Hepatoprotective Functions of Sulfur Containing Amino Acids: Possibilities of Hepatocellular Carcinoma Prevention

황함유 아미노산의 간기능 보호 작용: 간세포암 예방의 가능성

  • Ko, Kwang Suk (Department of Nutritional Science and Food Management, College of Health Science, Ewha Womans University)
  • 고광석 (이화여자대학교 건강과학대학 식품영양학과)
  • Received : 2012.08.27
  • Accepted : 2012.10.25
  • Published : 2012.12.31


While it is known that sulfur containing amino acids (SCAA) are very important in regulating hepatocyte growth and preventing liver-diseases, the fundamental molecular mechanisms of how they exert their hepatoprotective functions are not well known. Since it is widely understood that the hepatic concentrations of S-adenosylmethionine (SAMe) in chronic liver disease patients are severely decreased, the pathophysiological importance of SAMe and its downstream antioxidant, glutathione should be discussed in order to see a big picture of relationship between SCAA and liver diseases. Chronic SAMe deficient mice have shown spontaneous hepatocellular carcinoma development due to impaired mitochondria functions with low levels of prohibitin1 protein, and through deficiency in many genes which are known to ameliorate genetic instability, such as APEX1 and DUSP1, the functions of which are recovered by SAMe treatment. In this review, current knowledge of the basic concepts of the mechanisms through which SCAAs protect the liver will be discussed in detail. Also, a possible tumor suppressor in livers, prohibitin1, and its functional relationship with SAMe will be discussed.


sulfur-containing amino acids;S-adenosylmethionine;glutathione;prohibitin1;liver cancer


