ISSN 19907508, Biochemistry (Moscow) Supplement Series B: Biomedical Chemistry, 2014, Vol. 8, No. 4, pp. 273–285. © Pleiades Publishing, Ltd., 2014. Original Russian Text © A.V. Polonikov, V.P. Ivanov, A.D. Bogomazov, M.A. Solodilova, 2014, published in Biomeditsinskaya Khimiya.

Genetic and Biochemical Mechanisms of Involvement of Antioxidant Defense Enzymes in the Development of Bronchial Asthma: A Review A. V. Polonikova, 1, V. P. Ivanova, A. D. Bogomazovb, and M. A. Solodilovaa a

Kursk State Medical University, Department of Biology, Medical Genetics and Ecology, ul. Karla Marksa 3, Kursk, 305041 Russia tel./fax: +7 (4712) 588147; email: [email protected] b Kursk State Medical University, Department of Pediatrics, ul. Karl Marksa 3, Kursk, 305041 Russia tel./fax: +7 (910) 2731349; email: [email protected] Received September 23, 2013

Abstract—Recent achievements in the understanding genetic and biochemical mechanisms of the involve ment of antioxidant defense enzymes in the pathogenesis of bronchial asthma have been summarized and dis cussed in this review. We concluded that genetically determined abnormalities in the functioning of antioxi dant defense enzymes may play a substantial role in the development of bronchial asthma. Variation in genes for antioxidant defense enzymes in combination with prooxidant effects of the environment are responsible for a imbalance between oxidant and antioxidant processes with the shift of the redox state towards increased free radical production and induction of oxidative stress in the respiratory system, thereby contributing to the pathogenesis of bronchial asthma. Keywords: bronchial asthma, etiology and pathogenesis, biochemical abnormalities, oxidative stress, antiox idant defense enzymes, genetic polymorphism DOI: 10.1134/S1990750814040076 1

INTRODUCTION

The system of redox homeostasis is one of the oldest and most complex biological systems in man; it is based on antioxidant defense enzymes that control the direc tion and intensity of free radical oxidation (FRO) in organs and tissues of the body and provide adaptation to changing environmental conditions [1, 2]. Substrates for enzymes of the antioxidant system (AOS) are reac tive oxygen species (ROS), which at physiological con centrations regulate important biological processes in cells such as the mitogenic activity, initiation and real ization of apoptosis, cell adhesion, modulation of immune response, antibacterial defense, inflamma tory responses, signal transduction, contraction and relaxation of smooth muscle cells [3, 4]. However, excessive concentrations of ROS are toxic to biological structures, causing oxidative modification and inactiva tion of enzymes, proteins, DNA breaks, damage of cell membranes through increased lipid peroxidation and protein glycosylation [4]. The imbalance between the intensity of oxidant and antioxidant reactions caused by the impaired control for ROS generating and scaveng ing which results in accumulation of FRO products and induction of oxidative stress, common pathological mechanism of many human diseases. 1 To whom correspondence should be addressed

Being polymorphic in their structure, genes encod ing antioxidant defense enzymes, determine the indi vidual’s characteristics in the functioning of redox homeostasis and its responsiveness to oxidative stress. The present review is the first attempt to summarize the results of yet not numerous biomedical studies on the involvement of antioxidant defense enzymes in the molecular mechanisms of such common and socially significant disease as bronchial asthma. 1. THE MAIN RESULTS OF GENETIC STUDIES OF BRONCHIAL ASTHMA Bronchial asthma (BA) is a severe multifactorial inflammatory disease of the airways; its key element is the development of bronchial obstruction, manifested by recurrent episodes of wheezing, breathlessness, feel ing of fullness in the chest and cough. Molecular genetic aspects of the BA pathogenesis are the subject of inten sive research worldwide today. According to the HuGENet database (http://64.29.163.162:8080/ HuGENavigator), 1640 articles have been published on genetics of asthma in biomedical journals over the last 10 years. These include 1590 studies on the analy sis of genetic associations, 327 reports on the investi gation of geneenvironment interactions, 89 studies on genegene interactions, and 171 studies on phar macogenomics of BA. Results of 82 metaanalyses and 76 genomewide association studies (GWAS) of

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asthma have been already published. Much attention is paid to search for genes whose protein products are involved in regulation of immune and inflammatory processes including genes responsible for innate immune response, regulating local immunity, differ entiation and activity of Thelper cell type 2, and also genes, which determine functioning of bronchial epi thelial cells and those involved in airway remodeling and bronchial hyperreactivity [5]. In particular, the method of positional cloning has identified the 17q21 locus, including the ORMDL3 and GSDML genes which showed a strong association with susceptibility to childhood asthma [6]. The fine mapping of the 17q21 locus and also expression profiling of genes in lymphoblast cells from children with BA revealed a strong association of DNA polymorphisms with the expression level of the ORMDL3 gene [6]. According to the results of numerous linkage studies, a list of potentially important polymorphic genes for asthma susceptibility has been proposed; it includes IL4, IL4RA, IL13, ADRB2, TNF, HLADRB1, HLA DQB1, FCER1B, CD14, and ADAM33 genes [7]. How ever, with a few exceptions, the vast majority of genetic associations found with BA have not been confirmed in the largescale GWAS, performed by the interna tional consortia such as Decode [8], GABRIEL [9], EVA [10] and APCAT [11]. Nevertheless, a meta analysis of GWAS revealed a reasonably strong associ ations of asthma with polymorphisms of genes such as interleukin33 (IL33), thymic stromal lymphopoietin (TSLP), IL1RL1 gene, encoding IL33 receptor (ST2), ORMDL3/GSDML (locus at 17q21), SMAD3, RORA and HLADQ [12]. In fact, the IL33 and (ST2) loci were the only genes that showed a statistically significant association with BA in most genetic studies; despite the particular role of these genes in asthma pathogenesis remains unknown [7]. Inconsistency of results of genetic stud ies may be attributed to both interpopulation differ ences in genetic predisposition to BA (differences in haplotypic structure and frequences of diseasecaus ing alleles across populations of the world), and differ ences in environmental exposures (interpopulation differences in allergic sensitization, microbial and hel minth environment, influences of ecological factors of the chemical nature etc.) [12−14]. It should be noted that the results of genomewide studies were limited to the detection of the strongest associations of asthma with a few numbers of genetic variants, and found to be quite difficult to interpret with respect to disease pathogenesis [15, 16]. It should be also added that a proportion of the heritability explained by genes iden tified by genomewide association studies, is extremely small and this gives the reason to character ize such phenomenon as “missing heritability” [17]. This means that genes controlling immunopathologi cal mechanisms of asthma pathogenesis do not fully explain the reasons and molecular mechanisms of dis ease development in modern populations. There is a

