Relationship between oxidative stress, glutathione S-transferase polymorphisms and hydroxyurea treatment in sickle cell anemia

Silva, Danilo Gruenig Humberto; Junior, Edis Belini; Torres, Lidiane de Souza; Ricci, Octávio; Lobo, Clarisse; Bonini-Domingos, Cláudia Regina; Almeida, Eduardo Alves de

doi:10.1016/j.bcmd.2011.03.004

Cited by 46 publications

(39 citation statements)

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“…Therefore in these patients, we confirmed Hb F protective effect provided by HU use. Once increasing Hb F levels resulted in a decrease of the lipid peroxidation levels in accordance with our recent publications [44,46]. The protective effect is due to the increase in Hb F concentration that either inhibits or retards Hb S polymerisation [47], leading to a decreased intravascular sickling and an increasing nitric oxide bioavailability [48].…”

Section: Discussionsupporting

confidence: 85%

Genetic and biochemical markers of hydroxyurea therapeutic response in sickle cell anemia

et al. 2013

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BackgroundSickle cell anemia (SCA) presents a complex pathophysiology which can be affected by a number of modifying factors, including genetic and biochemical ones. In Brazil, there have been no studies verifying βS-haplotypes effect on oxidative stress parameters. This study evaluated βS-haplotypes and Hb F levels effects on oxidative stress markers and their relationship with hydroxyurea (HU) treatment in SCA patients.MethodsThe studied group was composed by 28 SCA patients. Thirteen of these patients were treated with HU and 15 of them were not. We used molecular methodology (PCR-RFLP) for hemoglobin S genotype confirmation and haplotypes identification. Biochemical parameters were measured using spectrophotometric methods (Thiobarbituric-acid-reactive substances and Trolox equivalent antioxidant capacity levels, catalase and GST activities) and plasma glutathione levels by High-performance liquid chromatography coupled to electrochemical detection.ResultsWe found the highest frequency of Bantu haplotype (48.2%) which was followed by Benin (32.1%). We observed also the presence of Cameroon haplotype, rare in Brazilian population and 19.7% of atypical haplotypes. The protective Hb F effect was confirmed in SCA patients because these patients showed an increase in Hb F levels that resulted in a 41.3% decrease on the lipid peroxidation levels (r =−0.74, p=0.01). Other biochemical parameters have not shown differential expression according to patient’s haplotypes. Bantu haplotype presence was related to the highest lipid peroxidation levels in patients (p < 0,01), but it also conferred a differential response to HU treatment, raising Hb F levels in 52.6% (p = 0.03) when compared with the group with the same molecular profile without HU usage.ConclusionsSCA patients with Bantu haplotype showed the worst oxidative status. However these patients also demonstrated a better response to the treatment with HU. Such treatment seems to have presented a “haplotype-dependent” pharmacological effect.

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Section: Discussionsupporting

confidence: 85%

Genetic and biochemical markers of hydroxyurea therapeutic response in sickle cell anemia

et al. 2013

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“…In the study of Tang et al [28], total antioxidant capacity (TAC) was the highest and MDA was the lowest in null/null genotype, which partially corresponds with our result. Silva et al [36] compared the level of TEAC to determine plasma antioxidant capacity in both wild, null/wild, wild/null, and both null genotype; there was no significant difference, which is different from our result. In the study of Bessa et al [33], the level of MDA, GSH, CAT, SOD, and GSH-Px among patients with hypertension was not significantly different among four GST genotype groups.…”

Section: Discussioncontrasting

confidence: 99%

Lymphocyte DNA damage and plasma antioxidant status in Korean subclinical hypertensive patients by glutathione S-transferase polymorphism

et al. 2017

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BACKGROUND/OBJECTIVESGlutathione S-transferase (GST) forms a multigene family of phase II detoxification enzymes which are involved in the detoxification of xenobiotics by conjugating substances with glutathione. The aim of this study is to assess the antioxidative status and the degree of DNA damage in the subclinical hypertensive patients in Korea using glutathione S-transferase polymorphisms.SUBJECTS/METHODSWe examined whether DNA damage and antioxidative status show a difference between GSTM1 or GSTT1 genotype in 227 newly diagnosed, untreated (systolic blood pressure (BP) ≥ 130 mmHg or diastolic BP ≥ 85 mmHg) subclinical hypertensive patients and 130 normotensive subjects (systolic BP < 120 mmHg and diastolic BP < 80 mmHg). From the blood of the subjects, the degree of the DNA damage in lymphocyte, the activities of erythrocyte superoxide dismutase, the catalase, and the glutathione peroxidase, the level of glutathione, plasma total radical-trapping antioxidant potential (TRAP), anti-oxidative vitamins, as well as plasma lipid profiles and conjugated diene (CD) were analyzed.RESULTSOf the 227 subjects studied, 68.3% were GSTM1 null genotype and 66.5% were GSTT1 null genotype. GSTM1 null genotype had an increased risk of hypertension (OR: 2.104, CI: 1.38-3.35), but no significant association in GSTT1 null genotype (OR 0.982, CI: 0.62-1.55). No difference in erythrocyte activities of superoxide dismutase, catalase, or glutathione peroxidase, and plasma TRAP, CD, lipid profiles, and GSH levels were observed between GSTM1 or GSTT1 genotype. Plasma levels of α-tocopherol increased significantly in GSTT1 wild genotype (P < 0.05); however, plasma level of β-carotene increased significantly in GSTT1 null genotype (P < 0.01). DNA damage assessed by the Comet assay was significantly higher in GSTM1 null genotype than wild genotype (P < 0.05).CONCLUSIONSThese results confirm the association between GSTM1 null genotype and risk of hypertension as they suggest that GSTM1 null genotype leads to an increased oxidative stress compared with wild genotype.

