The restorative effect of ascorbic acid on liver injury inducedby asymmetric dimethylarginine

The restorative effect of ascorbic acid on liver injury inducedby asymmetric dimethylarginine

We aimed to determine whether increased levels of asymmetric dimethylarginine (ADMA) directly cause hepatic deterioration and whether it is decreased by ascorbic acid (AA) as an antioxidant. The study included three groups: Control (n = 10), ADMA (n = 10), and ADMA + AA (n = 10). ADMA was administered at 2 mg kg-1 day-1 and AA was given at 50 mg kg-1 day-1 for 10 days. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase, and alkaline phosphatase activities were analyzed. Histomorphological evaluation of the liver was performed based on the Ishak scoring system. When compared with the control, ALT and ALP levels of the ADMA group were significantly higher (P = 0.006 and P = 0.041, respectively). When compared with the control, interface hepatitis, confluent necrosis, focal necrosis, histological activity index, severity of hepatitis, and portal inflammation were significantly higher in the group administered ADMA. The mentioned biochemical/histopathological parameters were lower in the ADMA + AA group when compared with the ADMA group even if no significant difference was encountered (P > 0.05). The results indicate that ADMA is a factor in the formation of liver injury. Insufficient recovery in biochemical/histopathological parameters when AA was given make us consider that different factors other than prooxidant factors are effective in the formation of liver injury.

___

  • Alaçam H, Avcı B, Şalış O, Dilek A, Kozan A, Mertoğlu C, Şahin M, Okuyucu A (2013). Does ADMA affect the oxidant/antioxidant balance in rats? Turk J Med Sci 43: 405–410.
  • Alacam H, Dikmen ZG, Yaman H, Cakir E, Deren O, Akgul EO, Aydin I, Kurt YG, Keskin U, Akalin S et al. (2011). The role of asymmetric dimethyl arginine and oxidant/antioxidant system in preeclampsia. Fetal Pediatr Pathol 30: 387–393.
  • Anderstam B, Katzarski K, Bergstrom J (1997). Serum levels of NG, NG-dimethyl-L-arginine, a potential endogenous nitric oxide inhibitor in dialysis patients. J Am Soc Nephrol 8: 1437–1442.
  • Avci B, Alacam H, Dilek A, Kozan A (2015). Effects of asymmetric dimethylarginine on inflammatory cytokines (TNF-alpha, IL-6 and IL-10) in rats. Toxicol Ind Health 31: 268–273.
  • Bal F, Bekpinar S, Unlucerci Y, Kusku-Kiraz Z, Onder S, Uysal M, Gurdol F (2014). Antidiabetic drug metformin is effective on the metabolism of asymmetric dimethylarginine in experimental liver injury. Diabetes Res Clin Pract 106: 295– 302.
  • Beltowski J, Kedra A (2006). Asymmetric dimethylarginine (ADMA) as a target for pharmacotherapy. Pharmacol Rep 58: 159–178.
  • Bode-Boger SM, Scalera F, Ignarro LJ (2007). The L-arginine paradox: importance of the L-arginine/asymmetrical dimethylarginine ratio. Pharmacol Ther 114: 295–306.
  • Cerwinka WH, Cooper D, Krieglstein CF, Feelisch M, Granger DN (2002). Nitric oxide modulates endotoxin-induced platelet-endothelial cell adhesion in intestinal venules. Am J Physiol Heart Circ Physiol 282: H1111–1117.
  • Closs EI, Graf P, Habermeier A, Cunningham JM, Forstermann U (1997). Human cationic amino acid transporters hCAT-1, hCAT-2A, and hCAT-2B: three related carriers with distinct transport properties. Biochemistry 36: 6462–6468.
  • Donpunha W, Kukongviriyapan U, Sompamit K, Pakdeechote P, Kukongviriyapan V, Pannangpetch P (2011). Protective effect of ascorbic acid on cadmium-induced hypertension and vascular dysfunction in mice. Biometals 24: 105–115.
  • Fan C, Zwacka RM, Engelhardt JF (1999). Therapeutic approaches for ischemia/reperfusion injury in the liver. J Mol Med (Berl) 77: 577–592.
  • Ferrigno A, Di Pasqua LG, Berardo C, Richelmi P, Vairetti M (2015). Liver plays a central role in asymmetric dimethylarginine-mediated organ injury. World J Gastroenterol 21: 5131–5137.