Supported by : 한국연구재단


  1. Lu SC, Mato JM. S-Adenosylmethionine in cell growth, apoptosis and liver cancer. J. Gastroen. Hepatol. 23(suppl 1): s73-s77 (2008)
  2. Mato JM, Lu SC. Role of S-adenosyl-L-methionine in liver health and injury. Hepatology 45: 1306-1312 (2007)
  3. Mudd SH, Poole JR. Labile methyl balances for normal humans of various dietary regimens. Metabolism 24: 721-735 (1975)
  4. Horowitz JH, Rypins EB, Henderson JM, Heymsfield SB, Moffitt SD, Bain RP, Chawla RK, Bleier JC, Rudman D. Evidence for impairment of transsulfuration pathway in cirrhosis. Gastroenterology 81: 668-675 (1981)
  5. Kinsell LW, Harper HA, Barton HC, Michaels GD, Weiss HA. Rate of disappearance from plasma of intravenously administered methionine in patients with liver damage. Science 106: 589-594 (1947)
  6. Tsukamoto HC, Lu SC. Current concepts in the pathogenesis of alcoholic liver injury. FASEB J. 15: 1335-1349 (2001)
  7. Vendemiale G, Altomare E, Trizio T, Le Grazie C, Di Padova C, Salerno MT, Carrieri V, Albano O. Effects of oral S-adenosyl-Lmethionine on hepatic glutathione in patients with liver disease. Scand. J. Gastroentero. 24: 407-415 (1989)
  8. Lu SC, Alvarez L, Huang ZZ, Chen L, An W, Corrales FJ, Avila MA, Kanel G, Mato JM. Methionine adenosyltransferase 1A knockout mice are predisposed to liver injury and exhibit increased expression of genes involved in proliferation. P. Natl. Acad. Sci. USA 98: 5560-5565 (2001)
  9. Lee TD, Sadda ME, Mendler MH, Bottiglieri T, Kanel G, Mato JM, Lu SC. Abnormal hepatic methionine and GSH metabolism in patients with alcoholic hepatitis. Alcohol Clin. Exp. Res. 28: 173-181 (2004)
  10. Martnez-Chantar ML, Corrales FJ, Martnez-Cruz LA, Garca-Trevijano ER, Huang ZZ, Chen L, Kanel G, Avila MA, Mato MJ, Lu SC. Spontaneous oxidative stress and liver tumors in mice lacking methionine adenosyltransferase 1A. FASEB J. 16: 1292- 1294 (2002)
  11. Santamara E, Avila MA, Latasa MU, Rubio A, Martin-Duce A, Lu SC, Mato JM, Corrales FJ. Functional proteomics of nonalcoholic steatohepatitis: mitochondrial proteins as targets of Sadenosylmethionine. P. Natl. Acad. Sci. USA 100: 30653070 (2003)
  12. Tomasi ML, Iglesias-Ara A, Yang H, Ramani K, Feo F, Pascale MR, Martnez-Chantar ML, Mato JM, Lu SC. S-adenosylmethionine regulates apurinic/apyrimidinic endonuclease 1 stability: Implication in hepatocarcinogenesis. Gastroenterology 136: 1025- 1036 (2009)
  13. Tomasi ML, Ramani K, Lopitz-Otsoa F, Rodrguez MS, Li TW, Ko K, Yang H, Bardag-Gorce F, Iglesias-Ara A, Feo F, Pascale MR, Mato JM, Lu SC. S-adenosylmethionine regulates dual-specificity mitogen-activated protein kinase phosphatase expression in mouse and human hepatocytes. Hepatology 51: 2152-2161 (2010)
  14. Medina J, Moreno-Otero R. Pathophysiological basis for antioxidant therapy in chronic liver disease. Drugs 65: 2445-2461 (2005)
  15. Sun S, Zhaing H, Xue B, Wu Y, Wang J, Yin Z, Luo L. Protective effect of glutathione against lipopolysaccharide-induced inflammation and mortality in rats. Inflamm Res. 55: 504-510 (2006)
  16. Bigatello LM, Broitman SA, Fattori L, Di Paoli M, Pontello M, Bevilacqua G, Nespoli A. Endotoxemia, encephalopathy, and mortality in cirrhotic patients. Am. J. Gastroenterol. 82: 11-15 (1987)
  17. Yang SQ, Lin HZ, Lane MD, Clemens M, Diehl AM. Obesity increases sensitivity to endotoxin liver injury: Implications for the pathogenesis of steatohepatitis. P. Natl. Acad. Sci. USA 94: 2557- 2562 (1997)
  18. Ko KS, Yang H, Noureddin M, Iglesia-Ara A, Xia M, Wagner C, Luka Z, Mato JM, Lu SC. Changes in S-adenosylmethionine and GSH homeostasis during endotoxemia in mice. Lab. Invest. 88: 1121-1129 (2008)
  19. Yang H, Ramani K, Xia M, Ko KS, Li TW, Oh P, Li J, Lu SC. Dysregulation of glutathione synthesis during cholestasis in mice: Molecular mechanisms and therapeutic implications. Hepatology 49: 1982-1991 (2009)
  20. Ko KS, Tomasi ML, Iglesias-Ara A, French BA, French SW, Ramani K, Lozano JJ, Oh P, He L, Stiles BL, Li TW, Yang H, Martnez-Chantar ML, Mato JM, Lu SC. Liver-specific deletion of prohibitin 1 results in spontaneous liver injury, fibrosis, and hepatocellular carcinoma in mice. Hepatology 52: 2096-2108 (2010)
  21. Nijtmans LG, de Jong L, Artal Sanz M, Coates PJ, Berden JA, Back JW, Muijsers AO, van der Spek H, Grivell LA. Prohibitin act as a membrane-bound chaperone for the stabilization of mitochondrial proteins. EMBO J. 19: 2444-2451 (2000)
  22. McClung JK, Danner DB, Stewart DA, Smith JR, Schneider EL, Lumpkin CK, Dell'Orco RT, Nuell MJ. Isolation of a cDNA that hybrid selects antiproliferative mRNA from rat liver. Biochem. Bioph. Res. Co. 164: 1316-1322 (1989)
  23. Nijtmans LG, Sanz MA, Grivell LA, Coates PJ. The mitochondrial PHB complex: Roles in mitochondrial respiratory complex assembly, aging, and degenerative disease. Cell. Mol. Life Sci. 59: 143-155 (2002)
  24. Chen XL, Zhou L, Yang J, Shen SP, Zhao SP, Wang YL. Hepatocellular carcinoma-associated protein markers investigated by MALDI-TOF MS. Mol. Med. Rep. 3: 589-596 (2012)
  25. Fujinaga H, Tsutsumi T, Yotsuyanagi H, Moriya K, Koike K. Hepatocarcinogenesis in Hepatitic C: HCV shrewdly exacerbates oxidative stress by modulating both production and scavenging of reactive oxygen species. Oncology 81(suppl 1): 11-17 (2011)
  26. Wang B, Wang S, Shao C, Wang G, Li Y, Cai L. Proteomic characterization of the late and persistent effects of cadmium at low doses on the rat liver. J. Appl. Toxicol. doi: 10.1002/jat. 1757 [Epub ahead of print] (2011)
  27. Yoo DR, Jang YH, Jeon YK, Kim JY, Jeon W, Choi YJ, Nam MJ. Proteomic identification of anti-cancer proteins in luteolintreated human hepatoma Huh-7 cells. Cancer Lett. 282: 48-54 (2009)
  28. Snchez-Quiles V, Santamara E, Segura V, Sesma L, Prieto J, Corrales FJ. Prohibitin deficiency blocks proliferation and induces apoptosis in human hepatoma cells: molecular mechanisms and functional implications. Proteomics 10: 1609-1620 (2010)
  29. Kakehashi A, Ishii N, Shibata T, Wei M, Okazaki E, Tachibana T, Fukushima S, Wanibuchi H. Mitochondrial prohibitins and septin 9 are implicated in the onset of rat hepatocarcinogenesis. Toxicol. Sci. 119: 61-72 (2011)
  30. Xu Z, Wu J, Zha X. Up-regulation of prohibitin 1 is involved in the proliferation and migration of liver cancer cells. Sci. China Life Sci. 54: 121-127 (2011)
  31. Snchez-Quiles V, Segura V, Bigaud E, He B, O'Malley BW, Santamara E, Prieto J, Corrales FJ. Prohibitin-1 deficiency promotes inflammation and increases sensitivity to liver injury. J. Proteomics. 75: 5783-5792 (2012)
  32. Surh YJ. Cancer Chemoprevention with dietary phytochemicals. Nat. Rev. Cancer 3: 768-780 (2003)
  33. Oz HS, Chen TS, Neuman M. Methionine deficiency and hepatic injury in a dietary steatohepatitis model. Digest. Dis. Sci. 53: 767-776 (2008)
  34. Young SN, Shalchi M. The effect of methionine and S-adenosylmethionine on S-adenosylmethionine level in the rat brain. J. Psychiat. Neurosci. 30: 44-48 (2005)
  35. Martnez-Chantar ML, Vzquez-Chantada M, Ariz U, Martnez N, Varela M, Luka Z, Capdevila A, Rodrguez J, Aransay AM, Matthiesen R, Yang H, Calvisi DF, Esteller M, Fraga M, Lu SC, Wagner C, Mato JM. Loss of the glycine N-methyltransferase gene leads to steatosis and hepatocellular carcinoma in mice. Hepatology 47: 1191-1199 (2008)

Cited by

  1. Single- and Repeated-dose Toxicities of Acanthopanax senticosus Fermentation Products in Rats vol.46, pp.2, 2014,