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Tissue-specific functions of individual glutathione peroxidases

https://doi.org/10.1016/S0891-5849(99)00173-2Get rights and content

Abstract

The family of glutathione peroxidases comprises four distinct mammalian selenoproteins. The classical enzyme (cGPx) is ubiquitously distributed. According to animal, cell culture and inverse genetic studies, its primary function is to counteract oxidative attack. It is dispensible in unstressed animals, and accordingly ranks low in the hierarchy of glutathione peroxidases. The gastrointestinal isoenzyme (GI-GPx) is most related to cGPx and is exclusively expressed in the gastrointestinal tract. It might provide a barrier against hydroperoxides derived from the diet or from metabolism of ingested xenobiotics. The extreme stability in selenium deficiency ranks this glutathione peroxidase highest in the hierarchy of selenoproteins and points to a more vital function than that of cGPx. Plasma GPx (pGPx) behaves similar to cGPx in selenium deficiency. It is directed to extracellular compartments and is expressed in various tissues in contact with body fluids, e.g., kidney, ciliary body, and maternal/fetal interfaces. It has to be rated as an efficient extracellular antioxidant device, though with low capacity because of the limited extracellular content of potential thiol substrates. Phospholipid hydroperoxide glutathione peroxidase (PHGPx), originally presumed to be a universal antioxidant enzyme protecting membrane lipids, appears to have adopted a variety of specific roles like silencing lipoxygenases and becoming an enzymatically inactive structural component of the mitochondrial capsule during sperm maturation. Thus, all individual isoenzymes are efficient peroxidases in principle, but beyond their mere antioxidant potential may exert cell- and tissue-specific roles in metabolic regulation, as is evident for PHGPx and may be expected for others.

Introduction

About 30 mammalian selenoproteins have been detected as bands in gels after pulse labeling of rats with 75Se [1]. About a dozen mammalian selenoproteins have been characterized in terms of sequence and function. Four of these are glutathione peroxidases (see below). Further, three 5′-deiodinases [2], [3], [4], selenoprotein P [5], [6], selenoprotein W [7], at least one thioredoxin reductase [8], and selenophosphate synthetase-2 [9] have been identified as selenoproteins. Most of the selenoproteins display an unusual tissue distribution suggesting functions distinct from common metabolic pathways. This holds not only true for three of the glutathione peroxidases: type I 5′deiodinase is expressed in the thyroid, liver, kidney, and pituitary gland; type II in the thyroid, placenta, pituitary gland, central nervous system, and in the brown fat tissue of rodents; type III in skin, placenta and central nervous system [10]. Selenoprotein P is found in plasma where it binds up to 70% of the plasma selenium in humans. It is also expressed in Leydig cells of testis and in cerebellum [6]. Selenoprotein W is a muscle protein [7]. Only for thioredoxin reductase and the selenophosphate synthetase-2 no preferential expression has been shown so far.

The classical or cytosolic glutathione peroxidase (cGPx) [11] was the first mammalian selenoprotein to be identified [12], [13]. The phospholipid hydroperoxide glutathione peroxidase (PHGPx) was first described in 1982 [14] and later verified as selenoprotein by sequencing [15], [16], as was plasma GPx (pGPx) [17] and the gastrointestinal form (GI-GPx) [18]. All glutathione peroxidases reduce hydrogen peroxide and alkyl hydroperoxides at the expense of glutathione. Their specificities for the hydroperoxide substrate, however, differ markedly. Whereas cGPx reduces only soluble hydroperoxides, such as H2O2, and some organic hydroperoxides, like hydroperoxy fatty acids, cumene hydroperoxide or t-butyl hydroperoxide [19], PHGPx [20] and to some extent pGPx [21] also reduce hydroperoxides of more complex lipids like phosphatidylcholine hydroperoxide. PHGPx, however, efficiently reduces hydroperoxo groups of thymine [22], lipoproteins [23], and cholesterol esters [24] and is unique in acting on hydroperoxides integrated in membranes [25]. The GI-GPx appears to have a specificity similar to that of cGPx [18], although it has not yet been systematically analyzed in this respect. All glutathione peroxidases utilize glutathione as thiol substrate which does not imply that GSH has to be considered the physiologic substrate of all glutathione peroxidases under all circumstances. For instance, pGPx has been shown also to use thioredoxin as reductant [26]. Although cGPx, pGPx, and GI-GPx are homotetramers, the PHGPx is a monomer with a molecular size smaller than the subunits of the other glutathione peroxidases [16]. The small size and its hydrophobic surface has been implicated in its ability to react with complex lipids in membranes.