clear need in the testing and validating new hypotheses of the pathogenesis of the disease, taking into consid eration a multiple results of experimental and clinical studies accumulated by global scientific community. 2. MOLECULAR AND BIOCHEMICAL ABNORMALITIES IN THE FUNCTIONING OF ANTIOXIDANT SYSTEM IN BRONCHIAL ASTHMA Recent literature data suggest that the pathogenetic basis of bronchial asthma is constituted by molecular biochemical abnormalities in redox homeostasis, char acterized by decreased antioxidant status, increased ROS production and oxidative stress [18, 19]. Oxidative stress is induced in the respiratory system by environ mental oxidants (bacterial and viral pathogens, plant and animal allergens, air pollutants, cigarette smoke, etc.) and due to decreased activity of AOS enzymes and excessive ROS generation. Besides pathogenetic role in asthma, oxidative stress is also responsible for secondary pathological changes of the airways and the lung [18]. As it has been noted above, patients with BA have a sig nificant imbalance between ROS production and anti oxidant defense [19, 20] due to enhanced activity of prooxidant enzymes and generation of free radicals, as well as a substantial reduction in activity and/or content of AOS enzymes. Significant changes in contents of oxidants, antioxidants and the presence oxidative stress markers in bronchoalveolar fluid, sputum, serum, plasma, airway cells and exhaled breath condensate in asthmatics, suggest systematic disorders of redox regu lation and their relation to the disease pathogenesis. In particular, increased levels of ROS such as hydroxyl and superoxide anion radicals [21], nitric oxide [22] and hydroperoxides [23] have been found in various biological fluids of BA patients. In addition, asthmatic patients are also characterized by decreased total plasma antioxidant status [24], and activity of AOS enzymes such as peroxidase [25] and superoxide dismutase [21]. Other biochemical abnormalities of redox homeostasis found in BA include increased lipid peroxidation (LPO) and increased production of proinflammatory isoprostanes (stereoisomers of pros taglandins), which also play an important role in the pathogenesis of the disease [26, 27]. It is known that the antioxidant system includes a large number of regulatory units, however, only anti oxidant defense enzymes are genetically determined. The enzymes are characterized by interindividual dif ferences in the activity and expression due to the pres ence of functionally unequal polymorphic alleles in their genes [28]. The presence of DNA polymor phisms in genes encoding AOS enzymes makes each person unique with respect to the regulation of the antioxidant status and FRO activity, thus determining individual resistance or sensitivity to the damaging effect of environmental oxidants and leading to patho logical processes such as bronchial asthma [29].

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3. ENZYMES GENERATING FREE RADICALS AND THEIR ROLE IN THE DEVELOPMENT OF BRONCHIAL ASTHMA Almost any oxidase reaction is accompanied by formation of free radicals, such as superoxide anion – radical ( O 2 ), hydrogen peroxide (H2O2), hydroxyl radical (•OH), nitric oxide (•NO), hypochlorous acid (HOCl–), peroxyl radical (ROO•), and hydroperoxyl radical (HOO–) [30]. Neutrophils, eosinophils, alveo lar macrophages, bronchial epithelial cells and endot helial cells are the main sources of ROS in the lung and the bronchial tree [31]. It is notably that lossoffunc tion genetic defects in the ROS generating enzymes (socalled prooxidant oxidases) and disorders inhib iting ROS production promote decreased nonspecific immune response, thereby contributing to chronic infection and inflammatory processes in the lung [4]. Excessive ROS generation by oxidases can deplete the resources of antioxidant defense, which ultimately results in oxidative damage of different cell types of the respiratory system [18]. The sources of free radicals in the lung tissues and airways are prooxidant enzymes such as NADPH oxidase of phagocytes, endothelial cell xanthine oxidase, mitochondrial cytochrome c oxidase and microsomal monooxygenases. 3.1. NADPH Oxidase NADPH is a membranebound enzyme that con sists of two membrane spanning subunits (gp91phox and gp22phox), three cytosolic subunits (p40phox, p47phox, and p67phox), and also guanosine triphosphate binding protein p21ras [32]. Proteins gp22phox (αsub unit of cytochrome b, CYBA) and gp91phox (βsubunit of cytochrome b, CYBB) bind FAD and form trans membrane cytochrome b558 [33]. αSubunit (CYBA) determines NADPH oxidase activity towards genera tion of superoxide anion radicals [34]. In the gene encoding αsubunit of NADPH oxidase several func tional polymorphisms have been identified: nucle otide substitution 242C>T (rs4673) in the coding region of exon 4, accompanied by an amino acid sub stitution His72Tyr in the protein region at heme bind ing site, transversion 640A>G (rs1049255) in the 3'untranslated region of the CYBA gene, and also promoter polymorphism –930A>G (rs9932581), influencing the transcriptional activity of the gene [35]. It is suggested that polymorphisms 242C>T and 640A>G in the CYBA gene influence the binding between proteins p22phox and gp91phox, thereby causing changes in ROS generating activity of NADPH oxi dase [36]. Our study performed among the Russian residents from the Kursk region revealed that the homozygous CYBA genotype 640AA was associated with increased risk of allergic asthma [37]. In the other study [38], we found an association of the pro moter polymorphism –930A>G with the develop ment of the nonallergic variant of BA in males.

