 were not decreased by Se deficiency [20].
  • Distinct promoters determine alternative transcription of gpx-4 into phospholipid-hydroperoxide glutathione peroxidase variants [8].
  • These results indicate that overexpression of PHGPx provides protection against damage resulting from simulated I/R injury, particularly in the mitochondria, and that the combination of mPHGPx and HSP60/10 imparts an added protective effect [1].
  • We compared the four groups in terms of body and brain weight, lead concentrations in the brain and blood, and the activities of superoxide dismutase (SOD), gluthatione peroxidase (GPx), and PHGPx mRNA in the brain [5].
  • IGF-I therapy increased significantly steroidogenesis and PHGPx activity (p < 0.05) [21].

Analytical, diagnostic and therapeutic context of Gpx4

  • In Northern and Western blotting experiments, both PHGPx transcript and protein were markedly expressed in pachytene spermatocytes and round spermatids [22].
  • We studied temporal changes in the subcellular localization and levels of a moonlighting protein, phospholipid hydroperoxide glutathione peroxidase (PHGPx), in spermatogenic cells and mature sperm of the rat by immunofluorescence and immunoelectron microscopy [11].
  • Northern blot analysis demonstrated that the mRNA for PHGPx was widely expressed in normal rat tissues, especially in the testis [2].
  • We found that the level of PHGPx mRNA in brain increased in the medium- and low-dose groups, but decreased in the high-dose group versus the non-lead-treated control group [5].
  • The existence and level of the PHGPx mRNA in the cauda epididymal sperm, testis, and liver from the Se-adequate rats were analyzed by the reverse transcription-polymerase chain reaction and the Southern blotting method [23].