  • Ferrigno A, Rizzo V, Bianchi A, Di Pasqua LG, Berardo C, Richelmi P, Vairetti M (2014). Changes in ADMA/DDAH pathway after hepatic ischemia/reperfusion injury in rats: the role of bile. Biomed Res Int 2014: 627434.
  • Forstermann U, Schmidt HH, Pollock JS, Sheng H, Mitchell JA, Warner TD, Nakane M, Murad F (1991). Isoforms of nitric oxide synthase. Characterization and purification from different cell types. Biochem Pharmacol 42: 1849–1857.
  • Garcia-Martinez R, Andreola F, Mehta G, Poulton K, Oria M, Jover M, Soeda J, Macnaughtan J, De Chiara F, Habtesion A et al. (2015). Immunomodulatory and antioxidant function of albumin stabilises the endothelium and improves survival in a rodent model of chronic liver failure. J Hepatol 62: 799–806.
  • Harbrecht BG, Doyle HR, Clancy KD, Townsend RN, Billiar TR, Peitzman AB (2001). The impact of liver dysfunction on outcome in patients with multiple injuries. Am Surg 67: 122– 126.
  • Hattori Y, Kasai K, Gross SS (1999). Cationic amino acid transporter gene expression in cultured vascular smooth muscle cells and in rats. Am J Physiol 276: H2020–2028.
  • Hierholzer C, Harbrecht B, Menezes JM, Kane J, MacMicking J, Nathan CF, Peitzman AB, Billiar TR, Tweardy DJ (1998). Essential role of induced nitric oxide in the initiation of the inflammatory response after hemorrhagic shock. J Exp Med 187: 917–928.
  • Hu T, Chouinard M, Cox AL, Sipes P, Marcelo M, Ficorilli J, Li S, Gao H, Ryan TP, Michael MD et al. (2006). Farnesoid X receptor agonist reduces serum asymmetric dimethylarginine levels through hepatic dimethylarginine dimethylaminohydrolase-1 gene regulation. J Biol Chem 281: 39831–39838.
  • Ishak K, Baptista A, Bianchi L, Callea F, De Groote J, Gudat F, Denk H, Desmet V, Korb G, MacSween RN et al. (1995). Histological grading and staging of chronic hepatitis. J Hepatol 22: 696–699.
  • Iwakiri Y, Grisham M, Shah V (2008). Vascular biology and pathobiology of the liver: Report of a single-topic symposium. Hepatology 47: 1754–1763.
  • Jacobi J, Sydow K, von Degenfeld G, Zhang Y, Dayoub H, Wang B, Patterson AJ, Kimoto M, Blau HM, Cooke JP (2005). Overexpression of dimethylarginine dimethylaminohydrolase reduces tissue asymmetric dimethylarginine levels and enhances angiogenesis. Circulation 111: 1431–1438.
  • Jeremy JY, Rowe D, Emsley AM, Newby AC (1999). Nitric oxide and the proliferation of vascular smooth muscle cells. Cardiovasc Res 43: 580–594.
  • Kelm M (1999). Nitric oxide metabolism and breakdown. Biochim Biophys Acta 1411: 273–289.
  • Kimoto M, Tsuji H, Ogawa T, Sasaoka K (1993). Detection of NG,NG-dimethylarginine dimethylaminohydrolase in the nitric oxide-generating systems of rats using monoclonal antibody. Arch Biochem Biophys 300: 657–662.
  • Kimoto M, Whitley GS, Tsuji H, Ogawa T (1995). Detection of NG,NG-dimethylarginine dimethylaminohydrolase in human tissues using a monoclonal antibody. J Biochem 117: 237–238.
  • Laleman W, Omasta A, Van de Casteele M, Zeegers M, Vander Elst I, Van Landeghem L, Severi T, van Pelt J, Roskams T, Fevery J et al. (2005). A role for asymmetric dimethylarginine in the pathophysiology of portal hypertension in rats with biliary cirrhosis. Hepatology 42: 1382–1390.
  • Lee DY, Teyssier C, Strahl BD, Stallcup MR (2005). Role of protein methylation in regulation of transcription. Endocr Rev 26: 147–170.
  • Leiper J, Murray-Rust J, McDonald N, Vallance P (2002). S-nitrosylation of dimethylarginine dimethylaminohydrolase regulates enzyme activity: further interactions between nitric oxide synthase and dimethylarginine dimethylaminohydrolase. P Natl Acad Sci USA 99: 13527–13532.
