Plasma Levels of Aminothiols, Nitrite, Nitrate, and Malondialdehyde in Myelodysplastic Syndromes in the Context of Clinical Outcomes and as a Consequence of Iron Overload
The role of oxidative stress in the initiation and progression of myelodysplastic syndromes (MDS) as a consequence of iron overload remains unclear. In this study we have simultaneously quantified plasma low-molecular-weight aminothiols, malondialdehyde, nitrite, and nitrate and have studied their correlation with serum iron/ferritin levels, patient treatment (chelation therapy), and clinical outcomes. We found significantly elevated plasma levels of total, oxidized, and reduced forms of cysteine , homocysteine , and cysteinylglycine and significantly depressed levels of total and oxidized forms of glutathione and nitrite in MDS patients compared to healthy donors. Moreover, total and oxidized cysteinylglycine and nitrite differed significantly between the analyzed MDS subgroups with different clinical classifications. Malondialdehyde levels in plasma correlated moderately with both serum ferritin levels and serum free iron levels and were significantly higher in patients with iron overload. The other analyzed compounds lacked correlation with iron overload (represented by serum iron/ferritin levels). For the first time our results have revealed significant differences in the concentrations of plasma aminothiols in MDS patients, when compared to healthy donors. We found no correlation of these parameters with iron overload and suggest the role of oxidative stress in the development of MDS disease. 1. Introduction Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematological disorders, characterized by ineffective hematopoiesis and a high risk of transformation into acute myeloid leukemia (AML). Although the origin of MDS development is not fully understood, it has been determined that oxidative stress plays an important role in the initialization and disease progression of MDS [1]. One of the suggested mechanisms causing oxidative stress in MDS is attributed to a non-transferrin-bound iron (NTBI or free iron), which has been found in higher levels in the early stages of MDS patients receiving frequent red blood cell (RBC) transfusions [2]. Several studies have found elevated levels of oxidative stress markers (reactive oxygen species) and reduced levels of antioxidants (reduced glutathione (GSH)) in MDS patients and their correlation with serum ferritin levels [3, 4]. However, increased oxidative stress was revealed, even in the patients not receiving transfusions [5]. The presence of several other oxidative stress markers has been described in patients with established MDS, independent of iron or ferritin levels [6–8]. Oxidative
References
[1]
M. J. Farquhar and D. T. Bowen, “Oxidative stress and the myelodysplastic syndromes,” International Journal of Hematology, vol. 77, no. 4, pp. 342–350, 2003.
[2]
N. Gattermann and E. A. Rachmilewitz, “Iron overload in MDS-pathophysiology, diagnosis, and complications,” Annals of Hematology, vol. 90, no. 1, pp. 1–10, 2011.
[3]
K. Saigo, M. Takenokuchi, Y. Hiramatsu et al., “Oxidative stress levels in myelodysplastic syndrome patients: their relationship to serum ferritin and haemoglobin values,” Journal of International Medical Research, vol. 39, no. 5, pp. 1941–1945, 2011.
[4]
H. Ghoti, J. Amer, A. Winder, E. Rachmilewitz, and E. Fibach, “Oxidative stress in red blood cells, platelets and polymorphonuclear leukocytes from patients with myelodysplastic syndrome,” European Journal of Haematology, vol. 79, no. 6, pp. 463–467, 2007.
[5]
A. Cortelezzi, C. Cattaneo, S. Cristiani et al., “Non-transferrin-bound iron in myelodysplastic syndromes: a marker of ineffective erythropoiesis?” Hematology Journal, vol. 1, no. 3, pp. 153–158, 2000.
[6]
A. Cortelezzi, N. S. Fracchiolla, F. Bamonti-Catena et al., “Hyperhomocysteinemia in myelodysplastic syndromes: specific association with autoimmunity and cardiovascular disease,” Leukemia and Lymphoma, vol. 41, no. 1-2, pp. 147–150, 2001.
[7]
C. M. Peddie, C. R. Wolf, L. I. Mclellan, A. R. Collins, and D. T. Bowen, “Oxidative DNA damage in CD34+ myelodysplastic cells is associated with intracellular redox changes and elevated plasma tumour necrosis factor-α concentration,” British Journal of Haematology, vol. 99, no. 3, pp. 625–631, 1997.
[8]
J. W. Choi, “No significant correlation exists between nitric oxide production and apoptosis in myelodysplastic syndromes,” Acta Haematologica, vol. 109, no. 1, pp. 50–52, 2003.
