DOI QR코드

DOI QR Code

Folic acid supplementation reduces oxidative stress and hepatic toxicity in rats treated chronically with ethanol

  • Lee, Soo-Jung (Department of Food and Nutrition, College of Bio-Nano Science, Hannam University) ;
  • Kang, Myung-Hee (Department of Food and Nutrition, College of Bio-Nano Science, Hannam University) ;
  • Min, Hye-Sun (Department of Food and Nutrition, College of Bio-Nano Science, Hannam University)
  • Received : 2011.10.04
  • Accepted : 2011.12.12
  • Published : 2011.12.31

Abstract

Folate deficiency and hyperhomocysteinemia are found in most patients with alcoholic liver disease. Oxidative stress is one of the most important mechanisms contributing to homocysteine (Hcy)-induced tissue injury. However it has not been examined whether exogenous administration of folic acid attenuates oxidative stress and hepatic toxicity. The aim of this study was to investigate the in vivo effect of folic acid supplementation on oxidative stress and hepatic toxicity induced by chronic ethanol consumption. Wistar rats (n = 32) were divided into four groups and fed 0%, 12%, 36% ethanol, or 36% ethanol plus folic acid (10 mg folic acid/L) diets. After 5 weeks, chronic consumption of the 36% ethanol diet significantly increased plasma alanine transaminase (ALT) (P < 0.05) and aspartate transaminase (AST) (P < 0.05), triglycerides (TG) (P < 0.05), Hcy (P < 0.001), and low density lipoprotein conjugated dienes (CD) (P < 0.05) but decreased total radical-trapping antioxidant potential (TRAP) (P < 0.001). These changes were prevented partially by folic acid supplementation. The 12% ethanol diet had no apparent effect on most parameters. Plasma Hcy concentration was well correlated with plasma ALT (r = $0.612^{**}$), AST (r = $0.652^*$), CD (r = $0.495^*$), and TRAP (r = $-0.486^*$). The results indicate that moderately elevated Hcy is associated with increased oxidative stress and liver injury in alcohol-fed rats, and suggests that folic acid supplementation appears to attenuate hepatic toxicity induced by chronic ethanol consumption possibly by decreasing oxidative stress.

