Amino Acids

pp 1–9 | Cite as

Comparison between the effects of selenomethionine and S-adenosylmethionine in preventing cholestasis-induced rat liver damage

  • Vesna Brzački
  • Bojan Mladenović
  • Dragan Dimić
  • Ljiljana Jeremić
  • Dragoljub Živanović
  • Davor Djukić
  • Nikola M. Stojanović
  • Dušan T. SokolovićEmail author
Original Article


We aimed to evaluate whether two methionine-related compounds, S-adenosylmethionine (SAM), and selenomethionine (SM), could lessen liver damage induced by regurgitated bile in a model of rat bile duct ligation (BDL). Hepatoprotective potentials of S-adenosylmethionine and selenomethionine were estimated based on the changes of serum liver damage parameters (aminotransferases, alkaline phosphatase, gamma-glutamyltranspeptidase and lactate dehydrogenase activity, and bilirubin concentration), tissue oxidative [xanthine oxidase (XO) and catalase activity, thiobarbituric acid reactive substances (TBARS) levels] and inflammatory [tumor necrosis factor-alfa (TNF-α) concentration] parameters, and morphological liver tissue alterations that follow cholestasis. The treatment regimens proved themselves able to prevent significant liver damage induced by cholestasis. Both SAM and SM decreased XO activity and TBARS levels and increased catalase activity, while only SM significantly reduced TNF-α concentration. Morphological changes related to bile-induced liver damage were also found to be partially diminished by SAM and SM. In view of the mechanisms of action of the two tested methionine-derived compounds, one might say that SM predominantly acted as an antioxidant, while SAM exerted its activity by potentially modulating different gene expression and protein structures. It is also worth mentioning that this is the first study (to the best of our knowledge) that dealt with the effects of SM on BDL-induced liver injury in rats and of the findings that speak favorably of this powerful antioxidant.


