Transsulfuration Pathway Defects and Increased Glutathione Degradation in Severe Acute Pancreatitis

  • Sakhawat H. Rahman
  • Asha R. Srinivasan
  • Anna Nicolaou
Original Article

Abstract

Glutathione depletion is a consistent feature of the progression of mild to severe acute pancreatitis. In this study, we examined the temporal relationship between cysteine, homocysteine, and cysteinyl-glycine levels; total reduced erythrocyte glutathione; gamma-glutamyl transpeptidase activity; and disease severity. Initially, cysteine concentration was low, at levels similar to those of healthy controls. However, glutathione was reduced whilst cysteinyl glycine and gamma-glutamyl transpeptidase activity were increased in both mild and severe attacks. As the disease progressed, glutathione and cysteinyl glycine were further increased in mild attacks and cysteine levels correlated with homocysteine (r = 0.8, P < 0.001) and gamma-glutamyl transpeptidase activity (r = 0.75, P < 0.001). The progress of severe attacks was associated with glutathione depletion, reduced gamma-glutamyl transpeptidase activity, and increased cysteinyl glycine that correlated with glutathione depletion (r = 0.99, P = 0.01). These results show that glutathione depletion associated with severe acute pancreatitis occurs despite an adequate cysteine supply and could be attributed to heightened oxidative stress coupled to impaired downstream biosynthesis.

Keywords

Oxidative stress Gamma glutamyl transpeptidase Acute pancreatitis Glutathione Homocysteine Cysteine 