Keywords

References

  1. Wu A, Chanarin I, Slavin G, Levi AJ. Folate deficiency in the alcoholic--its relationship to clinical and haematological abnormalities, liver disease and folate stores. Br J Haematol 1975; 29:469-78. https://doi.org/10.1111/j.1365-2141.1975.tb01844.x
  2. Herbert V, Zalusky R, Davidson CS. Correlation of folate deficiency with alcoholism and associated macrocytosis, anemia, and liver disease. Ann Intern Med 1963;58:977-88. https://doi.org/10.7326/0003-4819-58-6-977
  3. Halsted CH. Nutrition and alcoholic liver disease. Semin Liver Dis 2004;24:289-304. https://doi.org/10.1055/s-2004-832941
  4. Tsukamoto H, Lu SC. Current concepts in the pathogenesis of alcoholic liver injury. FASEB J 2001;15:1335-49. https://doi.org/10.1096/fj.00-0650rev
  5. Halsted CH, Villanueva JA, Devlin AM, Niemelä O, Parkkila S, Garrow TA, Wallock LM, Shigenaga MK, Melnyk S, James SJ. Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig. Proc Natl Acad Sci U S A 2002;99:10072-7. https://doi.org/10.1073/pnas.112336399
  6. Ji C, Kaplowitz N. Hyperhomocysteinemia, endoplasmic reticulum stress, and alcoholic liver injury. World J Gastroenterol 2004;10: 1699-708. https://doi.org/10.3748/wjg.v10.i12.1699
  7. Song Z, Zhou Z, Deaciuc I, Chen T, McClain CJ. Inhibition of adiponectin production by homocysteine: a potential mechanism for alcoholic liver disease. Hepatology 2008;47:867-79. https://doi.org/10.1002/hep.22074
  8. Song Z, Zhou Z, Uriarte S, Wang L, Kang YJ, Chen T, Barve S, McClain CJ. S-adenosylhomocysteine sensitizes to TNF-alpha hepatotoxicity in mice and liver cells: a possible etiological factor in alcoholic liver disease. Hepatology 2004;40:989-97. https://doi.org/10.1002/hep.20412
  9. Kruman II, Kumaravel TS, Lohani A, Pedersen WA, Cutler RG, Kruman Y, Haughey N, Lee J, Evans M, Mattson MP. Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer's disease. J Neurosci 2002;22:1752-62.
  10. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, Wilson PW, Wolf PA. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 2002;346:476-83. https://doi.org/10.1056/NEJMoa011613
  11. Mattson MP, Haberman F. Folate and homocysteine metabolism: therapeutic targets in cardiovascular and neurodegenerative disorders. Curr Med Chem 2003;10:1923-9. https://doi.org/10.2174/0929867033456864
  12. Hultberg B, Andersson A, Isaksson A. The cell-damaging effects of low amounts of homocysteine and copper ions in human cell line cultures are caused by oxidative stress. Toxicology 1997;123: 33-40. https://doi.org/10.1016/S0300-483X(97)00105-4
  13. Mattson MP, Kruman II, Duan W. Folic acid and homocysteine in age-related disease. Ageing Res Rev 2002;1:95-111. https://doi.org/10.1016/S0047-6374(01)00365-7
  14. Chern CL, Huang RF, Chen YH, Cheng JT, Liu TZ. Folate deficiency-induced oxidative stress and apoptosis are mediated via homocysteine-dependent overproduction of hydrogen peroxide and enhanced activation of NF-kappaB in human Hep G2 cells. Biomed Pharmacother 2001;55:434-42. https://doi.org/10.1016/S0753-3322(01)00095-6
  15. Starkebaum G, Harlan JM. Endothelial cell injury due to coppercatalyzed hydrogen peroxide generation from homocysteine. J Clin Invest 1986;77:1370-6. https://doi.org/10.1172/JCI112442
  16. Blundell G, Jones BG, Rose FA, Tudball N. Homocysteine mediated endothelial cell toxicity and its amelioration. Atherosclerosis 1996;122:163-72. https://doi.org/10.1016/0021-9150(95)05730-7
  17. Kruman II, Culmsee C, Chan SL, Kruman Y, Guo Z, Penix L, Mattson MP. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci 2000;20:6920-6.
  18. Niemelä O, Parkkila S, Ylä-Herttuala S, Villanueva J, Ruebner B, Halsted CH. Sequential acetaldehyde production, lipid peroxidation, and fibrogenesis in micropig model of alcoholinduced liver disease. Hepatology 1995;22:1208-14.
  19. Wu D, Cederbaum AI. Alcohol, oxidative stress and free radical damage. Alcohol Res Health 2003;27:277-84.
  20. Kessova I, Cederbaum AI. CYP2E1: biochemistry, toxicology, regulation and function in ethanol-induced liver injury. Curr Mol Med 2003;3:509-18. https://doi.org/10.2174/1566524033479609
  21. Albano E, Clot P, Morimoto M, Tomasi A, Ingelman-Sundberg M, French SW. Role of cytochrome P4502E1-dependent formation of hydroxyethyl free radical in the development of liver damage in rats intragastrically fed with ethanol. Hepatology 1996;23:155-63. https://doi.org/10.1002/hep.510230121
  22. Niemelä O, Parkkila S, Pasanen M, Viitala K, Villanueva JA, Halsted CH. Induction of cytochrome P450 enzymes and generation of protein-aldehyde adducts are associated with sex-dependent sensitivity to alcohol-induced liver disease in micropigs. Hepatology 1999;30:1011-7. https://doi.org/10.1002/hep.510300413
  23. Kono H, Rusyn I, Yin M, Gäbele E, Yamashina S, Dikalova A, Kadiiska MB, Connor HD, Mason RP, Segal BH, Bradford BU, Holland SM, Thurman RG. NADPH oxidase-derived free radicals are key oxidants in alcohol-induced liver disease. J Clin Invest 2000;106:867-72. https://doi.org/10.1172/JCI9020