[9]
D. Giustarini, I. Dalle-Donne, D. Tsikas, and R. Rossi, “Oxidative stress and human diseases: origin, link, measurement, mechanisms, and biomarkers,” Critical Reviews in Clinical Laboratory Sciences, vol. 46, no. 5-6, pp. 241–281, 2009.
[10]
M. T. M. Raijmakers, E. A. P. Steegers, and W. H. M. Peters, “Glutathione S-transferases and thiol concentrations in embryonic and early fetal tissues,” Human Reproduction, vol. 16, no. 11, pp. 2445–2450, 2001.
[11]
A. J. Garcia and R. Apitz-Castro, “Plasma total homocysteine quantification: an improvement of the classical high-performance liquid chromatographic method with fluorescence detection of the thiol-SBD derivatives,” Journal of Chromatography B, vol. 779, no. 2, pp. 359–363, 2002.
[12]
H. Li, C. J. Meininger, and G. Wu, “Rapid determination of nitrite by reversed-phase high-performance liquid chromatography with fluorescence detection,” Journal of Chromatography B, vol. 746, no. 2, pp. 199–207, 2000.
[13]
J. Woitzik, N. Abromeit, and F. Schaefer, “Measurement of nitric oxide metabolites in brain microdialysates by a sensitive fluorometric high-performance liquid chromatography assay,” Analytical Biochemistry, vol. 289, no. 1, pp. 10–17, 2001.
[14]
C. A. Davies, D. Perrett, Z. Zhang, B. R. Nielsen, D. R. Blake, and P. G. Winyard, “Simultaneous analysis of nitrite, nitrate and the nicotinamide nucleotides by capillary electrophoresis: application to biochemical studies and human extracellular fluids,” Electrophoresis, vol. 20, no. 10, pp. 2111–2117, 1999.
[15]
J. Suttnar, L. Má？ová, and J. E. Dyr, “Influence of citrate and EDTA anticoagulants on plasma malondialdehyde concentrations estimated by high-performance liquid chromatography,” Journal of Chromatography B, vol. 751, no. 1, pp. 193–197, 2001.
[16]
J. ？tikarová, J. Suttnar, K. Pimková, L. Chrastinová-Má Ová, J. Ermák, and J. E. Dyr, “Enhanced levels of asymmetric dimethylarginine in a serum of middle age patients with myelodysplastic syndrome,” Journal of Hematology and Oncology, vol. 6, no. 1, article 58, 2013.
[17]
H. Moshage, B. Kok, J. R. Huizenga, and P. L. M. Jansen, “Nitrite and nitrate determinations in plasma: a critical evaluation,” Clinical Chemistry, vol. 41, no. 6, pp. 892–896, 1995.
[18]
P. Kleinbongard, A. Dejam, T. Lauer et al., “Plasma nitrite reflects constitutive nitric oxide synthase activity in mammals,” Free Radical Biology and Medicine, vol. 35, no. 7, pp. 790–796, 2003.
[19]
T. Lauer, M. Preik, T. Rassaf et al., “Plasma nitrite rather than nitrate reflects regional endothelial nitric oxide synthase activity but lacks intrinsic vasodilator action,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 22, pp. 12814–12819, 2001.
[20]
S. Alusik, V. Jedlickova, Z. Paluch, and S. Zecova, “Plasma levels of nitrite/nitrate and inflammation markers in elderly individuals,” Bratislavské lekárske listy, vol. 109, no. 7, pp. 289–292, 2008.
[21]
K. Mikiwa, I. Tadashi, K. Kayoko, et al., “Plasma nitrate/nitrite concentration in healthy population and patients with diabetes mellitus: relationships with gender, aging and diabetic complications,” Bulletin of the Osaka Medical College, vol. 48, pp. 1–6, 2002.
[22]
C. J. Bates, M. A. Mansoor, J. Gregory, K. Pentieva, and A. Prentice, “Correlates of plasma homocysteine, cysteine and cysteinyl-glycine in respondents in the British National Diet and Nutrition Survey of young people aged 4-18 years, and a comparison with the survey of people aged 65 years and over,” British Journal of Nutrition, vol. 87, no. 1, pp. 71–79, 2002.
[23]
D. Modun, M. Krnic, J. Vukovic et al., “Plasma nitrite concentration decreases after hyperoxia-induced oxidative stress in healthy humans,” Clinical Physiology and Functional Imaging, vol. 32, no. 5, pp. 404–408, 2012.
[24]
I. C. Vermeulen Windsant, N. C. de Wit, J. T. Sertorio et al., “Blood transfusions increase circulating plasma free hemoglobin levels and plasma nitric oxide consumption: a prospective observational pilot study,” Critical Care, vol. 16, no. 3, article R95, 2012.