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Interestingly, an increased risk of developing the dis ease in the carriers of genotype –930GG was observed in smokers and individuals at low intake of fresh fruits and vegetables (sources of natural antioxidants). These findings demonstrate a synergism between the CYBA gene polymorphism and environmental factors of pro and antioxidant action on the risk of asthma. Relationship of CYBA gene polymorphisms and asthma was confirmed in the Czech population [39]. In particular, the authors found that the polymor phism 640A>G and the –930G/242T/640A haplo type were associated with an increased disease risk and sensitization to two types of allergens. 3.2. NADPH Dehydrogenase, Quinone 1 (NQO1) NQO1 is NADP oxidoreductase, an enzyme that catalyzes conversion of potentially toxic quinones into stable hydroquinones [40]. In addition, the enzyme is able to activate some quinones into hydroquinones by inducing autooxidation of biomolecules due to over production of free radicals [40]. NQO1 gene expres sion is induced as a result of activation of the aryl hydrocarbon receptor signaling cascade by polycyclic aromatic hydrocarbons (PAHs), components of air pollution and cigarette smoke. More than 20 common singlenucleotide polymorphisms (SNPs) have been identified in the NQO1 gene [41], and among them nucleotide substitutions in exons 6 and 4 leading to amino acid substitutions P187S (rs1800566) and R139W (rs4986998) are intensively investigated in relation to their functional effects. The enzyme activ ity in heterozygotes 187PS was 3 times lower than in the wildtype homozygotes 187PP, whereas homozy gotes 187SS have a completely inactivated enzyme [42]. Several studies have been undertaken to investi gate the relationship between NQO1 gene polymor phisms and risk of asthma and bronchial hyperreactiv ity in different ethnicities such as Mexican [43], South African [44], Taiwanese [45], Canadian [46] and sev eral populations of European descent [47]. However, the association of polymorphic variants of the NQO1 gene was established with either asthma pheno type or bronchial hyperreactivity only in Chinese [45] and Europeans [47]. We found association of the NQO1 gene polymorphism P187S with the risk of aller gic BA in women from the Russian population [48]. In the context of the involvement of this gene in the BA pathogenesis, it should be noted that activation of NQO1 expression or activity is accompanied by induction of the transcription factor Nrf2, which can block immunoglobulin E (IgE) production by Blym phocytes [49]. On the one hand, the low NQO1 activ ity (in individuals with the 187SS genotype) seems to increase IgE production by Bcells; on the other hand, accumulation of quinone radicals may induce oxida tive stress in the respiratory tract, thus promoting the development of asthma.

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3.3. Myeloperoxidase (MPO) MPO is a lysosomal enzyme that catalyzes the reaction of hydrogen peroxide conversion to hypochlorous acid, a highly reactive and toxic oxi dant, which can oxidize the biomolecules with much higher rates than hydrogen peroxide [4, 50]. The main biological functions of MPO include maintaining of cellular immunity through producing hypochlorous acid, which exhibits bactericidal properties against a broad spectrum of microorganisms [51]. MPO con sists of two identical dimers linked by a disulfide bond; each dimer comprises a glycosylated heavy αsubunit covalently bound to heme and nonglycosylated light βsubunit [50]. The most common polymorphism of the MPO gene is the promoter substitution –463G>A (rs2333227), accompanied by decreased MPO expres sion [52]. We found an association between the wild type genotype –463GG of the MPO gene and the risk of BA development in the Russian population [53]. Two independent studies confirmed the relationship between the MPO gene polymorphism and asthma susceptibility. The researchers observed a joint of the –463G>A MPO gene polymorphism and other AOS genes such as (NQO1 and CAT [54, 55]) on the asthma risk. The polymorphism –463G>A is located in the hormonebinding site of the promoter and affects MPO gene expression due to a loss of binding site for transcription factor SP1 [56]. It was found that the –463G allele is associated with a more than 25fold increase in the level of MPO gene transcription, as compared with the –463A allele [56]. As compared with persons with the genotypes –463GA and –463AA, carriers of the –463GG genotype have higher MPO activity in bronchoalveolar fluid [57]. Notably, neutrophils from BA patients have the increased MPO levels [58], which negatively correlated with forced expiratory volume in 1 s [59], the main indi cator of bronchial obstruction in BA patients. 3.4. FlavinContaining Monooxygenase Type 3 (FMO3) FMO3 is a microsomal enzyme that catalyzes NADPHdependent oxygenation of xenobiotics con taining nitrogen, sulfur, selenium, and phosphorus groups and also thiocarbamyl compounds, thus con verting such substances into watersoluble and less toxic metabolites [60]. On the one hand, being typical monooxygenase, this enzyme oxidizes heteroatom nucleophilic compounds exhibiting oxidant properties [60]. On the other hand, FMO3 has prooxidant prop erties, converting flavin into its dehydro form and reducing oxygen to hydrogen peroxide. Although the exact biological role of flavincontaining monooxyge nases is not fully understood, it has been shown that this enzyme can oxidize many biological thiols such as cysteine, cysteamine and glutathione, thus playing the role of a modulator of thioldisulfide redox potential of the cell [61]. Sixteen common polymorphisms have