  24. Lieber CS, DeCarli LM. Animal models of chronic ethanol toxicity. Methods Enzymol 1994;233:585-94.
  25. Araki A, Sako Y. Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. J Chromatogr 1987;422:43-52. https://doi.org/10.1016/0378-4347(87)80438-3
  26. Tamura T. Microbiological assay of folate. In: Picciano MF, Stokstad ELR, Gregory JF, editors. Folic Acid Metabolism in Health and Disease. New York: Wiley-Liss; 1990. p.121-37.
  27. Wagner J, Claverie N, Danzin C. A rapid high-performance liquid chromatographic procedure for the simultaneous determination of methionine, ethionine, S-adenosylmethionine, S-adenosylethionine, and the natural polyamines in rat tissues. Anal Biochem 1984;140:108-16. https://doi.org/10.1016/0003-2697(84)90140-4
  28. Rice-Evans C, Miller NJ. Total antioxidant status in plasma and body fluids. Methods Enzymol 1994;234:279-93.
  29. Kleinveld HA, Hak-Lemmers HL, Stalenhoef AF, Demacker PN. Improved measurement of low-density-lipoprotein susceptibility to copper-induced oxidation: application of a short procedure for isolating low-density lipoprotein. Clin Chem 1992;38:2066-72.
  30. Ahotupa M, Marniemi J, Lehtimäki T, Talvinen K, Raitakari OT, Vasankari T, Viikari J, Luoma J, Ylä-Herttuala S. Baseline diene conjugation in LDL lipids as a direct measure of in vivo LDL oxidation. Clin Biochem 1998;31:257-61. https://doi.org/10.1016/S0009-9120(98)00018-6
  31. Esterbauer H, Striegl G, Puhl H, Rotheneder M. Continuous monitoring of in vitro oxidation of human low density lipoprotein. Free Radic Res Commun 1989;6:67-75. https://doi.org/10.3109/10715768909073429
  32. Wieland P, Lauterburg BH. Oxidation of mitochondrial proteins and DNA following administration of ethanol. Biochem Biophys Res Commun 1995;213:815-9. https://doi.org/10.1006/bbrc.1995.2202
  33. Kurose I, Higuchi H, Watanabe N, Miura S, Tomita K, Yonei Y, Takaishi M, Zeki S, Nakamura T, Saito H, Kato S, Ishii H. CD18/ICAM-1-dependent nitric oxide production of Kupffer cells as a cause of mitochondrial dysfunction in hepatoma cells: influence of chronic alcohol feeding. Free Radic Biol Med 1997;22:229-39. https://doi.org/10.1016/S0891-5849(96)00332-2
  34. Rouach H, Fataccioli V, Gentil M, French SW, Morimoto M, Nordmann R. Effect of chronic ethanol feeding on lipid peroxidation and protein oxidation in relation to liver pathology. Hepatology 1997;25:351-5. https://doi.org/10.1002/hep.510250216
  35. Bleich S, Bleich K, Kropp S, Bittermann HJ, Degner D, Sperling W, Rüther E, Kornhuber J. Moderate alcohol consumption in social drinkers raises plasma homocysteine levels: a contradiction to the 'French Paradox'? Alcohol Alcohol 2001;36:189-92. https://doi.org/10.1093/alcalc/36.3.189
  36. Stickel F, Choi SW, Kim YI, Bagley PJ, Seitz HK, Russell RM, Selhub J, Mason JB. Effect of chronic alcohol consumption on total plasma homocysteine level in rats. Alcohol Clin Exp Res 2000;24:259-64. https://doi.org/10.1111/j.1530-0277.2000.tb04606.x
  37. Carmel R, James SJ. Alcohol abuse: an important cause of severe hyperhomocysteinemia. Nutr Rev 2002;60:215-21. https://doi.org/10.1301/00296640260184309
  38. Austin RC, Lentz SR, Werstuck GH. Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease. Cell Death Differ 2004;11 Suppl 1:S56-64. https://doi.org/10.1038/sj.cdd.4401451
  39. Knerr S, Schaefer J, Both S, Mally A, Dekant W, Schrenk D. 2,3,7,8-Tetrachlorodibenzo-p-dioxin induced cytochrome P450s alter the formation of reactive oxygen species in liver cells. Mol Nutr Food Res 2006;50:378-84. https://doi.org/10.1002/mnfr.200500183
  40. Parlesak A, Schäfer C, Paulus SB, Hammes S, Diedrich JP, Bode C. Phagocytosis and production of reactive oxygen species by peripheral blood phagocytes in patients with different stages of alcohol-induced liver disease: effect of acute exposure to low ethanol concentrations. Alcohol Clin Exp Res 2003;27:503-8. https://doi.org/10.1097/01.ALC.0000056688.27111.49
  41. Doshi SN, McDowell IF, Moat SJ, Payne N, Durrant HJ, Lewis MJ, Goodfellow J. Folic acid improves endothelial function in coronary artery disease via mechanisms largely independent of homocysteine lowering. Circulation 2002;105:22-6. https://doi.org/10.1161/hc0102.101388
  42. Blasco C, Caballería J, Deulofeu R, Lligoña A, Parés A, Lluis JM, Gual A, Rodés J. Prevalence and mechanisms of hyperhomocysteinemia in chronic alcoholics. Alcohol Clin Exp Res 2005;29:1044-8. https://doi.org/10.1097/01.ALC.0000169265.36440.EE
  43. Nakano E, Higgins JA, Powers HJ. Folate protects against oxidative modification of human LDL. Br J Nutr 2001;86:637-9. https://doi.org/10.1079/BJN2001478
  44. Verhaar MC, Wever RM, Kastelein JJ, van Dam T, Koomans HA, Rabelink TJ. 5-methyltetrahydrofolate, the active form of folic acid, restores endothelial function in familial hypercholesterolemia. Circulation 1998;97:237-41. https://doi.org/10.1161/01.CIR.97.3.237