  • Leiper J, Vallance P (1999). Biological significance of endogenous methylarginines that inhibit nitric oxide synthases. Cardiovasc Res 43: 542–548.
  • Lluch P, Torondel B, Medina P, Segarra G, Del Olmo JA, Serra MA, Rodrigo JM (2004). Plasma concentrations of nitric oxide and asymmetric dimethylarginine in human alcoholic cirrhosis. J Hepatol 41: 55–59.
  • Lopez A, Lorente JA, Steingrub J, Bakker J, McLuckie A, Willatts S, Brockway M, Anzueto A, Holzapfel L, Breen D et al. (2004). Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock. Crit Care Med 32: 21–30.
  • Milewski K, Hilgier W, Albrecht J, Zielinska M (2015). The dimethylarginine (ADMA)/nitric oxide pathway in the brain and periphery of rats with thioacetamide-induced acute liver failure: modulation by histidine. Neurochem Int 88: 26–31.
  • Mookerjee RP, Dalton RN, Davies NA, Hodges SJ, Turner C, Williams R, Jalan R (2007a). Inflammation is an important determinant of levels of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) in acute liver failure. Liver Transpl 13: 400–405.
  • Mookerjee RP, Malaki M, Davies NA, Hodges SJ, Dalton RN, Turner C, Sen S, Williams R, Leiper J, Vallance P et al. (2007b). Increasing dimethylarginine levels are associated with adverse clinical outcome in severe alcoholic hepatitis. Hepatology 45: 62–71.
  • Mookerjee RP, Mehta G, Balasubramaniyan V, Mohamed Fel Z, Davies N, Sharma V, Iwakiri Y, Jalan R (2015). Hepatic dimethylarginine-dimethylaminohydrolase1 is reduced in cirrhosis and is a target for therapy in portal hypertension. J Hepatol 62: 325–331.
  • Mookerjee RP, Wiesenthal A, Icking A, Hodges SJ, Davies NA, Schilling K, Sen S, Williams R, Novelli M, Muller-Esterl W et al. (2007c). Increased gene and protein expression of the novel eNOS regulatory protein NOSTRIN and a variant in alcoholic hepatitis. Gastroenterology 132: 2533–2541.
  • Nagda G, Bhatt DK (2011). Alleviation of lindane induced toxicity in testis of Swiss mice (Mus musculus) by combined treatment with vitamin C, vitamin E and alpha-lipoic acid. Indian J Exp Biol 49: 191–199.
  • Nakagami H, Osako MK, Takami Y, Hanayama R, Koriyama H, Mori M, Hayashi H, Shimizu H, Morishita R (2009). Vascular protective effects of ezetimibe in ApoE-deficient mice. Atherosclerosis 203: 51–58.
  • Nakamura T, Sato E, Fujiwara N, Kawagoe Y, Ueda Y, Suzuki T, Ueda S, Adachi H, Okuda S, Yamagishi S (2009). Ezetimibe decreases serum levels of asymmetric dimethylarginine (ADMA) and ameliorates renal injury in non-diabetic chronic kidney disease patients in a cholesterol-independent manner. Pharmacol Res 60: 525–528.
  • Nijveldt RJ, Teerlink T, Siroen MP, van Lambalgen AA, Rauwerda JA, van Leeuwen PA (2003a). The liver is an important organ in the metabolism of asymmetrical dimethylarginine (ADMA). Clin Nutr 22: 17–22.
  • Nijveldt RJ, Teerlink T, Van Der Hoven B, Siroen MP, Kuik DJ, Rauwerda JA, van Leeuwen PA (2003b). Asymmetrical dimethylarginine (ADMA) in critically ill patients: high plasma ADMA concentration is an independent risk factor of ICU mortality. Clin Nutr 22: 23–30.
  • Okuyucu A, Salis O, Alici O, Ilkaya F, Altuntas A, Guvenli A, Zengin H, Terzi Y, Dilek A, Alacam H (2015) The protective effect of ascorbic acid on exogenous asymmetric dimethylarginine induced intimal thickness and cholesterol increase in rats. Acta Medica Mediterranea 31: 835–840.
  • Paik WK, Kim S (1968). Protein methylase I. Purification and properties of the enzyme. J Biol Chem 243: 2108–2114.