been found in the FMO3 gene; however, only one SNP causing E158K (rs2266782) and located in exon 4 is studied with respect to functional activity. Our study did not reveal any association between this polymor phism with BA risk in the Russian population [62]. 4. THE ROLE OF ANTIOXIDANT ENZYMES METABOLIZING SUPEROXIDE RADICALS AND HYDROPEROXIDES IN THE DEVELOPMENT OF BRONCHIAL ASTHMA Superoxide anion radicals exhibit not only damag ing effect on airway epithelial cells, they can readily react with the NO radical with formation of more toxic peroxynitrite [4]. Several enzymes are known to be involved in the detoxification of superoxide anion radicals. These include superoxide dismutase, catalase and glutathione peroxidase. 4.1. Superoxide Dismutase 1 (SOD1) SOD1 is a major antioxidant enzyme that catalyzes conversion of superoxide anion radical to molecular oxygen and hydrogen peroxide [63]. The enzyme is a metalloprotein of 32–33 kDa, which consists of two subunits, each binds one atom of copper and zinc. The SOD1 gene contains many SNPs, among which the most studied is the nucleotide substitution +35A>C (rs2234694), which causes reduction of SOD1 activity [64]. Although SOD activity in blood is lower in BA patients [65], only one genetic study investigated the role of SOD1 gene polymorphism in the Finnish population [66], but the authors did not reveal its asso ciation with asthma susceptibility. 4.2. Superoxide Dismutase 2 (SOD2) SOD2 is a mitochondrial enzyme that catalyzes the reaction of interaction between two superoxide anion radical molecules with water yielding hydrogen perox ide and molecular oxygen. SOD2 consists of four sub units with molecular mass of 20 kDa. The substitution 47C>T in the SOD2 gene results in amino acid substi tution V16A (rs4880) in the signal peptide [67]. The enzyme encoded by this genetic variant is character ized by a marked decrease (by 30–40%) in its catalytic activity. Although decreased SOD2 activity was found in BA asthma [68], we failed to find any association between the SOD2 gene V16A polymorphism and dis ease risk [62]. 4.3. Superoxide Dismutase 3 (SOD3) SOD3 is an antioxidant enzyme catalyzing the reaction of dismutation of superoxide anion radicals generated by the NADPHdependent oxidase system of neutrophils [4]. The enzyme represents a tetrameric glycoprotein of 30 kDa. Although many polymor

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phisms have been identified in the SOD3 gene, there are three the most common SNPs causing substitu tions A40T, F131C and R213G. Studies in Chinese and Finnish populations showed no association between SOD3 gene polymorphisms and the develop ment of BA [66, 69]. We did not find any association between the SOD3 gene polymorphism A40T and BA risk in the Russian population [62].

choalveolar fluid from asthmatic patients [74] demon strated a significant (by more than 50%) decrease of CAT. Moreover, the results of biochemical investiga tions of blood performed by Novák et al. [75] con firmed participation of the CAT gene in the pathogen esis of the disease.

4.4. Catalase (CAT)

Glutathione peroxidases represent a family of seleniumcontaining enzymes that, like catalase, catalyze the reaction of hydroperoxide reduction in a glutathionedependent manner in various types of cells. GPx affinity to H2O2 is higher than in catalase, and therefore GPx operates more efficiently at low concentrations of the substrate [4]. In the biomedical literature, there are controversial data regarding GPx activity in BA patients. In some studies, no dif ferences were found in blood GPx activity between BA patients and healthy subjects, whereas in other studies such differences have been revealed [76]. Glutathione peroxidase 1 (GPx1) is an enzyme of 84–88 kDa that consists of four identical subunits, each contains one selenium atom [3]. The main func tion of GPx1 is protection of biomembranes and intracellular organelles from oxidative damage by hydrogen peroxide, organic hydroperoxides, hydrop eroxides of fatty acids and phospholipids [77]. In fact, GPx1 is an adaptive enzyme and its activity is regu lated by LPO products and ROS. GPx1 is a major intracellular antioxidant enzyme, which is expressed in all tissues, including the lung and airways (in bron chial and alveolar epithelium, dendritic cells and monocytes) [77]. Although the GPX1 gene is highly polymorphic, the most frequent and functionally sig nificant SNP is rs1050450, causing amino acid substi tution P198L. It was found that catalytic activity of this enzyme in heterozygotes of the mutant allele 198L of the GPX1 gene is 40% lower than in the wild type allele (198P) carriers [78]. We found the associa tion between the L198P polymorphism of the GPX1 gene and predisposition to allergic asthma in male smokers [79, 80]. Decreased enzyme activity in smokers who were carriers of the genotype 198LP can exacerbate the process of detoxification of hydroper oxides; their accumulation favors conditions for oxi dative stress, bronchoconstriction and inflammation of the bronchial tree in BA. Glutathione peroxidase 2 (GPx2) is an enzyme, which protects cells from excess of LPO products ingested and produced in the gastrointestinal tract. Two common SNPs have been found in the GPX2 gene [81]; one results in amino acid substitution G173V (rs17880492). We have not been detected any associa tion between this polymorphism and the risk of BA in the Russian population [62]. Glutathione peroxidase 3 type (GPx3) is an extra cellular enzyme detoxifying hydrogen peroxide,