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“…44 In a phase 2 clinical trial of N-acetylcysteine in SCD patients, administration of the drug decreased the percentage of dense cells, normalized RBC glutathione levels, and decreased the frequency of vaso-occlusive crises. 45 One of the multiple beneficial mechanisms of hydroxyurea in SCD may be reduction of systemic oxidative stress in humans, 46,47 and there is an inverse correlation between hemoglobin F levels and markers of systemic oxidative stress in an SCD mouse model. 48 Trials of antioxidant agents in mouse models of SCD also appear to reduce markers of acute and chronic inflammation.…”

Section: Nadph Oxidase and Ros In Sickle Erythrocytes 2105mentioning

confidence: 99%

Erythrocyte NADPH oxidase activity modulated by Rac GTPases, PKC, and plasma cytokines contributes to oxidative stress in sickle cell disease

George

Pushkaran

Konstantinidis

et al. 2013

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• Sickle RBC ROS production is mediated in part by NADPH oxidase activity.• Sickle RBC ROS production can be induced by plasma signaling molecules.Chronic inflammation has emerged as an important pathogenic mechanism in sickle cell disease (SCD). One component of this inflammatory response is oxidant stress mediated by reactive oxygen species (ROS) generated by leukocytes, endothelial cells, plasma enzymes, and sickle red blood cells (RBC). Sickle RBC ROS generation has been attributed to sickle hemoglobin auto-oxidation and Fenton chemistry reactions catalyzed by denatured heme moieties bound to the RBC membrane. In this study, we demonstrate that a significant part of ROS production in sickle cells is mediated enzymatically by NADPH oxidase, which is regulated by protein kinase C, Rac GTPase, and intracellular Ca 21 signaling within the sickle RBC. Moreover, plasma from patients with SCD and isolated cytokines, such as transforming growth factor b1 and endothelin-1, enhance RBC NADPH oxidase activity and increase ROS generation. ROS-mediated damage to RBC membrane components is known to contribute to erythrocyte rigidity and fragility in SCD. Erythrocyte ROS generation, hemolysis, vaso-occlusion, and the inflammatory response to tissue damage may therefore act in a positive-feedback loop to drive the pathophysiology of sickle cell disease. These findings suggest a novel pathogenic mechanism in SCD and may offer new therapeutic targets to counteract inflammation and RBC rigidity and fragility in SCD. (Blood. 2013;121(11):2099-2107 IntroductionVaso-occlusion and hemolysis from the rigid and concurrently fragile red blood cells (RBC) in patients with sickle cell disease (SCD) cause a variety of acute and chronic manifestations ranging from frequent and severe painful crises to stroke and chronic organ failure. Chronic inflammation has emerged as an important pathogenic mechanism in SCD, and oxidative stress is increasingly recognized as a component of this chronic inflammatory state, inducing damage to a variety of subcellular and tissue structures. 1,2Patients with SCD have decreased plasma levels of glutathione, vitamin C, and vitamin E, presumably due to consumption by increased oxidant production. [3][4][5] RBC and other cell types show evidence of lipid peroxidation and oxidative damage to structural proteins.6-8 Additionally, plasma from SCD patients has elevated levels of advanced glycation end products 9,10 and products of lipid peroxidation (F-2 isoprostanes, malonaldehyde, and 4-hydroxynonenal), [11][12][13] all of which are markers of oxidative stress. There are several postulated mechanisms for the increased oxidative stress in patients with SCD. Sickle (SS) RBC reactive oxygen species (ROS) generation has been attributed to sickle hemoglobin auto-oxidation and iron-mediated Fenton chemistry reactions catalyzed by denatured heme moieties bound to the RBC membrane.14 Plasma hemoglobin and free heme resulting from chronic hemolysis generate superoxide radicals via the same nonenzymatic mechanisms. 15 In...

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Relationship between oxidative stress, glutathione S-transferase polymorphisms and hydroxyurea treatment in sickle cell anemia

Cited by 46 publications

References 58 publications

Genetic and biochemical markers of hydroxyurea therapeutic response in sickle cell anemia

Genetic and biochemical markers of hydroxyurea therapeutic response in sickle cell anemia

Lymphocyte DNA damage and plasma antioxidant status in Korean subclinical hypertensive patients by glutathione S-transferase polymorphism

Erythrocyte NADPH oxidase activity modulated by Rac GTPases, PKC, and plasma cytokines contributes to oxidative stress in sickle cell disease

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