References

  1. 1.
    McKay CJ, Evans S, Sinclair M, Carter CR, Imrie CW (1999) High early mortality rate from acute pancreatitis in Scotland, 1984–1995. Br J Surg 86:1302–1305. doi: 10.1046/j.1365-2168.1999.01246.x PubMedCrossRefGoogle Scholar
  2. 2.
    Buter A, Imrie CW, Carter CR, Evans S, McKay CJ (2002) Dynamic nature of early organ dysfunction determines outcome in acute pancreatitis. Br J Surg 89:298–302. doi: 10.1046/j.0007-1323.2001.02025.x PubMedCrossRefGoogle Scholar
  3. 3.
    UK guidelines for the management of acute pancreatitis. Gut 2005;54(Suppl 3):iii1–iii9. doi: 10.1136/gut.2004.057026 Google Scholar
  4. 4.
    Kikuchi Y, Shimosegawa T, Moriizumi S, Kimura K, Satoh A, Koizumi M et al (1997) Transgenic copper/zinc-superoxide dismutase ameliorates caerulein-induced pancreatitis in mice. Biochem Biophys Res Commun 233:177–181. doi: 10.1006/bbrc.1997.6421 PubMedCrossRefGoogle Scholar
  5. 5.
    Schulz HU, Niederau C, Klonowski-Stumpe H, Halangk W, Luthen R, Lippert H (1999) Oxidative stress in acute pancreatitis. Hepatogastroenterology 46:2736–2750PubMedGoogle Scholar
  6. 6.
    Altomare E, Grattagliano I, Vendemiale G, Palmieri V, Palasciano G (1996) Acute ethanol administration induces oxidative changes in rat pancreatic tissue. Gut 38:742–746. doi: 10.1136/gut.38.5.742 PubMedCrossRefGoogle Scholar
  7. 7.
    Zhao W, Diz DI, Robbins ME (2007) Oxidative damage pathways in relation to normal tissue injury. Br J Radiol 80(Spec No 1):S23–S31PubMedCrossRefGoogle Scholar
  8. 8.
    Ryter SW, Kim HP, Hoetzel A, Park JW, Nakahira K, Wang X et al (2007) Mechanisms of cell death in oxidative stress. Antioxid Redox Signal 9:49–89. doi: 10.1089/ars.2007.9.49 PubMedCrossRefGoogle Scholar
  9. 9.
    Wong GH, Goeddel DV (1988) Induction of manganous superoxide dismutase by tumor necrosis factor: possible protective mechanism. Science 242:941–944. doi: 10.1126/science.3263703 PubMedCrossRefGoogle Scholar
  10. 10.
    Schoenberg MH, Buchler M, Beger HG (1994) Oxygen radicals in experimental acute pancreatitis. Hepatogastroenterology 41:313–319PubMedGoogle Scholar
  11. 11.
    Nonaka A, Manabe T, Tobe T (1991) Effect of a new synthetic ascorbic acid derivative as a free radical scavenger on the development of acute pancreatitis in mice. Gut 32:528–532. doi: 10.1136/gut.32.5.528 PubMedCrossRefGoogle Scholar
  12. 12.
    Telek G, Scoazec JY, Chariot J, Ducroc R, Feldmann G, Roz C (1999) Cerium-based histochemical demonstration of oxidative stress in taurocholate-induced acute pancreatitis in rats. A confocal laser scanning microscopic study. J Histochem Cytochem 47:1201–1212PubMedGoogle Scholar
  13. 13.
    Kusterer K, Poschmann T, Friedemann A, Enghofer M, Zendler S, Usadel KH (1993) Arterial constriction, ischemia-reperfusion, and leukocyte adherence in acute pancreatitis. Am J Physiol 265:G165–G171PubMedGoogle Scholar
  14. 14.
    Fu K, Sarras MP Jr, De Lisle RC, Andrews GK (1997) Expression of oxidative stress-responsive genes and cytokine genes during caerulein-induced acute pancreatitis. Am J Physiol 273:G696–G705PubMedGoogle Scholar
  15. 15.
    Rau B, Poch B, Gansauge F, Bauer A, Nussler AK, Nevalainen T et al (2000) Pathophysiologic role of oxygen free radicals in acute pancreatitis: initiating event or mediator of tissue damage? Ann Surg 231:352–360. doi: 10.1097/00000658-200003000-00008 PubMedCrossRefGoogle Scholar
  16. 16.
    Luthen R, Niederau C, Grendell JH (1995) Intrapancreatic zymogen activation and levels of ATP and glutathione during caerulein pancreatitis in rats. Am J Physiol 268:G592–G604PubMedGoogle Scholar
  17. 17.
    Sevillano S, de la Mano AM, Manso MA, Orfao A, De Dios I (2003) N-acetylcysteine prevents intra-acinar oxygen free radical production in pancreatic duct obstruction-induced acute pancreatitis. Biochim Biophys Acta 1639:177–184PubMedGoogle Scholar
  18. 18.
    Neuschwander-Tetri BA, Ferrell LD, Sukhabote RJ, Grendell JH (1992) Glutathione monoethyl ester ameliorates caerulein-induced pancreatitis in the mouse. J Clin Invest 89:109–116. doi: 10.1172/JCI115550 PubMedCrossRefGoogle Scholar
  19. 19.
    Hardman J, Shields C, Schofield D, McMahon R, Redmond HP, Siriwardena AK (2005) Intravenous antioxidant modulation of end-organ damage in L-arginine-induced experimental acute pancreatitis. Pancreatology 5:380–386. doi: 10.1159/000086538 PubMedCrossRefGoogle Scholar