Cited by

  1. Epigenetic medicine and fetal alcohol spectrum disorders vol.5, pp.1, 2013, https://doi.org/10.2217/epi.12.80
  2. Effects of vitamin C and E supplementation on oxidative stress and liver toxicity in rats fed a low-fat ethanol diet vol.7, pp.2, 2013, https://doi.org/10.4162/nrp.2013.7.2.109
  3. Role of homocysteine and folic acid on the altered calcium homeostasis of platelets from rats with biliary cirrhosis vol.28, pp.7, 2017, https://doi.org/10.1080/09537104.2016.1265920
  4. Ethanol-Induced Upregulation of 10-Formyltetrahydrofolate Dehydrogenase Helps Relieve Ethanol-Induced Oxidative Stress vol.34, pp.3, 2014, https://doi.org/10.1128/MCB.01427-13
  5. L-Serine Supplementation Attenuates Alcoholic Fatty Liver by Enhancing Homocysteine Metabolism in Mice and Rats vol.145, pp.2, 2015, https://doi.org/10.3945/jn.114.199711
  6. deficiency in aged rats pp.1664-2821, 2019, https://doi.org/10.1024/0300-9831/a000537
  7. Plasma homocysteine, methionine and S-adenosylhomocysteine levels following high-dose methotrexate treatment in pediatric patients with acute lymphoblastic leukemia or Burkitt lymphoma: association wi vol.55, pp.7, 2011, https://doi.org/10.3109/10428194.2013.850684
  8. Protective Effect of Folic Acid on Oxidative DNA Damage: A Randomized, Double-Blind, and Placebo Controlled Clinical Trial vol.94, pp.45, 2011, https://doi.org/10.1097/md.0000000000001872
  9. One crisis, diverse impacts—Tissue-specificity of folate deficiency-induced circulation defects in zebrafish larvae vol.12, pp.11, 2011, https://doi.org/10.1371/journal.pone.0188585
  10. Folic acid supplementation reduces multigenerational sperm miRNA perturbation induced by in utero environmental contaminant exposure vol.5, pp.4, 2019, https://doi.org/10.1093/eep/dvz024
  11. Folic acid and flaxseed oil supplements in Ossimi ewes: effect on body weight changes, progesterone profile, blood chemistry, and litter traits vol.52, pp.1, 2020, https://doi.org/10.1007/s11250-019-02017-7
  12. Human Amnion Epithelial Cells Produce Soluble Factors that Enhance Liver Repair by Reducing Fibrosis While Maintaining Regeneration in a Model of Chronic Liver Injury vol.29, pp.None, 2011, https://doi.org/10.1177/0963689720950221
  13. Folic acid attenuates high-fat diet-induced steatohepatitis via deacetylase SIRT1-dependent restoration of PPARα vol.26, pp.18, 2020, https://doi.org/10.3748/wjg.v26.i18.2203
  14. Hematological and renoprotective effects of folic acid and lentil extract in diclofenac sodium exposed rats vol.83, pp.None, 2011, https://doi.org/10.1590/1519-6984.247360