CAT is a peroxisomal enzyme that catalyzes the reaction of hydrogen peroxide neutralization to molecular oxygen and water [4]. The enzyme is a chromoprotein with molecular mass of 24 kDa, con sisting of four subunits. In cooperation with glu tathione peroxidase and superoxide dismutase CAT protects cells against oxidative stress induced by exces sive accumulation of hydroperoxides. It is suggested that CAT does not have high affinity to H2O2 and therefore the enzyme cannot metabolize low concen trations of hydrogen peroxide in cytosol. In contrast, CAT actively degrades H2O2 in peroxisomes where its concentration is mostly high. It is known that induc tion of catalase is the first stage of cellular response to oxidative stimuli of the environment [70]. Three com mon polymorphisms –21A>T, –262C>T and ⎯844C>T in the 5'untranslated region of the CAT gene have been identified. The –262C>T SNP changes the regulatory nucle otide sequence required for binding of the transcrip tion factor and thus influences catalase gene expres sion [71]. The association of the polymorphism – 262C> T with the risk of asthma has been investigated in two studies [69, 72]. Islam et al. [72] have found association of the –262T allele with an increased risk of developing BA in Spanish children, whereas in the other study performed by Mak et al. on the Chinese population [69], this allele was found to be associated with a decreased risk of the disease. The protective effect of the –262T allele was also observed by Nadif et al. [70]. In this study, the authors examined miners exposed to coal dust and found that erythrocyte cata lase activity was proportionally decreased with the increase of dust concentrations, but only in carriers of the –262T allele. We found no association between the polymorphism –262C>T and BA risk in the Russian population, but we found for the first time an associa tion of the polymorphism –21A>T (rs7943316) with susceptibility to asthma in male smokers and individ uals with low consumption of fresh fruits and vegeta bles [73]. Taking into consideration the linkage dise quilibrium between the –262C>T and –21A>T poly morphisms [71, 73], it is reasonable to suggest that the reduced CAT activity, determined by the defective allele ⎯21A of the CAT gene, is associated with an increased risk of developing BA due to the induction of oxidative stress at insufficient detoxification of hydro peroxides. The results of a proteomic survey in bron

4.5. Glutathione Peroxidases (GPx)

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organic hydroperoxides and fatty acids hydroperox ides [82]. GPx3 accounts for almost 50% of GPx in the lung and bronchi [83]. It has been found that BA patients have an increased level of GPx3 in bronchoalveolar fluid and increased mRNA levels in bronchial epithelial cells as compared with healthy individuals [84]. Authors of this study suggested that these changes found in BA patients were induced by excessive accumulation of ROS followed by oxidative stress. The most com mon polymorphism of the GPX3 gene is a nucleotide substitution G>A (rs2070593), characterized by syn onymous amino acid change T39T. Our study per formed in the Russian population showed no associa tion between this polymorphism and the risk of bron chial asthma [62]. Glutathione peroxidase 4 (GPx4) is a membrane bound enzyme, detoxifying phospholipid hydroperox ides in cell membranes and lipoproteins [85]. There is a positive relationship between GPx4 expression/activ ity and the level of selenium supply: the highest enzyme concentration determines its highest activity [85]. The most common polymorphism of the GPX4 gene is SNP C718T (rs713041) which is located in the 3'untrans lated region of the gene and influences its transcrip tional activity. A study of this polymorphism did not reveal the relationship of this SNP with the risk of asthma in Russians from Kursk region [62]. 5. THE ROLE OF ANTIOXIDANT ENZYMES OF GLUTATHIONE METABOLISM IN THE DEVELOPMENT OF BRONCHIAL ASTHMA Glutathione is the major natural antioxidant, involved in the regulation of immune and inflammatory processes in the respiratory system. It also plays a cru cial role in maintaining the intracellular redox homeo stasis, protecting cells of the lung and airways cells against oxidative stress [86]. When ROS production exceeds the capacity of the injured tissue to neutralize their action, depletion of intracellular glutathione con tent can lead to formation of oxidative stress and dam age of cells of the respiratory system and the subsequent development of the inflammatory process. It is known that maintenance of sufficient levels of reduced glu tathione (GSH) in immune cells is a key mechanism maintaining the balance of Th1/Th2 immune responses and presentation of antigen [76]. GSH performs detox ification of hydrogen peroxide, and hydroperoxides derived from the reaction of ROS with polyunsaturated fatty acids of cell membranes, and thus glutathione pro tects the respiratory tract against oxidative damage. In turn, imbalance between GSH and GSSG (glutathione disulfide) in combination with impaired activity or expression of AOS enzymes may impair receptor induced and ROSmediated signal transduction con trolling immune responses and that may be important for the development of BA [76]. Experimental and clin

ical studies of BA revealed impairments in metabolic activity of glutathione and enzymes involved in its metabolism. In particular, patients with adult asthma are characterized by increased levels of total and oxi dized glutathione in sputum and bronchoalveolar fluid as compared with healthy subjects [76]. At the same time, children suffering from BA were found to have significantly lower GSH levels in exhaled breath con densate as compared with healthy children [76]. Apparently, the variability of glutathione levels may be associated with impaired activity and/or content of enzymes, which are directly and indirectly involved in its metabolism. Enzymes participating in glutathione metabolism include glutathione reductase, glutamate cysteine ligase, glutathione Stransferase, glutathione peroxidases, glutamyl transpeptidase and glutathione synthase. 5.1. Glutathione Reductase (GSR) GSR is an enzyme catalyzing the reaction of NADPH dependent reduction of the active form of glutathione (GSH) from its disulfide form (GSSG) [4]. GSR consists of two subunits of 50–55 kDa. Clin ical and biochemical studies have shown contradictory results on changes in the content and activity of this enzyme in BA. Gumral et al. found decreased erythro cyte GSR levels in BA patients during exacerbations [87]. However, Fitzpatrick et al. [88] found no differ ence in GSR activity of bronchoalveolar fluid between BA patients and healthy individuals. Our study per formed in the Russian population has shown associa tion between the polymorphism T>C (rs2551715) in intron 9 of the GSR gene with the risk of allergic BA [62], thus demonstrating for the first time potential involvement of the GSR gene in the pathogenesis of the disease. 5.2. Glutamate Cysteine Ligase (GCL) GCL is an enzyme, also known as γglutamyl cys teine synthase, catalyzes the first rate limiting step of glutathione biosynthesis, formation of the dipeptide intermediate product (LγglutamylLcysteine), which is then converted by glutathione synthase in GSH. GCL consists of two subunits: heavy or catalytic subunit (GCLC) and light or modulatory subunit (GCLM). One of the most studied functional poly morphisms of the GCLC gene is –129C>T (rs17883901). It was found that the carriers of the – 129T allele are characterized by 50⎯60% lower pro moter activity of the GCLC gene in response to stimu lation of endothelial cells with hydrogen peroxide than carriers of allele –129C [89]. Two tightly linked poly morphisms –588C>T (rs41303970) and –23G/T (rs743119) have been identified at the 5'flanking region of the GCLM gene. They are associated with a decreased activity of the promoter of the gene in response to oxidative stimuli, as well as to a decreased