  20. 20.
    Demols A, Van Laethem JL, Quertinmont E, Legros F, Louis H, Le Moine O et al (2000) N-acetylcysteine decreases severity of acute pancreatitis in mice. Pancreas 20:161–169. doi: 10.1097/00006676-200003000-00009 PubMedCrossRefGoogle Scholar
  21. 21.
    Sanfey H, Bulkley GB, Cameron JL (1984) The role of oxygen-derived free radicals in the pathogenesis of acute pancreatitis. Ann Surg 200:405–413. doi: 10.1097/00000658-198410000-00003 PubMedCrossRefGoogle Scholar
  22. 22.
    Esrefoglu M, Gul M, Ates B, Yilmaz I (2006) Ultrastructural clues for the protective effect of ascorbic acid and N-acetylcysteine against oxidative damage on caerulein-induced pancreatitis. Pancreatology 6:477–485. doi: 10.1159/000094665 PubMedCrossRefGoogle Scholar
  23. 23.
    Biolo G, Antonione R, De Cicco M (2007) Glutathione metabolism in sepsis. Crit Care Med 35:S591–S595. doi: 10.1097/01.CCM.0000278913.19123.13 PubMedCrossRefGoogle Scholar
  24. 24.
    Dickinson DA, Forman HJ (2002) Cellular glutathione and thiols metabolism. Biochem Pharmacol 64:1019–1026. doi: 10.1016/S0006-2952(02)01172-3 PubMedCrossRefGoogle Scholar
  25. 25.
    Kalil AC, Sevransky JE, Myers DE, Esposito C, Vandivier RW, Eichacker P et al (2006) Preclinical trial of L-arginine monotherapy alone or with N-acetylcysteine in septic shock. Crit Care Med 34:2719–2728. doi: 10.1097/01.CCM.0000242757.26245.03 PubMedCrossRefGoogle Scholar
  26. 26.
    Eaton S (2006) The biochemical basis of antioxidant therapy in critical illness. Proc Nutr Soc 65:242–249. doi: 10.1079/PNS2005471 PubMedGoogle Scholar
  27. 27.
    Escames G, Acuna-Castroviejo D, Lopez LC, Tan DX, Maldonado MD, Sanchez-Hidalgo M et al (2006) Pharmacological utility of melatonin in the treatment of septic shock: experimental and clinical evidence. J Pharm Pharmacol 58:1153–1165. doi: 10.1211/jpp.58.9.0001 PubMedCrossRefGoogle Scholar
  28. 28.
    Yu YM, Burke JF, Young VR (1993) A kinetic study of L-2H3-methyl-1-13C-methionine in patients with severe burn injury. J Trauma 35:1–7. doi: 10.1097/00005373-199307000-00001 PubMedCrossRefGoogle Scholar
  29. 29.
    Finkelstein JD (1990) Methionine metabolism in mammals. J Nutr Biochem 1:228–237. doi: 10.1016/0955-2863(90)90070-2 PubMedCrossRefGoogle Scholar
  30. 30.
    Arnold J, Campbell IT, Samuels TA, Devlin JC, Green CJ, Hipkin LJ et al (1993) Increased whole body protein breakdown predominates over increased whole body protein synthesis in multiple organ failure. Clin Sci (Lond) 84:655–661Google Scholar
  31. 31.
    Wolfe RR, Jahoor F, Hartl WH (1989) Protein and amino acid metabolism after injury. Diabetes Metab Rev 5:149–164PubMedGoogle Scholar
  32. 32.
    Vina J, Gimenez A, Puertes IR, Gasco E, Vina JR (1992) Impairment of cysteine synthesis from methionine in rats exposed to surgical stress. Br J Nutr 68:421–429. doi: 10.1079/BJN19920099 PubMedCrossRefGoogle Scholar
  33. 33.
    Malmezat T, Breuille D, Pouyet C, Buffiere C, Denis P, Mirand PP et al (2000) Methionine transsulfuration is increased during sepsis in rats. Am J Physiol Endocrinol Metab 279:E1391–E1397PubMedGoogle Scholar
  34. 34.
    Rahman SH, Ibrahim K, Larvin M, Kingsnorth A, McMahon MJ (2004) Association of antioxidant enzyme gene polymorphisms and glutathione status with severe acute pancreatitis. Gastroenterology 126:1312–1322. doi: 10.1053/j.gastro.2004.02.002 PubMedCrossRefGoogle Scholar
  35. 35.
    Bradley EL 3rd (1993) A clinically based classification system for acute pancreatitis. Ann Chir 47:537–541PubMedGoogle Scholar
  36. 36.
    Fortin LJ, Genest J Jr (1995) Measurement of homocyst(e)ine in the prediction of arteriosclerosis. Clin Biochem 28:155–162. doi: 10.1016/0009-9120(94)00073-5 PubMedCrossRefGoogle Scholar
  37. 37.
    Blackburn A, Bibby MC, Lucock MD, Nicolaou A (2004) Temporal evaluation of methionine synthase and related metabolites in the MAC15A mouse adenocarcinoma animal model. Int J Cancer 112:577–584. doi: 10.1002/ijc.20451 PubMedCrossRefGoogle Scholar
  38. 38.