Nature’s need for so many glutathione peroxidases is not clear. Did the evolutionary pressure to cope with aerobic life result in redundant selenoperoxidases on top of backup systems like thioredoxin-fueled peroxiredoxins [27] to make sure that not a single one of the deleterious hydroperoxides can reach its targets? Not very likely so. Over the last years the image of hydroperoxides has changed from mere toxic compounds into molecules involved in cellular signaling, e.g., in TNF [28] or IL-1 [29] mediated activation of NF-κB. Hydroperoxides have further been shown to trigger programmed cell death [30], [31] and to play a role in the proliferation [32] and differentiation [33] of cells. They also contribute to maturation of red blood cells [34], [35]. Thus, it may not be advantageous to remove hydroperoxides wherever they appear. It may rather turn out that the maintenance of a certain peroxide tone is necessary for an adequate function of cells. The regulation of the delicate regional redox balance might therefore be one of the more important functions of peroxidases and of glutathione peroxidases in particular.

Interestingly, the individual glutathione peroxidases are not equally distributed. They display surprising preferences for certain organs and tissues. The aim of this article is to compile the knowledge on glutathione peroxidases with particular emphasis on tissue-specific expression and related functions. For general enzymology, catalytic mechanism, structural comparison and regulation of expression of glutathione peroxidases the reader is referred to recent reviews [36], [37], [38].

Section snippets

Ranking order of glutathione peroxidases

Biosynthesis of selenoproteins, of course, depends on the availability of selenium. Selenium is incorporated as selenocysteine into the growing polypeptide chain. Unexpectedly, selenium is evenly used for the biosynthesis of the selenoproteins only at optimum selenium supply. At limiting concentrations, however, selenium is preferentially channeled into some of the selenoproteins, whereas others are less well supplied. In consequence, some selenoproteins respond fast to selenium deficiency with

Distribution

pGPx was first detected in blood plasma and found to be different from cGPx [17]. It was subsequently purified and cloned from human [52] and mouse [53] placenta, from where it is released into the maternal circulation [54]. Because the plasma GSH concentration of about 30μM is not able to maintain a GPx turnover at reasonable rates and for longer than a few catalytic cycles [55], the role of an extracellular GPx was not easily understood. This was probably the reason why pGPx was not studied

Conclusion and outlook

Four decades after the discovery of cGPx and 25 years after its characterization as a selenoprotein, the field of glutathione-mediated and selenium-catalyzed peroxide metabolism remains fascinating. Only one aspect of the field so far could be established as originally proposed: the role of cGPx as an emergency device to counteract oxidative stress. However, the bewildering multiplicity of glutathione peroxidases that is further complicated by structurally related or unrelated nonselenium

Acknowledgements

The work was supported by the Deutsche Forschungsgemeinschaft, DFG (INK 26/A1-1,TP3) and the European Community (Biomed II program, PL 963202). Thanks go to “Mr. glutathione peroxidase,” Leopold Flohé, for critically reading the manuscript and stimulating discussions.

References (165)

  • F. Ursini et al.

    The selenoenzyme phospholipid hydroperoxide glutathione peroxidase

    Biochim. Biophys. Acta

    (1985)
  • Y. Yamamoto et al.