  • Pilz S, Putz-Bankuti C, Meinitzer A, Marz W, Kienreich K, Stojakovic T, Pieber TR, Stauber RE (2015). Association of homoarginine and methylarginines with liver dysfunction and mortality in chronic liver disease. Amino Acids 47: 1817–1826.
  • Rodionov RN, Murry DJ, Vaulman SF, Stevens JW, Lentz SR (2010). Human alanine-glyoxylate aminotransferase 2 lowers asymmetric dimethylarginine and protects from inhibition of nitric oxide production. J Biol Chem 285: 5385–5391.
  • Sanyal AJ, Bosch J, Blei A, Arroyo V (2008). Portal hypertension and its complications. Gastroenterology 134: 1715–1728.
  • Schmidt RJ, Domico J, Samsell LS, Yokota S, Tracy TS, Sorkin MI, Engels K, Baylis C (1999). Indices of activity of the nitric oxide system in hemodialysis patients. Am J Kidney Dis 34: 228–234.
  • Shah V, Toruner M, Haddad F, Cadelina G, Papapetropoulos A, Choo K, Sessa WC, Groszmann RJ (1999). Impaired endothelial nitric oxide synthase activity associated with enhanced caveolin binding in experimental cirrhosis in the rat. Gastroenterology 117: 1222–1228.
  • Sheen JM, Chen YC, Tain YL, Huang LT (2014). Increased circulatory asymmetric dimethylarginine and multiple organ failure: bile duct ligation in rat as a model. Int J Mol Sci 15: 3989–4006.
  • Siroen MP, Warle MC, Teerlink T, Nijveldt RJ, Kuipers EJ, Metselaar HJ, Tilanus HW, Kuik DJ, van der Sijp JR, Meijer S et al. (2004). The transplanted liver graft is capable of clearing asymmetric dimethylarginine. Liver Transpl 10: 1524–1530.
  • Sydow K, Munzel T (2003). ADMA and oxidative stress. Atheroscler Suppl 4: 41–51.
  • Tran CT, Leiper JM, Vallance P (2003). The DDAH/ADMA/NOS pathway. Atheroscler Suppl 4: 33–40.
  • Trocha M, Merwid-Lad A, Szuba A, Sozanski T, Magdalan J, Szelag A, Kopacz M, Kuzniar A, Nowak D (2012). Effect of quercetin-5’-sulfonic acid sodium salt on SOD activity and ADMA/ DDAH pathway in extracorporeal liver perfusion in rats. Adv Clin Exp Med 21: 423–431.
  • Tsutsui M, Shimokawa H, Otsuji Y, Ueta Y, Sasaguri Y, Yanagihara N. (2009). Nitric oxide synthases and cardiovascular diseases: insights from genetically modified mice. Circ J 73: 986–993.
  • Tsutsui M, Shimokawa H, Otsuji Y, Yanagihara N (2010). Pathophysiological relevance of NO signaling in the cardiovascular system: novel insight from mice lacking all NO synthases. Pharmacol Ther 128: 499–508.
  • Ueda S, Kato S, Matsuoka H, Kimoto M, Okuda S, Morimatsu M, Imaizumi T (2003). Regulation of cytokine-induced nitric oxide synthesis by asymmetric dimethylarginine: role of dimethylarginine dimethylaminohydrolase. Circ Res 92: 226– 233.
  • Vallance P, Leiper J (2004). Cardiovascular biology of the asymmetric dimethylarginine: dimethylarginine dimethylaminohydrolase pathway. Arterioscler Thromb Vasc Biol 24: 1023–1030.
  • Wilcken DE, Sim AS, Wang J, Wang XL (2007). Asymmetric dimethylarginine (ADMA) in vascular, renal and hepatic disease and the regulatory role of L-arginine on its metabolism. Mol Genet Metab 91: 309–317.
  • Yilmaz MI, Saglam M, Sonmez A, Caglar K, Cakir E, Kurt Y, Eyileten T, Tasar M, Acikel C, Oguz Y et al. (2007). Improving proteinuria, endothelial functions and asymmetric dimethylarginine levels in chronic kidney disease: ramipril versus valsartan. Blood Purif 25: 327–335.
  • Zakrzewicz D, Eickelberg O (2009). From arginine methylation to ADMA: a novel mechanism with therapeutic potential in chronic lung diseases. BMC Pulm Med 9: 5