[25]
U. Drei？igacker, M.-T. Suchy, N. Maassen, and D. Tsikas, “Human plasma concentrations of malondialdehyde (MDA) and the F2-isoprostane 15(S)-8-iso-PGF2α may be markedly compromised by hemolysis: evidence by GC-MS/MS and potential analytical and biological ramifications,” Clinical Biochemistry, vol. 43, no. 1-2, pp. 159–167, 2010.
[26]
B. Mayer and P. Andrew, “Nitric oxide synthases: catalytic function and progress towards selective inhibition,” Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 358, no. 1, pp. 127–133, 1998.
[27]
B. de Chiara, V. Sedda, M. Parolini et al., “Plasma total cysteine and cardiovascular risk burden: action and interaction,” Scientific World Journal, vol. 2012, Article ID 303654, 2012.
[28]
N. Jacob, E. Bruckert, P. Giral, M. J. Foglietti, and G. Turpin, “Cysteine is a cardiovascular risk factor in hyperlipidemic patients,” Atherosclerosis, vol. 146, no. 1, pp. 53–59, 1999.
[29]
T. Müller and S. Muhlack, “Cysteinyl-glycine reduction as marker for levodopa-induced oxidative stress in Parkinson's disease patients,” Movement Disorders, vol. 26, no. 3, pp. 543–546, 2011.
[30]
S. Passi, M. Grandinetti, F. Maggio, A. Stancato, and C. De Luca, “Epidermal oxidative stress in vitiligo,” Pigment Cell Research, vol. 11, no. 2, pp. 81–85, 1998.
[31]
B. De Chiara, A. Mafrici, J. Campolo et al., “Low plasma glutathione levels after reperfused acute myocardial infarction are associated with late cardiac events,” Coronary Artery Disease, vol. 18, no. 2, pp. 77–82, 2007.
[32]
H. Shimizu, Y. Kiyohara, I. Kato et al., “Relationship between plasma glutathione levels and cardiovascular disease in a defined population: the Hisayama study,” Stroke, vol. 35, no. 9, pp. 2072–2077, 2004.
[33]
M. H. Hanigan, H. F. Frierson Jr., P. E. Swanson, and B. R. De Young, “Altered expression of gamma-glutamyl transpeptidase in human tumors,” Human Pathology, vol. 30, no. 3, pp. 300–305, 1999.
[34]
A. Raza, N. Galili, S. Smith et al., “Phase 1 multicenter dose-escalation study of ezatiostat hydrochloride (TLK199 tablets), a novel glutathione analog prodrug, in patients with myelodysplastic syndrome,” Blood, vol. 113, no. 26, pp. 6533–6540, 2009.
[35]
D. A. Dickinson and H. J. Forman, “Glutathione in defense and signaling: lessons from a small thiol,” Annals of the New York Academy of Sciences, vol. 973, pp. 488–504, 2002.
[36]
M. Tager, A. Ittenson, A. Franke, A. Frey, H. G. Gassen, and S. Ansorge, “γ-glutamyl transpepsidase-cellular expression in populations of normal human mononuclear cells and patients suffering from leukemias,” Annals of Hematology, vol. 70, no. 5, pp. 237–242, 1995.
[37]
M. J. Proctor, D. Talwar, S. M. Balmar et al., “The relationship between the presence and site of cancer, an inflammation-based prognostic score and biochemical parameters. Initial results of the Glasgow Inflammation Outcome Study,” British Journal of Cancer, vol. 103, no. 6, pp. 870–876, 2010.
[38]
B. Diergaarde, R. Brand, J. Lamb et al., “Pooling-based genome-wide association study implicates gamma- glutamyltransferase 1 (GGT1) gene in pancreatic carcinogenesis,” Pancreatology, vol. 10, no. 2-3, pp. 194–200, 2010.
[39]
G. M. de Donatis, R. Moschini, M. Cappiello, A. del Corso, and U. Mura, “Cysteinyl-glycine in the control of glutathione homeostasis in bovine lenses,” Molecular Vision, vol. 16, pp. 1025–1033, 2010.
[40]
A. Vasikova, M. Belickova, E. Budinska, and J. Cermak, “A distinct expression of various gene subsets in CD34+ cells from patients with early and advanced myelodysplastic syndrome,” Leukemia Research, vol. 34, no. 12, pp. 1566–1572, 2010.
[41]
P. Valent, O. Krieger, R. Stauder et al., “Iron overload in myelodysplastic syndromes (MDS): diagnosis, management, and response criteria: A proposal of the Austrian MDS platform,” European Journal of Clinical Investigation, vol. 38, no. 3, pp. 143–149, 2008.