Bile duct ligation S-adenosylmethionine Selenomethionine Oxidative damage 



This work was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia (Project No. III 43012).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The experiments were performed in accordance with The European Council Directive (EU Directive of 2010; 2010/63/EU) and were approved by the local Ethics Committee of the Faculty of Medicine, University of Niš.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. Anstee QM, Day CP (2012) S-adenosylmethionine (SAMe) therapy in liver disease: a review of current evidence and clinical utility. J Hepatol 57:1097–1109CrossRefGoogle Scholar
  2. Aribi M, Meziane W, Habi S, Boulatika Y, Marchandin H, Aymeric J-L (2015) Macrophage bactericidal activities against staphylococcus aureus are enhanced in vivo by selenium supplementation in a dose-dependent manner. PLoS One 10:e0135515CrossRefGoogle Scholar
  3. Bárcena C, Quirós PM, Durand S, Mayoral P, Rodríguez F, Caravia XM, Mariño G, Garabaya C, Fernández-García MT, Kroemer G, Freije JMP, López-Otín C (2018) Methionine restriction extends lifespan in progeroid mice and alters lipid and bile acid metabolism. Cell Rep 24:2392–2403CrossRefGoogle Scholar
  4. Battelli MG, Polito L, Bortolotti M, Bolognesi A (2016) Xanthine oxidoreductase-derived reactive species: physiological and pathological effects. Oxid Med Cell Longev 2016:3527579CrossRefGoogle Scholar
  5. Bjelaković G, Beninati S, Pavlović D, Sokolović D, Stojanović I, Jevtović T, Bjelaković GB, Nikolić J, Basić J (2007) Selenomethionine induces polyamine biosynthesis in regenerating rat liver tissue. Amino Acids 33:525–529CrossRefGoogle Scholar
  6. Boelsterli UA, Rakhit G, Balazs T (1983) Modulation by S-adenosyl-l-methionine of hepatic Na + , K + -ATPase, membrane fluidity, and bile flow in rats with ethinyl estradiol-induced cholestasis. Hepatology 3:12–17CrossRefGoogle Scholar
  7. Brigelius-Flohe R, Sies H (2015) Diversity of selenium functions in health and disease. CRC Press, Boca Roton, FloridaCrossRefGoogle Scholar
  8. Cederbaum AI (2010) Hepatoprotective effects of S-adenosyl-l-methionine against alcohol- and cytochrome P450 2E1-induced liver injury. World J Gastroenterol 16:1366–1376CrossRefGoogle Scholar
  9. Chawla RK, Watson WH, Eastin CE, Lee EY, Schmidt J, McClain CJ (1998) S-adenosylmethionine deficiency and TNF-alpha in lipopolysaccharide-induced hepatic injury. Am J Physiol 275:G125–129Google Scholar
  10. Fang HQ, Liu YB, Li HJ, Peng SY, Wu YL, Xu B, Wang JW, Li JT, Wang XB (2003) Effects of glycine on plasma and liver tissue changes of TNF-alpha, ET-1 and nitric oxide contents in rats with obstructive jaundice. World J Gastroenterol 9:2374–2376CrossRefGoogle Scholar
  11. Galicia-Moreno M, Favari L, Muriel P (2013) Trolox mitigates fibrosis in a bile duct ligation model. Fundam Clin Pharmacol 27:308–318CrossRefGoogle Scholar
  12. Krysiak R, Okopien B (2011) The effect of levothyroxine and selenomethionine on lymphocyte and monocyte cytokine release in women with hashimoto’s thyroiditis. J Clin Endocrinol Metab 96:2206–2215CrossRefGoogle Scholar
  13. Le MD, Enbom E, Traum PK, Medici V, Halsted CH, French SW (2013) Alcoholic liver disease patients treated with S-adenosyl-l-methionine: an in-depth look at liver morphologic data comparing pre and post treatment liver biopsies. Exp Mol Pathol 95:187–191CrossRefGoogle Scholar
  14. Li S, Tan HY, Wang N, Zhang ZJ, Lao L, Wong CW, Feng Y (2015) The role of oxidative stress and antioxidants in liver diseases. Int J Mol Sci 16:26087–26124CrossRefGoogle Scholar
  15. Lieber CS (2002) S-adenosyl-l-methionine: its role in the treatment of liver disorders. Am J Clin Nutr 76:1183S–1187SCrossRefGoogle Scholar
  16. Long Y, Dong X, Yuan Y, Huang J, Song J, Sun Y, Lu Z, Yang L, Yu W (2015) Metabolomics changes in a rat model of obstructive jaundice: mapping to metabolism of amino acids, carbohydrates and lipids as well as oxidative stress. J Clin Biochem Nutr 57:50–59CrossRefGoogle Scholar
  17. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275Google Scholar
  18. Medici V, Virata MC, Peerson JM, Stabler SP, French SW, Gregory JF 3rd, Albanese A, Bowlus CL, Devaraj S, Panacek EA, Richards JR, Halsted CH (2011) S-adenosyl-l-methionine treatment for alcoholic liver disease: a double-blinded, randomized, placebo-controlled trial. Alcohol Clin Exp Res 35:1960–1965CrossRefGoogle Scholar
  19. Michael Brown J, Ball JG, Wright MS, Van Meter S, Valentovic MA (2012) Novel protective mechanisms for S-adenosyl-l-methionine against acetaminophen hepatotoxicity: improvement of key antioxidant enzymatic function. Toxicol Lett 212:320–328CrossRefGoogle Scholar