    Klauke R, Schmidt E, Lorentz K (1993) Recommendations for carrying out standard ECCLS procedures (1988) for the catalytic concentrations of creatine kinase, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyltransferase at 37 degrees C. Standardization Committee of the German Society for Clinical Chemistry, Enzyme Working Group of the German Society for Clinical Chemistry. Eur J Clin Chem Clin Biochem 31:901–909PubMedGoogle Scholar
  39. 39.
    Larvin M, McMahon MJ (1989) APACHE-II score for assessment and monitoring of acute pancreatitis. Lancet 2:201–205. doi: 10.1016/S0140-6736(89)90381-4 PubMedCrossRefGoogle Scholar
  40. 40.
    Mishra V, Baines M, Wenstone R, Shenkin A (2005) Markers of oxidative damage, antioxidant status and clinical outcome in critically ill patients. Ann Clin Biochem 42:269–276. doi: 10.1258/0004563054255461 PubMedCrossRefGoogle Scholar
  41. 41.
    Lyons J, Rauh-Pfeiffer A, Ming-Yu Y, Lu XM, Zurakowski D, Curley M et al (2001) Cysteine metabolism and whole blood glutathione synthesis in septic pediatric patients. Crit Care Med 29:870–877. doi: 10.1097/00003246-200104000-00036 PubMedCrossRefGoogle Scholar
  42. 42.
    Hammarqvist F, Luo JL, Cotgreave IA, Andersson K, Wernerman J (1997) Skeletal muscle glutathione is depleted in critically ill patients. Crit Care Med 25:78–84. doi: 10.1097/00003246-199701000-00016 PubMedCrossRefGoogle Scholar
  43. 43.
    Benedetti A, Comporti M, Esterbauer H (1980) Identification of 4-hydroxynonenal as a cytotoxic product originating from the peroxidation of liver microsomal lipids. Biochim Biophys Acta 620:281–296PubMedGoogle Scholar
  44. 44.
    Vander Jagt DL, Hunsaker LA, Vander Jagt TJ, Gomez MS, Gonzales DM, Deck LM et al (1997) Inactivation of glutathione reductase by 4-hydroxynonenal and other endogenous aldehydes. Biochem Pharmacol 53:1133–1140. doi: 10.1016/S0006-2952(97)00090-7 PubMedCrossRefGoogle Scholar
  45. 45.
    Kaplowitz N (1980) Physiological significance of glutathione S-transferases. Am J Physiol 239:G439–G444PubMedGoogle Scholar
  46. 46.
    Mosharov E, Cranford MR, Banerjee R (2000) The quantitatively important relationship between homocysteine metabolism and glutathione synthesis by the transsulfuration pathway and its regulation by redox changes. Biochemistry 39:13005–13011. doi: 10.1021/bi001088w PubMedCrossRefGoogle Scholar
  47. 47.
    Vina JR, Gimenez A, Corbacho A, Puertes IR, Borras E, Garcia C et al (2001) Blood sulfur-amino acid concentration reflects an impairment of liver transsulfuration pathway in patients with acute abdominal inflammatory processes. Br J Nutr 85:173–178PubMedGoogle Scholar
  48. 48.
    Rao AM, Drake MR, Stipanuk MH (1990) Role of the transsulfuration pathway and of gamma-cystathionase activity in the formation of cysteine and sulfate from methionine in rat hepatocytes. J Nutr 120:837–845PubMedGoogle Scholar
  49. 49.
    Liaw KY, Askanazi J, Michelson CB, Kantrowitz LR, Furst P, Kinney JM (1980) Effect of injury and sepsis on high-energy phosphates in muscle and red cells. J Trauma 20:755–759. doi: 10.1097/00005373-198009000-00008 PubMedCrossRefGoogle Scholar
  50. 50.
    Tresadern JC, Threlfall CJ, Wilford K, Irving MH (1988) Muscle adenosine 5′-triphosphate and creatine phosphate concentrations in relation to nutritional status and sepsis in man. Clin Sci (Lond) 75:233–242Google Scholar
  51. 51.
    Gasparetto A, Corbucci GG, Candiani A, Gohil K, Edwards RH (1983) Effect of tissue hypoxia and septic shock on human skeletal muscle mitochondria. Lancet 2:1486. doi: 10.1016/S0140-6736(83)90823-1 PubMedCrossRefGoogle Scholar
  52. 52.
    Walker KW, Gilbert HF (1995) Oxidation of kinetically trapped thiols by protein disulfide isomerase. Biochemistry 34:13642–13650. doi: 10.1021/bi00041a045 PubMedCrossRefGoogle Scholar
  53. 53.
    Keppler D (1999) Export pumps for glutathione S-conjugates. Free Radic Biol Med 27:985–991. doi: 10.1016/S0891-5849(99)00171-9 PubMedCrossRefGoogle Scholar
  54. 54.
    Singer M, Brealey D (1999) Mitochondrial dysfunction in sepsis. Biochem Soc Symp 66:149–166PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Sakhawat H. Rahman
    • 1
    • 2
  • Asha R. Srinivasan
    • 3
  • Anna Nicolaou
    • 3
  1. 1.Academic Unit of SurgeryThe University of Leeds, The General InfirmaryLeedsUK
  2. 2.Royal Free Hospital, Royal Free and University College Medical SchoolLondonUK
  3. 3.School of PharmacyUniversity of BradfordBradfordUK

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