    Glutathione peroxidase isolated from plasma reduces phospholipid hydroperoxides

    Arch. Biochem. Biophys.

    (1993)
  • Y. Bao et al.

    Reduction of thymine hydroperoxide by phospholipid hydroperoxide glutathione peroxidase and glutathione transferases

    FEBS Lett.

    (1997)
  • W. Sattler et al.

    Reduction of HDL- and LDL-associated cholesterylester and phospholipid hydroperoxides by phospholipid hydroperoxide glutathione peroxidase and ebselen (PZ51)

    Arch. Biochem. Biophys.

    (1994)
  • J.P. Thomas et al.

    Protective action of phospholipid hydroperoxide glutathione peroxidase against membrane-damaging lipid peroxidation

    J. Biol. Chem.

    (1990)
  • F. Ursini et al.

    The role of selenium peroxidases in the protection against oxidative damage of membranes

    Chem. Phys. Lipids

    (1987)
  • M. Björnstedt et al.

    The thioredoxin and glutaredoxin systems are efficient electron donors to human plasma glutathione peroxidase

    J. Biol. Chem.

    (1994)
  • P.A. Sandstrom et al.

    Lipid hydroperoxides induce apoptosis in T cells displaying a HIV-associated glutathione peroxidase deficiency

    J. Biol. Chem.

    (1994)
  • J.M. Dypbukt et al.

    Different prooxidant levels stimulate growth, trigger apoptosis, or produce necrosis of insulin-secreting RINm5F cells. The role of intracellular polyamines

    J. Biol. Chem.

    (1994)
  • H. Kühn et al.

    Occurrence of lipoxygenase products in membranes of rabbit reticulocytes

    J. Biol. Chem.

    (1990)
  • F. Weitzel et al.

    Phospholipid hydroperoxide glutathione peroxidase activity in various mouse organs during selenium deficiency and repletion

    Biochim. Biophys. Acta

    (1990)
  • M.J. Christensen et al.

    Dietary selenium stabilizes glutathione peroxidase mRNA in rat liver

    J. Nutr.

    (1992)
  • G. Bermano et al.

    Selective control of cytosolic glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase mRNA stability by selenium supply

    FEBS Lett.

    (1996)
  • T. Nakane et al.

    Effect of selenium deficiency on cellular and extracellular glutathione peroxidasesimmunochemical detection on mRNA analysis in rat kidney and serum

    Free Radic. Biol. Med.

    (1998)
  • M.S. Saedi et al.

    Effect of selenium status on mRNA levels for glutathione peroxidase in rat liver

    Biochem. Biophys. Res. Comm.

    (1988)
  • X.G. Lei et al.

    Glutathione peroxidase and phospholipid hydroperoxide glutathione peroxidase are differentially egulated in rats by dietary selenium

    J. Nutr.

    (1995)
  • M.J. Christensen et al.

    Tissue specificity of selenoprotein gene expression in rats

    J. Nutr. Biochem.

    (1995)
  • F.F. Chu et al.

    Expression of plasma glutathione peroxidase in human liver in addition to kidney, heart, lung, and breast in humans and rodents

    Blood

    (1992)
  • N. Avissar et al.

    Partial sequence of human plasma glutathione peroxidase and immunologic identification of milk glutathione peroxidase as the plasma enzyme

    J. Nutr.

    (1991)
  • S. Himeno et al.

    Tissue-specific expression of glutathione peroxidase gene in guinea pigs

    Biochim. Biophys. Acta

    (1993)
  • T.M. Buttke et al.

    Oxidative stress as a mediator of apoptosis

    Immunol. Today

    (1994)
  • W. Dröge et al.

    HIV-induced cysteine deficiency and T-cell disfunction—a rationale for treatment with N-acetylcysteine

    Immunol. Today

    (1992)
  • B.M. Dworkin

    Selenium deficiency in HIV infection and the acquired immunodeficiency syndrome (AIDS)

    Chem. Biol. Interact.