  20. Mladenović B, Mladenović N, Brzački V, Petrović N, Kamenov A, Golubović M, Ničković V, Stojanović NM, Sokolović DT (2018) Exogenous putrescine affects polyamine and arginine metabolism in rat liver following bile ductus ligation. Can J Physiol Pharmacol 96:1232–1237CrossRefGoogle Scholar
  21. Moffatta BA, Ashihara H (2002) Purine and pyrimidine nucleotide synthesis and metabolism. Arabidopsis Book 1:e0018CrossRefGoogle Scholar
  22. Mun KC, Kwak CS, Kwon KY (1996) The protective effect of allopurinol on cholestatic liver injury induced by bile duct ligation. J Korean Med Sci 11:239–243CrossRefGoogle Scholar
  23. Muriel P, Suarez OR, Gonzalez P, Zuñiga L (1994) Protective effect of S-adenosyl-l-methionine on liver damage induced by biliary obstruction in rats: a histological, ultrastructural and biochemical approach. J Hepatol 21:95–102CrossRefGoogle Scholar
  24. Ničković VP, Novaković T, Lazarević S, Lj Šulović, Živković Z, Živković J, Mladenović B, Stojanović NM, Petrović V, Sokolović DT (2018) Pre- vs. post-treatment with melatonin in CCl4-induced liver damage: oxidative stress inferred from biochemical and pathohistological studies. Life Sci 202:28–34CrossRefGoogle Scholar
  25. Osawa Y, Hoshi M, Yasuda I, Saibara T, Moriwaki H, Kozawa O (2013) Tumor necrosis factor-α promotes cholestasis-induced liver fibrosis in the mouse through tissue inhibitor of metalloproteinase-1 production in hepatic stellate cells. PLoS One 8:e65251CrossRefGoogle Scholar
  26. Schimpl G, Pesendorfer P, Kuesz AM, Ratschek M, Höllwarth ME (2000) The impact of hepatic xanthine oxidase and xanthine dehydrogenase activities on liver function in chronic cholestasis. Pediatr Surg Int 16:297–301CrossRefGoogle Scholar
  27. Serwin AB, Wasowicz W, Chodynicka B (2006) Selenium supplementation, soluble tumor necrosis factor-α receptor type 1, and C-reactive protein during psoriasis therapy with narrowband ultraviolet B. Nutrition 22:860–864CrossRefGoogle Scholar
  28. Smith PJ, Tappel AL, Chow CK (1974) Glutathione peroxidase activity as a function of dietary selenomethionine. Nature 247:392–393CrossRefGoogle Scholar
  29. Sokolović D, Nikolić J, Kocić G, Jevtovic-Stoimenov T, Veljkovic A, Stojanovic M, Stanojkovic Z, Sokolovic DM, Jelic M (2013) The effect of ursodeoxycholic acid on oxidative stress level and DNase activity in rat liver after bile duct ligation. Drug Chem Toxicol 36:141–148CrossRefGoogle Scholar
  30. Song Z, Uriarte S, Sahoo R, Chen T, Barve S, Hill D, McClain C (2005) S-adenosylmethionine (SAMe) modulates interleukin-10 and interleukin-6, but not TNF, production via the adenosine (A2) receptor. Biochim Biophys Acta 1743:205–213CrossRefGoogle Scholar
  31. Tag CG, Sauer-Lehnen S, Tacke F, Tolba RH, Weiskirchen R (2015) Bile duct ligation in mice: induction of inflammatory liver injury and fibrosis by obstructive cholestasis. J Vis Exp 96:52438Google Scholar
  32. Ulrey CL, Liu L, Andrews LG, Tollefsbol TO (2005) The impact of metabolism on DNA methylation. Hum Mol Genet 14:R139–R147CrossRefGoogle Scholar
  33. Xie W, Cao Y, Xu M, Wang J, Zhou C, Yang X, Geng X, Zhang W, Li N, Cheng J (2017) Prognostic significance of elevated cholestatic enzymes for fibrosis and hepatocellular carcinoma in hospital discharged chronic viral hepatitis patients. Sci Rep 7:10289CrossRefGoogle Scholar
  34. Xu F, Wei XD (2017) Assessment of adjuvant ademetionine therapy for the bilirubin metabolism and target organ function of neonatal jaundice. J Hainan Med Univ 23:103–106Google Scholar
  35. ZamychkinaL KS, Kryukova V (1967) Role of the bile-forming function of the liver in methionine metabolism. Bull Exp Biol Med 63:272–274CrossRefGoogle Scholar
  36. Zhong GG, Jiang Y, Li ZB, Zhang BG, Zhang WJ, Yue G (1990) Protective action of selenium and manganese on xanthine and xanthine oxidase induced oxidative damage to cultured heart cells. Chin Med J 103:735–742Google Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2019

Authors and Affiliations

  • Vesna Brzački
    • 1
    • 2
  • Bojan Mladenović
    • 1
    • 2
  • Dragan Dimić
    • 2
    • 3
  • Ljiljana Jeremić
    • 4
    • 5
  • Dragoljub Živanović
    • 5
    • 6
  • Davor Djukić
    • 7
  • Nikola M. Stojanović
    • 7
  • Dušan T. Sokolović
    • 8
    Email author
  1. 1.Clinic for GastroenterologyClinical Center NišNišSerbia
  2. 2.Department of Internal Medicine, Faculty of MedicineUniversity of NišNišSerbia
  3. 3.Clinic for EndocrinologyClinical Center NišNišSerbia
  4. 4.Clinic for General SurgeryClinical Center NišNišSerbia
  5. 5.Department for Surgery, Faculty of MedicineUniversity of NišNišSerbia
  6. 6.Clinic for Pediatric Surgery and OrthopedicsClinical Center NišNišSerbia
  7. 7.Faculty of MedicineUniversity of NišNišSerbia
  8. 8.Department of Biochemistry, Faculty of MedicineUniversity of NišNišSerbia

Personalised recommendations