DNA damage and oxidative stress response to seleni

Authors: E Jablonska S Raimondi J Gromadzinska E Reszka E Wieczorek M B Krol A SmokPieniazek M Nocun M Stepnik K Socha M H Borawska W Wasowicz

Publish Date: 2015/12/10

Volume: 55, Issue: 8, Pages: 2469-2484

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Abstract

Selenium both essential and toxic element is considered to protect against cancer though human supplementation trials have generated many inconsistent data Genetic background may partially explain a great variability of the studies related to selenium and human health The aim of this study was to assess whether functional polymorphisms within two selenoproteinencoding genes modify the response to selenium at the level of oxidative stress DNA damage and mRNA expression especially in the individuals with a relatively low selenium statusAfter genotype stratification the effect of GPX1 rs1050450 on lower GPx1 activity responsiveness was confirmed however in terms of DNA damage we failed to indicate that individuals homozygous for variant allele may especially benefit from the increased selenium intake Surprisingly considering gene and time interaction GPX1 polymorphism was observed to modify the level of DNA strand breaks during washout showing a significant increase in GPX1 wildtype homozygotes Regardless of the genotype selenium supplementation was associated with a selectively suppressed selenoprotein mRNA expression and inconsistent changes in oxidative stress response indicating for overlapped antioxidant and prooxidant effects Intriguingly DNA damage was not influenced by supplementation but it was significantly increased during washoutSelenium Se is an essential trace element the importance of which for human health is indicated by the presence of at least 25 selenoproteins containing the element in a form of selenocysteine Sec the twentyfirst proteinogenic amino acid The unusual uniqueness of selenium stems from the fact that Sec is incorporated into selenoprotein polypeptide chain cotranslationally driven by UGA mRNA codon in the presence of a specific molecular machinery including SectRNA Sec insertion sequence SECIS element and protein factors such as SECISbinding protein SBP2 and Secspecific translation elongation factor eEFSec which all together allow for insertion of Sec instead of premature termination of biosynthesis as UGA usually serves as the termination codon 1 2 The uniqueness of selenium is also reflected by its biological activity in terms of which the element is most often described as “doubleedge sword” “essential poison” or “twofaced element” 3 That is due to high redox properties—Se exerts both nutritional and toxic activities within a relatively narrow range of doses highlighted by a relatively small difference between the recommended daily intake 55 µg or 70 µg in USA and Europe respectively and the estimated upper tolerable limit 300 400 or 450 µg/day according to different sources 4 5 6 Most of the scientific interest related to Se is associated with its anticancer properties which have been suggested based on numerous in vitro and in vivo studies as well as on some although not all human observational studies and human longterm supplementation trials 7 8 Mechanism of anticancer activity of Se remains elusive but it is generally considered that it results both from antioxidant and redoxrelated properties of Se exerted at a nutritional level and linked mainly to the activity of seleniumdependent enzymes selenoproteins with catalytic activity as well as from its prooxidant effects observed at supranutritional intake and associated with the activity of low molecular weight Se compounds 9 10 11 12 However in the recent years the hypothesis on cancer protective activity of Se has been seriously undermined by the results of a large randomized doubleblind prospective study ie SELECT which has been conducted to test whether Se as selenomethionine and vitamin E as alphatocopherol may reduce the risk of prostate cancer in men and which has finally failed to indicate any protective effects of the element either alone or in the combination with vitamin E 13 Additionally some concern has been paid to Se supplementation in terms of its possible diabetogenic effects adding more uncertainty to assessing the relationship between selenium and human health 14 15On the basis of several gene association studies pointing to the importance of genetic polymorphism in the risk of human cancer as well as other diseases it has been hypothesized that biological activity of Se in the human body may be modified by genetic polymorphism of selected selenoproteins 16 17 Human selenoproteins cover many biologically important functions like those related to antioxidant defense system thyroid hormone metabolism and redox balance maintenance all of which are driven mainly by redoxrelated selenoproteins including five glutathione peroxidases GPx1 GPx2 GPx3 GPx4 GPx6 three iodothyronine deiodinases DI1 DI2 DI3 three thioredoxin reductases TRxR1 TRxR2 TRxR3 or methionineRsulfoxide reductase MsrB1 known also as SelR or SelX Selenoprotein P Sepp1 is the only selenoprotein which possesses multiple Sec residues and which is mainly responsible for Se transport within the body but has been also shown to exert catalytic and antioxidant activities 18 Functions of other selenoproteins are specifically linked to the selenoprotein synthesis selenophoshate synthetase 2—SPS2 muscle development selenoprotein N—SelN or endoplasmic reticulum function 15kDa selenoprotein—Sep15 selenoprotein S—SelS selenoprotein K—SelK whereas functions of many other like selenoprotein H—SelH selenoprotein I—SelI selenoprotein M—SelM selenoprotein O—SelO selenoprotein W—SelW selenoprotein T—SelT or selenoprotein V—SelV still remain unknown 19 20 It has been demonstrated that some polymorphic variants in genes encoding for selected selenoproteins including GPX1 glutathione peroxidase 1 GPX4 glutathione peroxidase 4 SEPP1 selenoprotein P SELS selenoprotein S and SEP15 15kDa selenoprotein have functional significance and may influence expression or activity of the protein either at the transcription translation or posttranslational level thus explaining their association with the altered risk of cancer at several sites 17Despite the commonly appreciated approach to include genetic profile in the design of intervention trials or in the interpretation of study results only few authors have followed this direction and those who have focused only on single specific end points linked mainly to oxidative stress markers and/or DNA damage 21 22 23 24 25 Notably the genotype modifying effects are more likely to be observed within the subjects with a relatively low Se status 24 Thus the aim of this study was to analyze the potential influence of two functional singlenucleotide polymorphisms SNPs present within the coding region of two selenoprotein genes GPX1 rs1050450 Pro198Leu and SEPP1 rs3877899 Ala234Thr on the multilevel biological response to Se supplementation Due to a low dietary intake of Se in the Polish population 26 individuals from Poland who constituted the study group seemed to be relevant to investigate the possible gene–selenium interactions Biomarkers of relevance included markers of Se status plasma Se and Sepp1 concentrations markers of oxidative stress activity of antioxidant enzymes in plasma or erythrocytes plasma lipid peroxidation oxidative burst in the wholeblood leukocytes DNA strand breaks DNA oxidation and mRNA expression of selected encoding selenoproteins or related genes GPX1 GPX4 TRXR1 SEP15 SEPP1 SELS SELW SBP2

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