    (1994)
  • P.A. Sandstrom et al.

    Antioxidant defenses influence HIV-1 replication and associated cytopathic effects

    Free Radic. Biol. Med.

    (1998)
  • P.A. Sandstrom et al.

    Lipid hydroperoxide induced apoptosislack of inhibition by bcl-2 over-expression

    FEBS Lett.

    (1995)
  • J.B. de Haan et al.

    Mice with a homozygous null mutation for the most abundant glutathione peroxidase, Gpx1, show increased susceptibility to the oxidative stress-inducing agents paraquat and hydrogen peroxide

    J. Biol. Chem.

    (1998)
  • W.H. Cheng et al.

    Cellular glutathione peroxidase is the mediator of body selenium to protect against paraquat lethality in transgenic mice

    J. Nutr.

    (1998)
  • A. Spector et al.

    Variation in cellular glutathione peroxidase activity in lens epithelial cells, transgenics and knockouts does not significantly change the response to H2O2 stress

    Exp. Eye Res.

    (1996)
  • D. Behne et al.

    Newly found selenium-containing proteins in the tissues of the rat

    Biol. Trace Elem. Res.

    (1996)
  • P. Steinert et al.

    Analysis of the mouse selenoprotein P gene

    Biol. Chem.

    (1998)
  • S.C. Vendeland et al.

    Rat skeletal muscle selenoprotein WcDNA clone and mRNA modulation by dietary selenium

    Proc. Natl. Acad. Sci. USA

    (1995)
  • T. Tamura et al.

    A new selenoprotein from human lung adenocarcinoma cellspurification, properties, and thioredoxin reductase activity

    Proc. Natl. Acad. Sci. USA

    (1996)
  • M.J. Guimaraes et al.

    Identification of a novel selD homolog from eukaryotes, bacteria, and archea; is there an autoregulatory mechanism in selenocysteine metabolism?

    Proc. Natl. Acad. Sci. USA

    (1996)
  • J. Köhrle

    Local activation and inactivation of thyroid hormons

    Mol. Cell. Endocrin.

    (1999)
  • Mills; G. C. Hemoglobin catabolism I. Glutathione peroxidase, and erythrocyte enzyme which protects hemoglobin from...
  • J.T. Rotruck et al.

    SeleniumBiochemical role as a component of glutathione peroxidase

    Science

    (1973)
  • R. Schuckelt et al.

    Phospholipid hydroperoxide glutathione peroxidase is a selenoenzyme distinct from the classical glutathione peroxidase as evident from cDNA and amino acid sequencing

    Free Radic. Comms.

    (1991)
  • S.G. Rhee et al.

    A family of novel peroxidases, peroxiredoxins

    Biofactors

    (1999)
  • C. Kretz-Remy et al.

    Inibition of IκB-a phosphorylation and degradation and subsequent NF-κB activation by glutathione peroxidase overexpression

    J. Cell Biol.

    (1996)
  • R. Brigelius-Flohé et al.

    Interleukin-1-induced nuclear factor kappaB activation is inhibited by overexpression of phospholipid hydroperoxide glutathione peroxidase in a human endothelial cell line

    Biochem. J.

    (1997)
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    Regina Brigelius-Flohé was trained in biochemistry at the University of Tübingen from 1968 to 1974. While there, she started to study the toxicity as well as the physiology of oxidative stress, a topic she has never completely left during her scientific life. After completing her doctorate, she worked with Dr. Sies in Münich and Düsseldorf measuring glutathione mixed disulfides, then she was hidden in the industry for 7 years where she learned molecular biology and how to produce tons of heterologous proteins with bacteria. Dr. Brigelius-Flohé is now a professor at the University of Potsdam and is head of the Department of Vitamins and Artherosclerosis at the German Institute of Human Nutrition. Her present work concentrates on vitamin E metabolism and the role of glutathione peroxidases and hydroperoxides in the redox regulation of cytokine signaling and processes relevant for atherogenesis.

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