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level of plasma GSH [90]. We have found the associa tion of polymorphisms –588C>T and –23G>T of the GCLM gene with the risk of nonallergic asthma in Rus sians [91]. It is suggested that the presence of the “low active” –588T allele promotes a decrease in intracel lular glutathione production in response to oxidative stress and increases the sensitivity of airways to oxida tive damage. 5.3. Glutathione Transferases (GSTs) GSTs represent a large family of antioxidant enzymes that play an important role in protecting cells against oxidative stress, neutralization and prep aration for the excretion of substances with poten tially toxic and carcinogenic properties that they acquired due to metabolic activation at the first phase of biotransformation of xenobiotics [92]. The enzy matic reaction catalyzed by GST consists in nucleo philic addition (conjugation) of reduced glutathione to nonpolar components containing an electrophilic atom of carbon, nitrogen or sulfur. GSTs are pre sented by three major families, two of which include mitochondrial and cytosolic GST, while the third family includes microsomal GSTs also known as MAPEG (membrane associated proteins in eicosanoid and glutathione metabolism), which are involved in metabolism of eicosanoids and glu tathione [93]. Cytosolic GSTs are inducible antioxi dant and biotransformation enzymes, including at least 17 isoforms, pooled into more than 8 major classes: α (GSTA1⎯GSTA5), μ (GSTM1⎯GSTM5), π (GSTP1), σ (GSTS1), θ (GSTT1 and GSTT2), ω (GSTO1 and GSTO2), ξ (GSTZ1), and κ (GSTK1) [92]. Numerous studies found associa tion of polymorphic variants of different GST genes with asthma and other allergic diseases. GSTs μ are divided into 5 groups: GSTM1, GSTM2, GSTM3, GSTM4 and GSTM5. The iso forms GSTM1, GSTM3 together with GSTP1 cata lyze conjugation of reduced glutathione with reactive epoxide metabolites of PAHs derived due to their acti vation by the cytochrome P450 system. GSTM1 sub strates include products of industrial pollution, pesti cides, insecticides, herbicides, anticancer drugs, endogenous unsaturated aldehydes, PAHs, organo phosphorus compounds, nitro compounds, heterocy clic amines, arene oxides, quinones, epoxides and hydroperoxides [92], many of which may be etiologi cally related to the development of BA. The most intensively investigated mutation of the GSTM1 gene is a deletion spanning exons 6 and 7 (socalled null or deletion polymorphism), which blocks gene expres sion [92]. Association of the GSTM1 null polymor phism with increased risk of asthma was confirmed by metaanalysis of multiple studies performed in differ ent populations [94]. GSTs θ are subdivided into two groups: GSTT1 and GSTT2. The isoform GSTT1 catalyzes conjuga

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tion of glutathione with highly reactive oxidants, components of tobacco smoke and air pollutants, as well as LPO products [92]. There is a deletion in the coding region (exon 4) of the GSTT1 gene (socalled nullpolymorphism), which blocks synthesis of this enzyme [95]. Many studies have been undertaken to investigate the relationship between the GSTT1 dele tion polymorphism and the risk of bronchial asthma. Results of the metaanalysis [94] showed that the deletion polymorphism of the GSTT1 gene repre sents a genetic marker for predisposition to asthma, including in the Russian population [96]. GST π. This is the most dominant form among all classes of cytosolic GSTs in the lung. Two common and functionally significant SNPs have been identified in the GSTP1 gene: I105V (rs1695) and A114V (rs1138272), which are in linkage disequilibrium with each other [97]. Three allelic variants of the GSTP1 gene have been described: GSTP1*A (I105, A114), GSTP1*B (V105, A114), and GSTP1*C (V105, V114), which are characterized by different activities in xenobiotic metabolism. The I105 allele is more active in metabolism of 3,4dichloro1nitrobenzene, while the V105 allele variant is 7 times more active in metabolism of PAHs [95]. It was found that polymorphic variants of the GSTP1 gene (especially I105V) are associated with BA in some European populations [98]. We also found an association between the I105V GSTP1 gene poly morphism and the risk of childhood asthma [99], whereas the I105V and A114V polymorphisms of the GSTP1 gene and deletion polymorphism of the GSTM1 and GSTT1 genes did not show association with adult asthma in the Russian population [100, 101]. Genetic and biochemical studies on glutamyl transpeptidase and glutathione synthase in bronchial asthma have not been conducted so far. 6. THE ROLE OF OTHER ANTIOXIDANT ENZYMES IN THE DEVELOPMENT OF BRONCHIAL ASTHMA Among other AOS genes investigated for associa tion with the risk of BA, certain attention has been paid to genes encoding nitric oxide synthases (NOS), the enzymes catalyzing the reaction of NADPH and oxygen dependent formation of nitric oxide (NO) from Larginine [102]. Three NOS isoforms are known: NOS1 (neuronal), NOS2 (inducible) and NOS3 (endothelial) [102]. Polymorphisms NOS1, NOS2, and NOS3 (NOS2) are associated with the level of NO in exhaled air [103], and this parameter is increased in BA patients [104]. Genetic and epidemiological studies revealed association of the risk of asthma with the number of CA nucleotide repeats in intron 2 [105] and exon 29 [106], as well as AATrepeats in intron 20 [104] of the NOS1 gene. Although associations of polymorphisms of the NOS2 and NOS3 genes with the disease risk have

