Review Protection against reactive oxygen species by selenoproteins Holger Steinbrenner a , Helmut Sies a,b,c, ⁎ a Institute for Biochemistry and Molecular Biology I, Heinrich-Heine-University, Düsseldorf, Germany b Institut für Umweltmedizinische Forschung (IUF), Heinrich-Heine-University, Düsseldorf, Germany c King Saud University, Riyadh, Saudi Arabia abstract article info Article history: Received 20 January 2009 Accepted 27 February 2009 Available online 5 March 2009 Keywords: ROS Oxidative stress Selenium Selenoprotein P Glutathione peroxidase Thioredoxin reductase Reactive oxygen species (ROS) are derived from cellular oxygen metabolism and from exogenous sources. An excess of ROS results in oxidative stress and may eventually cause cell death. ROS levels within cells and in extracellular body fluids are controlled by concerted action of enzymatic and non-enzymatic antioxidants. The essential trace element selenium exerts its antioxidant function mainly in the form of selenocysteine residues as an integral constituent of ROS-detoxifying selenoenzymes such as glutathione peroxidases (GPx), thioredoxin reductases (TrxR) and possibly selenoprotein P (SeP). In particular, the dual role of selenoprotein P as selenium transporter and antioxidant enzyme is highlighted herein. A cytoprotective effect of selenium supplementation has been demonstrated for various cell types including neurons and astrocytes as well as endothelial cells. Maintenance of full GPx and TrxR activity by adequate dietary selenium supply has been proposed to be useful for the prevention of several cardiovascular and neurological disorders. On the other hand, selenium supplementation at supranutritional levels has been utilised for cancer prevention: antioxidant selenoenzymes as well as prooxidant effects of selenocompounds on tumor cells are thought to be involved in the anti-carcinogenic action of selenium. © 2009 Elsevier B.V. All rights reserved. 1. Introduction Reactive oxygen species (ROS) include free radicals such as the superoxide anion, hydroxyl and lipid radicals as well as oxidizing non-radical species such as hydrogen peroxide, peroxynitrite and singlet oxygen. ROS are continuously produced in the respiratory chain of mitochondria by one-electron reduction of molecular oxygen. NAD(P)H oxidases, xanthine oxidase, myeloperoxidase, cyclooxygenase and lipoxygenase are major enzymatic sources of ROS in mammalian cells, whereas UV irradiation represents an example for an environmental ROS-inducing factor. At higher concentrations, ROS can damage cellular macromolecules including DNA, proteins and lipids. Thus, cells possess antioxidative systems for detoxification of ROS and repair of deleterious oxidative modifica- tions on cellular structures. Oxidative stress, resulting from an imbalance of oxidants and antioxidants in favor of the oxidants [1], may lead to subsequent cell death and is thought to be involved in the pathogenesis of diverse illnesses ranging from cardiovascular and neurological diseases to some forms of cancer [2]. On the other hand, low levels of ROS modulate signal transduction pathways, as it has been revealed for insulin-induced superoxide and hydrogen peroxide [3]. A number of hormones, growth factors and cytokines have been shown to elicit ROS production upon binding to their respective receptors. Based on the novel role of ROS as part of intracellular signaling cascades, the definition of oxidative stress has been refined recently as a “disruption of redox signaling and control” [4]. Among the dietary supplements, ingested by many individuals to improve their state of health, the essential micronutrient selenium has received attention for its antioxidant properties. Usually, humans take up selenium with their diet, predominantly from cereals, fish and meat. Selenium-enriched yeast and garlic are two natural products containing selenium mostly as highly bioavailable selenomethionine or gamma-glutamyl-Se-methylselenocysteine [5]. In addition, inor- ganic selenium compounds such as sodium selenite are available. Most of the antioxidant capacity of selenium appears to rely on ROS-degrading selenoenzymes, containing selenocysteine in their catalytic center. In contrast to other metal ions, which are associated with their respective apoproteins as cofactors, selenium is co- translationally incorporated into selenoproteins as selenocysteine [6], the selenium analogue of cysteine. The selenoproteome of all species investigated so far is rather small. Based on computational sequence analyses, genes for 25 human selenoproteins have been Biochimica et Biophysica Acta 1790 (2009) 1478–1485 Abbreviations: ApoER-2, apolipoprotein E receptor 2; GPx, glutathione peroxidase; LDL, low-density-lipoproteins; mRNA, messenger ribonucleic acid; MSeA, methylsele- ninic acid; NADPH, nicotinamide adenine dinucleotide phosphate, reduced form; NO, nitric oxide; NPC, Nutritional Prevention of Cancer trial; ROS, reactive oxygen species; PKC, protein kinase C; SeP, selenoprotein P; siRNA, small interfering ribonucleic acid; TGF-β1, transforming growth factor β1; TrxR, thioredoxin reductase; UV, ultraviolet ⁎ Corresponding author. Institute for Biochemistry and Molecular Biology I, Heinrich- Heine-Universität Duesseldorf, Universitätsstrasse 1, Geb. 22.03, D-40225 Düsseldorf, Germany. Tel.: +49 211 8115956; fax: +49 211 8115980. E-mail address: sies@uni-duesseldorf.de (H. Sies). 0304-4165/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.bbagen.2009.02.014 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbagen