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Erythrocyte glutathione transferase: a potential new biomarker in chronic kidney diseases which correlates with plasma homocysteine

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Abstract

The erythrocyte glutathione S-transferase (e-GST) is a member of a superfamily of inducible enzymes involved in cell detoxification that shows an increased expression in chronic kidney disease (CKD) patients. We propose a new automated analysis procedure for e-GST activity that has been validated in 72 CKD patients and 62 maintenance hemodialysis patients (MHD). Regression analysis was carried out to assess association between e-GST activity data, main clinical variables, and plasma homocysteine (Hcy), a modified sulfur amino acid known as potential risk factor for cardiovascular disease that is increased above normal levels in more than 90% of the uremic patients. An increased e-GST activity was confirmed in MHD patients (N = 62; 10.2 ± 0.4 U/gHb) compared with healthy subjects (N = 80; 5.8 ± 0.4 U/gHb), and as an original finding, a significant increase of e-GST activity was observed in pre-dialysis CKD patients with a positive correlation with disease severity weighted according to the four stages of “Kidney Disease Outcomes Quality Initiative” classification (7.4 ± 0.5, 8 ± 1, 9.5 ± 0.6, 12 ± 1 U/gHb, respectively). No correlation was found between e-GST activity and hemoglobin, transferrin, blood iron and the markers of systemic inflammation and renal function such as alpha-1 acid glycoprotein and high-sensitive C-Reactive Protein, beta-2 microglobulin and the index of malnutrition-inflammation PINI, while a significant correlation was observed for the first time between plasma Hcy and e-GST activity (r 2 = 0.64, P < 0.0001) in MHD patients. Hcy, however, was not identified as an inhibitor of e-GST enzyme. The results in this study suggest the potential for automated e-GST analysis as a valuable tool to further explore phase II-related uremic toxicity in CKD and MHD patients.

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References

  • Adams PA, Sikakana CN (1990) Factors affecting the inactivation of human placental glutathione S-transferase pi. The kinetic mechanism and pH-dependence of solvational and 1-chloro-2,4-dinitrobenzene-mediated inactivation of the enzyme. Biochem Pharmacol 39:1883–1889

    Article  PubMed  CAS  Google Scholar 

  • Anwar W, Guéant JL, Abdelmouttaleb I, Adjalla C, Gérard P, Lemoel G, Erraess N, Moutabarrek A, Namour F (2001) Hyperhomocysteinemia is related to residual glomerular filtration and folate, but not to methylenetetrahydrofolate-reductase and methionine synthase polymorphisms, in supplemented end-stage renal disease patients undergoing hemodialysis. Clin Chem Lab Med 39:747–752

    Article  PubMed  CAS  Google Scholar 

  • Armstrong RN (1997) Structure, catalytic mechanism, and evolution of the glutathione transferases. Chem Res Toxicol 10:2–18

    Article  PubMed  CAS  Google Scholar 

  • Awasthi YC, Sharma R, Singhal SS (1994) Human glutathione S-transferase. Int J Biochem 26:295–308

    Article  PubMed  CAS  Google Scholar 

  • Bethea M, Forman DT (1990) Beta 2-microglobulin: its significance and clinical usefulness. Ann Clin Lab Sci 20:163–168

    PubMed  CAS  Google Scholar 

  • Bostom AG, Lathrop L (1997) Hyperhomocysteinemia in end-stage renal disease: prevalence, etiology, and potential relationship to arteriosclerotic outcomes. Kidney Int 52:495–502

    Article  Google Scholar 

  • Carmagnol F, Sinet PM, Rapin J, Jerome H (1981) Glutathione-S-transferase of human red blood cells; assay, values in normal subjects and in two pathological circumstances: hyperbilirubinemia and impaired renal function. Clin Chem Acta 117:209–217

    Article  CAS  Google Scholar 

  • Dessì M, Noce A, Agnoli A, De Angelis S, Fuiano L, Tozzo C, Taccone-Gallucci M, Fuiano G, Federici G (2009) The usefulness of the prognostic inflammatory and nutritional index (PINI) in a haemodialysis population. Nutr Metab Cardiovasc Dis 19:811–815

    Article  PubMed  Google Scholar 

  • Fry AC, Singh DK, Chandna SM, Farrington K (2007) Relative importance of residual renal function and convection in determining beta-2-microglobulin levels in high-flux haemodialysis and on-line haemodiafiltration. Blood Purif 225:295–302

    Article  Google Scholar 

  • Galli F, Rovidati S, Benedetti S, Buoncristiani U, Covarelli C, Floridi A, Canestrai F (1999) Overexpression of erythrocyte glutathione-S-transferase in uremia and dialysis. Clin Chem 45:1781–1788

    PubMed  CAS  Google Scholar 

  • Habig WH, Pabst MJ, Jakoby WB (1974) Glutathione S-transferases: the first enzymatic step in mercapturic acid formation. J Biol Chem 22:7130–7139