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not been found, their links with asthmarelated pheno types such as IgE level, atopy, and NO concentration in exhaled air have been documented [103, 107]. We inves tigated associations with BA some other genes repre senting the antioxidant system: peroxiredoxin 1 (PRDX1), thioredoxin reductase 1 (TXNRD1), paraox onases (PON1 and PON2) in the Russian population [62]. However, the only association of the Q192R poly morphism of the PON1 gene with asthma was found. The table summarizes the results of the main stud ies, which revealed association between genes encod ing AOS enzymes with the development of BA asthma in different populations of the world. 7. MOLECULAR AND BIOCHEMICAL MECHANISMS OF INVOLVEMENT OF THE ANTIOXIDANT SYSTEM IN PATHOGENESIS OF BRONCHIAL ASTHMA Results of numerous studies pointed out the exist ence of primary impairments in the functioning of the antioxidant system in asthma, characterized by the decreased activity and/or content of AOS enzymes, which correlates with the severity of disease and bron chial obstruction. These abnormalities retain during the asthma attacks and are detected at the phase of clinical remission. Although, genetic studies investi gating the association of AOS gene polymorphisms with the risk of BA are still in their infancy, neverthe less, good evidence exists that genes encoding these enzymes are important part of genetic predisposition to asthma, which realizes its pathological effects through weakening the antioxidant status and increas ing activity of freeradical processes. These biochemi cal abnormalities are triggered by environmental fac tors such as smoking, chemical pollution and others. Genes for antioxidant defense enzymes are a part of the polygenic basis the asthma development, and the complex nature of genegene interactions in the anti oxidant system explains the genetic differences between individuals and populations in terms of pre disposition to the disease (genetic heterogeneity of asthma) and the variability of the clinical phenotypes (allergic and nonallergic variants of asthma). These suggestions have been directly confirmed in our recent study performed using modern bioinformatics approaches to the analysis of genegene interactions [62]. We have analyzed for the first time interactions between 34 functionally important polymorphisms in genes encoding AOS enzymes in allergic and nonaller gic variants of asthma. It was found that the predispo sition to the distinct pathogenetic variants of asthma is determined by various AOS genes, which closely inter act with genes controlling well characterized immuno pathological mechanisms of the disease. Moreover, it should be noted that the complexity of interactions between the genes can determine different vectors of pathophysiological changes underlying allergic and nonallergic phenotypes of bronchial asthma. We have

provided convincing evidences of a comprehensive involvement of AOS genes in the pathogenesis BA as well as for their relation with biochemical abnormali ties in redox regulation found by a number of studies. Thus, we can distinguish the main pathogenetic mechanisms, by which polymorphic variants of genes of AOS enzymes are involved in the development of BA. The pathogenetic basis for the development of BA constitutes not only known immunopathological disorders, but also genetically determined imbalance in the functioning of prooxidant and antioxidant enzymes. On the one hand, prooxidant effects on the respiratory system are realized through effects of environmental factors, such as tobacco smoke, air pollutants and other agents. On the other hand, the environmental influences are exacerbated due to increased activity of oxidant enzymes and diminished activity of antioxidant defense enzymes. In particular, NADPH oxidase can act as an enzyme generating a large number of ROS. The “proactive” alleles of the αsubunit (CYBA) of NADPH oxidase are associated with the risk of allergic and nonallergic types of BA. Weakness in the functioning of antioxidant defense enzymes in asthma may be due to deficiency and/or decreased activity of enzymes such as: (1) GPx 1, 2, 3 and 4 types and catalase detoxifying hydrogen perox ide and organic hydroperoxides; (2) enzymes of glu tathione metabolism (GCL and GSR), which may cause deficiency of the endogenous natural antioxi dant glutathione; (3) other enzymes (eg, NQO1, EPHX1, PON1 and PON2), involved in detoxifica tion of reactive metabolites, including those borne by cytochrome P450dependent metabolic activation at phase 1 of biotransformation of xenobiotics. Bio chemical abnormalities caused by deficiency of the antioxidant status and excessive production of free – radicals such as O 2 , H2O2, HOCl, HO–, ROOH, and R(O), make redox homeostasis overloaded, thereby promoting induction of oxidative stress, one of important mechanism of asthma. Numerous studies support the hypothesis that oxidative stress plays a key role in the development of BA and realizes the nega tive effects through the mechanisms including dam age of the airway epithelium, increased contractility of smooth muscle cells of the bronchi and their hyper reactivity, increased vascular permeability and cell exudation, airways inflammation and obstruction, well known pathophysiological characterizing asth matic phenotype [18–20, 108]. For example, release of cytokines caused oxidative stress induces activation and migration of inflammatory cells, leading to air way obstruction, disruption of mucocilliary transport and bronchial hyperreactivity. The cells infiltrating the bronchial mucosa, produce a large amount of ROS, which in turn cause protein oxidation, activa tion of LPO by promoting the release of chemoattrac tants and arachidonic acid from cell membranes. Arachidonic acid causes increasing in vascular per

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+/del (del/del)

0.35 (0.15–0.85) 1.73 (–) 6.77 (1.97–23.18)1 5.41 (1.62–18.06)2 2.21 (1.17–4.19) 2.51 (1.04–6.06)1

BA (adults) BA (children) Nonallergic BA (adults)

Genotype –21AA

Genotype del/del

Genotype del/del

Genotype –588TT/–23TT Genotype –588CT/23GT

Genotype 198PL

1.93 (1.05–3.55)

BA (children)

BA (adult and childhood)