  1. Overexpression of PHGPx and HSP60/10 protects against ischemia/reoxygenation injury. Hollander, J.M., Lin, K.M., Scott, B.T., Dillmann, W.H. Free Radic. Biol. Med. (2003) [Pubmed]
  2. Molecular cloning and functional expression of a cDNA for rat phospholipid hydroperoxide glutathione peroxidase: 3'-untranslated region of the gene is necessary for functional expression. Imai, H., Sumi, D., Hanamoto, A., Arai, M., Sugiyama, A. J. Biochem. (1995) [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. Hyperresistance to cholesterol hydroperoxide-induced peroxidative injury and apoptotic death in a tumor cell line that overexpresses glutathione peroxidase isotype-4. Hurst, R., Korytowski, W., Kriska, T., Esworthy, R.S., Chu, F.F., Girotti, A.W. Free Radic. Biol. Med. (2001) [Pubmed]
  5. Effects of lead exposure on the expression of phospholipid hydroperoxidase glutathione peroxidase mRNA in the rat brain. Kang, J.K., Sul, D., Kang, J.K., Nam, S.Y., Kim, H.J., Lee, E. Toxicol. Sci. (2004) [Pubmed]
  6. Dual function of the selenoprotein PHGPx during sperm maturation. Ursini, F., Heim, S., Kiess, M., Maiorino, M., Roveri, A., Wissing, J., Flohé, L. Science (1999) [Pubmed]
  7. Testosterone mediates expression of the selenoprotein PHGPx by induction of spermatogenesis and not by direct transcriptional gene activation. Maiorino, M., Wissing, J.B., Brigelius-Flohé, R., Calabrese, F., Roveri, A., Steinert, P., Ursini, F., Flohé, L. FASEB J. (1998) [Pubmed]
  8. Distinct promoters determine alternative transcription of gpx-4 into phospholipid-hydroperoxide glutathione peroxidase variants. Maiorino, M., Scapin, M., Ursini, F., Biasolo, M., Bosello, V., Flohé, L. J. Biol. Chem. (2003) [Pubmed]
  9. Mitochondrial phospholipid hydroperoxide glutathione peroxidase plays a major role in preventing oxidative injury to cells. Arai, M., Imai, H., Koumura, T., Yoshida, M., Emoto, K., Umeda, M., Chiba, N., Nakagawa, Y. J. Biol. Chem. (1999) [Pubmed]
  10. Phospholipid hydroperoxide glutathione peroxidase of rat testis. Gonadotropin dependence and immunocytochemical identification. Roveri, A., Casasco, A., Maiorino, M., Dalan, P., Calligaro, A., Ursini, F. J. Biol. Chem. (1992) [Pubmed]
  11. Spatiotemporal changes of levels of a moonlighting protein, phospholipid hydroperoxide glutathione peroxidase, in subcellular compartments during spermatogenesis in the rat testis. Haraguchi, C.M., Mabuchi, T., Hirata, S., Shoda, T., Yamada, A.T., Hoshi, K., Yokota, S. Biol. Reprod. (2003) [Pubmed]
  12. Overexpression of phospholipid hydroperoxide glutathione peroxidase modulates acetyl-CoA, 1-O-alkyl-2-lyso-sn-glycero-3-phosphocholine acetyltransferase activity. Sakamoto, H., Tosaki, T., Nakagawa, Y. J. Biol. Chem. (2002) [Pubmed]
  13. Functional interaction of phospholipid hydroperoxide glutathione peroxidase with sperm mitochondrion-associated cysteine-rich protein discloses the adjacent cysteine motif as a new substrate of the selenoperoxidase. Maiorino, M., Roveri, A., Benazzi, L., Bosello, V., Mauri, P., Toppo, S., Tosatto, S.C., Ursini, F. J. Biol. Chem. (2005) [Pubmed]
  14. Selenium regulation of transcript abundance and translational efficiency of glutathione peroxidase-1 and -4 in rat liver. Weiss Sachdev, S., Sunde, R.A. Biochem. J. (2001) [Pubmed]
  15. Up-regulation of phospholipid hydroperoxide glutathione peroxidase in rat casein-induced polymorphonuclear neutrophils. Hattori, H., Imai, H., Hanamoto, A., Furuhama, K., Nakagawa, Y. Biochem. J. (2005) [Pubmed]
  16. Enzymatic and immunochemical evaluation of phospholipid hydroperoxide glutathione peroxidase (PHGPx) in testes and epididymal spermatozoa of rats of different ages. Tramer, F., Micali, F., Sandri, G., Bertoni, A., Lenzi, A., Gandini, L., Panfili, E. Int. J. Androl. (2002) [Pubmed]
  17. Cu/Zn superoxide dismutase, catalase and glutathione peroxidase mRNA expression in the rat testis after surgical cryptorchidism and efferent duct ligation. Zini, A., Schlegel, P.N. J. Urol. (1997) [Pubmed]
  18. Testis glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase activities in aminoguanidine-treated diabetic rats. Unlüçerçi, Y., Bekpinar, S., Koçak, H. Arch. Biochem. Biophys. (2000) [Pubmed]
  19. Suppression of leukotriene formation in RBL-2H3 cells that overexpressed phospholipid hydroperoxide glutathione peroxidase. Imai, H., Narashima, K., Arai, M., Sakamoto, H., Chiba, N., Nakagawa, Y. J. Biol. Chem. (1998) [Pubmed]
  20. Dietary selenium requirements based on glutathione peroxidase-1 activity and mRNA levels and other Se-dependent parameters are not increased by pregnancy and lactation in rats. Sunde, R.A., Evenson, J.K., Thompson, K.M., Sachdev, S.W. J. Nutr. (2005) [Pubmed]
  21. Little effects of insulin-like Growth Factor-I on testicular atrophy induced by hypoxia. Diez-Caballero, F., Castilla-Cortázar, I., Garcia-Fernandez, M., Puche, J.E., Diaz-Sanchez, M., Casares, A.D., Aliaga-Montilla, M.A., Rodriguez-Borrajo, C., Gonzalez-Barón, S. BMC urology [electronic resource]. (2006) [Pubmed]
  22. Differential splicing of the phospholipid hydroperoxide glutathione peroxidase gene in diploid and haploid male germ cells in the rat. Puglisi, R., Tramer, F., Panfili, E., Micali, F., Sandri, G., Boitani, C. Biol. Reprod. (2003) [Pubmed]
  23. Analysis of the phospholipid hydroperoxide glutathione peroxidase mRNA in the rat spermatozoon and effect of selenium deficiency on the mRNA. Mizuno, K., Hirata, S., Hoshi, K., Shinohara, A., Chiba, M. Biological trace element research. (2000) [Pubmed]
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