    Google Scholar 

  • Hayes JD, Flanagan JU, Jowsey IR (2005) Glutathione transferases. Ann Rev Pharmacol Toxicol 45:51–88

    Article  CAS  Google Scholar 

  • Jacobs MH (1932) Osmotic properties of the erythrocyte. Biol Bull 62:178–194

    Article  CAS  Google Scholar 

  • Jacobs LH, van de Kerkhof JJ, Mingels AM, Passos VL, Kleijnen VW, Mazairac AH, van der Sande FM, Wodzig WK, Konings CJ, Leunissen KM, van Dieijen-Visser MP, Kooman JP (2010) Inflammation, overhydration and cardiac biomarkers in haemodialysis patients: a longitudinal study. Nephrol Dial Transplant 25:243–248

    Article  PubMed  CAS  Google Scholar 

  • Kalantar-Zadeh K, Block G, Humphreys MH, McAllister CJ, Kopple JD (2004) A low, rather than a high, total plasma homocysteine is an indicator of poor outcome in hemodialysis patients. J Am Soc Nephrol 15:442–453

    Article  PubMed  CAS  Google Scholar 

  • K-DOQI (2004) Clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis 43(5 Suppl 1):S1–S290

    Google Scholar 

  • Kendrick J, Chonchol MB (2008) Non traditional risk factors for cardiovascular disease in patients with chronic kidney disease. Nat Clin Pract Nephrol 4:672–681

    Article  PubMed  Google Scholar 

  • Kluijtmans LA, van den Heuvel LP, Boers GH, Frosst P, Stevens EM, van Oost BA, den Heijer M, Trijbels FJ, Rozen R, Blom HJ (1996) Molecular genetic analysis in mild hyperhomocysteinemia: a common mutation in the methylenetatrahydrofolate reductase gene in a genetic risk factor for cardiovascular disease. Am J Hum Genet 58:35–41

    PubMed  CAS  Google Scholar 

  • Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D (1999) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130:461–470

    PubMed  CAS  Google Scholar 

  • Lo Bello M, Battistoni A, Mazzetti AP, Board PG, Muramatsu M, Federici G, Ricci G (1995) Site-directed mutagenesis of human glutathione transferase P1–1: spectral, kinetic and structural properties of Cys-47 and Lys-54 mutants. J Biol Chem 270:1249–1253

    Article  PubMed  CAS  Google Scholar 

  • Lubos E, Loscalzo J, Handy DE (2007) Homocysteine and glutathione peroxidase-1. Antioxid Redox Signal 9:1923–1940

    Article  PubMed  CAS  Google Scholar 

  • Passing H, Bablock W (1984) Comparison of several regression procedures for method comparison studies and determination of sample size. Application of linear regression procedures for method comparison studies in clinical chemistry. Part II. J Clin Chem Clin Biochem 22:431–445

    PubMed  CAS  Google Scholar 

  • Pastore A, De Angelis S, Casciani S, Ruggia R, Di Giovamberardino G, Noce A, Splendiani G, Cortese C, Federici G, Dessi M (2006) Effects of folic acid before and after vitamin B12 on plasma homocysteine concentrations in hemodialysis patients with known MTHFR genotypes. Clin Chem 52:145–148

    Article  PubMed  CAS  Google Scholar 

  • Ricci G, Del Boccio G, Pennelli A, Aceto A, Whitehead EP, Federici G (1989) Nonequivalence of the two subunits of horse erythrocyte glutathione transferase in their reaction with sulfhydryl reagents. J Biol Chem 264:5462–5467

    PubMed  CAS  Google Scholar 

  • Sheehan D, Meade G, Foley VM, Dowd CA (2001) Structure, function and evolution of glutathione transferases: implications for classification of non-mammalian members of an ancient enzyme superfamily. Biochem J 360:1–16

    Article  PubMed  CAS  Google Scholar 

  • van Guldener C (2006) Why is homocysteine elevated in renal failure and what can be expected from homocysteine-lowering? Nephrol Dial Transplant 21:1161–1166

    Article  PubMed  Google Scholar 

  • Welch GN, Loscalzo J (1998) Homocysteine and atherothrombosis. N Engl J Med 338:1042–1050

    Article  PubMed  CAS  Google Scholar 

  • Wrone EM, Hornberger JM, Zehnder JL, McCann LM, Coplon NS, Fortmann SP (2004) Randomized trial of folic acid for prevention of cardiovascular events in end-stage renal disease. J Am Soc Nephrol 15:420–426

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Francesco Galli or Giorgio Ricci.

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M. Dessì, A. Noce, and K. F. Dawood equally contributed to this work.

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Dessì, M., Noce, A., Dawood, K.F. et al. Erythrocyte glutathione transferase: a potential new biomarker in chronic kidney diseases which correlates with plasma homocysteine. Amino Acids 43, 347–354 (2012). https://doi.org/10.1007/s00726-011-1085-x

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  • DOI: https://doi.org/10.1007/s00726-011-1085-x

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