BA (adult and childhood)

Nonallergic BA (adults)

Allergic BA (adults)

1.39 (1.09–1.77)

1.28 (1.09–1.52)

2.03 (1.05–3.90)

0.33 (0.15–0.70)

6.35 (1.1–37.5) 0.73 (–)

Allergic BA (females) BA (children)

Allergic BA (males)

1.6 (1.3–1.8)

BA (children)

1.36 (1.03–1.84)4 1.54 (1.10–2.24)4

0.4 (0.2–0.8)3

BA (children) BA (adults)

1.43 (1.06–1.93)

BA (adults)

0.43 (0.24–0.78)

0.63 (0.41–0.96) 1.76 (1.07–2.90) 2.86 (1.06–7.77)1 3.11 (1.01–9.63)2

Allergic BA (adults)

Nonallergic BA (males)

Allergic BA (adults)

clinical variant odds ratio (OR) and 95% con of bronchial asthma (BA) fidential interval (95% CI)

Association with bronchial asthma

Haplotype –930G/242T/640A Genotypes 187PS or 187SS Genotype 187P Genotype 1574CC Genotypes 187PS or 187SS Genotype 187SS Allele 187S Genotypes –463GA or –463AA Genotypes –262CT or –262TT Allele –262T Allele c. 671083T

Genotype –930GG

Genotype 640AG Genotype 640AA

Genetic variant

[79] [80]

Russians, 213/205 Russians, 195/167

Metaanalysis of 22 studies, 4416/23902 Metaanalysis of 19 studies, 3852/22880

[94]

[94]

[91]

[73]

Russians, 215/214

Russians, 221/214

[69] [46]

[72]

[53]

[48] [46]

[45]

US Spanish cohort of 576 individuals Chinese, 251/316 Canadians, 254 families

Russians, 215/214

Russians, 215/214 Canadians, 254 families

Chinese, 215/877

[47]

[43]

Mexicans, 218 families European cohort of 2,920 individuals

[39]

[38]

[37]

Reference

Czechs, 305/311

Russians, 215/214

Russians, 209/210

Population, number of BA patients/healthy controls

1 In smokers, 2 in individuals with low intake of fresh vegetables and fruits, 3 in 0/0 GSTM1 homozygous carriers exposed to high ozone concentrations, 4 treated with NO . 2

GSTT1

+/del (del/del)

P198L (rs1050450)

CAT

GSTM1

–262C>T (rs1001179) c.671083C>T (rs11032703) –21A/T (rs7943316)

MPO

GCLM

–463G>A (rs2333227)

NQO1

–588C/T (rs41303970) –23G>T (rs743119)

P187S (rs1800566) 1574G>C (rs2917666) R139W (rs4986998)

CYBA

Polymorphism (SNP ID)

640A>G (rs1049255) 242C>T (rs4673) – 930A>G (rs9932581)

AOS gene/ enzyme

Summary of the main studies found association between AOS genes and the development of BA in various populations of the world

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meability, smooth muscle cell contractility, mucocili ary secretion, and bronchial hyperresponsiveness [13]. It should be noted that oxidative damage can be accumulated in the respiratory tract, leading to per sistence of asthma attacks and further release of proinflammatory mediators, exacerbating the disease. Enhanced respiratory burst in airway epithelial cells is a consequence of oxidative stress caused by autooxi dation of phagocytes and intracellular release of oxi dants (mainly superoxide anion radicals); this finally results in secondary airway damage, maintenance of the inflammatory process and bronchial remodeling. In conclusion it should be noted that taking into consideration the genetic heterogeneity and complex ity of the mechanisms of BA pathogenesis, it seems appropriate to perform further genetic and biochemi cal studies with a focus on polymorphic genes for anti oxidant defense enzymes in combination with oxidant and antioxidant environmental risk factors in order to identify geneenvironment interactions underlying molecular basis of the disease. The study of the molec ular mechanisms involved in the regulation of redox homeostasis will identify “weak links” in the function ing of the antioxidant defense system and shed a light into the pathogenesis of asthma. Genetically deter mined biochemical disorders in redox homeostasis in bronchial asthma suggest a clear need in introduction of elements of antioxidant therapy into clinical prac tice. Such approach should be focused on the correc tion of molecular disorders of the antioxidant status which is impaired long before the clinical onset of asthma. In light of actual trends in the development and modernization of medicine, this approach would be effectively utilized by personalized medicine for selecting appropriate and optimal therapies based on the context of a patient’s antioxidant status. REFERENCES 1. Skulachev, V.P., Biochemistry (Moscow), 1998, vol. 63, pp. 1335–1343. 2. Velichkovskii,B.T., Vestnik RAMN, 2010, no. 6, pp. 45–52. 3. Kulinskii, V.I., Soros Educat. J., 1999, no. 1, pp. 2–7. 4. Halliwell, B.B. and Gutteridge, M.C.J., Free Radicals in Biology and Medicine, Fourth Edn., Oxford Univer sity Press, 2007. 5. Vercelli, D., Nat. Rev. Immunol., 2008, vol. 8, pp. 169– 182. 6. Moffatt, M.F., Kabesch, M., Liang, L., Dixon, A.L., Strachan, D., Heath, S., Depner, M., von Berg, A., Bufe, A., Rietschel, E., Heinzmann, A., Simma, B., Frischer, T., WillisOwen, S.A., Wong, K.C., Illig, T., Vogelberg, C., Weiland, S.K., von Mutius, E., Abeca sis, G.R., Farrall, M., Gut, I.G., Lathrop, G.M., and Cookson, W.O., Nature, 2007, vol. 448, pp. 470–473. 7. Wjst, M., Sargurupremraj, M., and Arnold, M., Curr. Opin. Allergy Clin. Immunol., 2013, vol. 13, pp. 112– 118.

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