Effect of Dietary Folate on Hyperhomocysteinemia and Cellular Toxicity Induced Alcohol Administration in Rat Liver

  • Kim, Chung-Hyeon (Department 01 Internal Medicine, Seoul National University Hospital) ;
  • Kim, Ki-Nam (Department of Food and Nutritional Science, Ewha Womans University, Asia Food and Nutrition Research Institute) ;
  • Kim, Yeon-Soo (Department of Food and Nutritional Science, Ewha Womans University, Asia Food and Nutrition Research Institute) ;
  • Chang, Nam-Soo (Department of Food and Nutritional Science, Ewha Womans University, Asia Food and Nutrition Research Institute)
  • Published : 2005.06.30

Abstract

The critical role of folate in the remethylation pathway for methionine synthesis from homocysteine has been well documented. Hyperhomocysteinemia resulting from inadequate folate nutrition has been implicated in increased incidence of macrovascular diseases, colorectal cancer, neural tube defects, etc. Chronic exposure to ethanol impairs folate nutrition and one-carbon metabolism in the liver, which often results in fatty liver due to a defective remetylation process. This study was carried out to investigate the chronic effects of moderate levels of alcohol and dietary folate on plasma homocysteine levels, and on histopathology and biochemical functions of the liver. Rats were raised on experimental diets with three levels of folate (0, 2, 8 mg/kg diet), and 50% ethanol (1.8 ml/kg body weight) was administered intragastically by intubation tubes three times a week for 10 weeks. Plasma homocysteine concentrations were found to be significantly influenced by dietary folate intake and alcohol administration. Among all treatment groups, plasma homocysteine levels were the highest in the animals receiving a combined treatment of folate deficient diet and alcohol administration. Plasma homocysteine concentrations were negatively correlated with folate concentration in the plasma (p<0.01) and liver (p<0.05). Among alcohol treated rats, increase in plasma homocysteine values due to macrovascular and microvascular fatty changes and spotted necrosis were observed more frequently in folate-deficient animals diet than those on folate-adequate and folate supplemented diets in alcohol-treated rats. These results indicate that folate supplementation above the recommended level might be beneficial in the prevention of alcohol-related hyperhomocysteinemia and abnormal histologic changes in the liver.

Keywords

References

  1. Kang, S.S., Wong, P.W.K. & Norusis, M. Homocysteinemia due to folate deficiency. Metabolism. Metabolism. 36, 458-462 (1987)
  2. Wilcken, D.E.L., Dudman, N.P.B., Tyrrell P.A. & Robertson, M.R. Folic acid lowers elevated plasma homocysteine in chronic renal insufficiency: Possible imploications for prevention of vasculardisease. Metabolism. 37, 677-701 (1988) https://doi.org/10.1016/0026-0495(88)90090-X
  3. Lewis, C.A., Pancharuntti, N. & Sauberlich, H.E. Plasma folate adequacy as determined by hoomocysteine level. Ann. N. Y. Acad. Sci. 669, 360-362 (1992) https://doi.org/10.1111/j.1749-6632.1992.tb17123.x
  4. Herbert, V. Recommended dietary intakes (RDI) of folate in humans. Am. J. Clin. Nutr. 45, 661-670 (1987) https://doi.org/10.1093/ajcn/45.4.661
  5. Zimmermann, M.B. & Shane, B. Supplemental folic acid. Am. J. Clin. Nutr. 58, 127-128 (1993) https://doi.org/10.1093/ajcn/58.2.127
  6. Swain, R.A., Clair, L.S. The role of folic acid in deficiency states and prevention of disease. J. Fam. Pract. 44, 138-144 (1997)
  7. Kim, Y.I. et al. Severe folate deficiency causes secondary depletion of choline and phosphocholine in rat liver. J. Nutr. 124, 2197-2203(1994) https://doi.org/10.1093/jn/124.11.2197
  8. Masser, P.A., Taylor, L.M. & Porter, J.M. Importance of elevated plasma homocysteine levels as a risk factor for atherosclerosis. Ann. Thorac. Surg. 58, 1240- 1246 (1994) https://doi.org/10.1016/0003-4975(94)90522-3
  9. McCully, K.S. Homocysteine and vascular disease. Nat. Med. 2, 386-389 (1996) https://doi.org/10.1038/nm0496-386
  10. Berwanger, C.S., Jeremy, J.Y. & Stansby, G. Homocysteinemia and vascular disease. Br. J. Surg. 82, 726-731 (1995). https://doi.org/10.1002/bjs.1800820604
  11. Ubbink, J.B. Vitamin nutrition status and homocysteine: An atherogenic risk factor. Nutr. Rev. 52, 383- 393 (1994) https://doi.org/10.1111/j.1753-4887.1994.tb01369.x
  12. US public health service. Recommendation for the use of folic acid to reduce numbers of cases of spinal bifida and other neutral tube defects. M.M.W.R. 41, 1- 7 (1992)
  13. Marsack, C.R., Alsop, C.L., Kurinczuk, J.J. & Bower, C. Pre-pregnancy counseling for the primary prevention of birth defects: Rubella vaccination and folate intake. Med. J. Australia. 162, 403-406 (1995)
  14. Phull, E., Hirst, S.L. Folic acid in pregnancy. Br. J. General. Pract 45, 688 (1995)
  15. Pietrzik, K. et al. Folate status and pregnancy outcome. Ann. NY. Acad. Sci. 669, 371-373 (1992) https://doi.org/10.1111/j.1749-6632.1992.tb17127.x
  16. Report of the American Institute of Nutrition. Ad Hoc committee on standard for nutritional studies. J. Nutr. 107, 1340-1348 (1977) https://doi.org/10.1093/jn/107.7.1340
  17. McGuffin, R., Goff, P. & Hillman, R.S. The effect of diet and alcohol on the development of folate deficiency in the rat. Br. J. Haemat. 31, 185-192 (1975) https://doi.org/10.1111/j.1365-2141.1975.tb00849.x
  18. Gloria, L. et al. Nutritional deficiencies in chronic alcoholics: Relation to dietary intake and alcohol consumption. Am. J. Gastroenterol. 92, 485-489 (1997)
  19. Halsted, C.H., Robles, E.A. & Mezey, E. Intestinal malabsorption in folate-deficient alcoholics. Gastroenterol. 64, 526-532 (1973)
  20. Halsted, C.H., Robles, E.A. & Mezey, E. Decreased jejunal uptake of labeled folic acid (3H-PGA) in alcoholic patients: Roles of alcohol and nutrition. N. Engl. J. Med. 285, 701-706 (1971) https://doi.org/10.1056/NEJM197109232851301
  21. Wilinson, J.A. & Shane, B. Folate metabolixm in the ethanol fed rat. J. Nutr. 112, 604-609 (1982) https://doi.org/10.1093/jn/112.4.604
  22. Weir, D.G., McGing, P.G. & Scott, J.M. Folate metabolism, the enterohepatic circulation and alcohol. Biochem. Pharm. 34, 1-7 (1985) https://doi.org/10.1016/0006-2952(85)90092-9
  23. McMartin, K.E. & Collins, T.D. Role of ethanol metabolism in the alcohol-induced increase in urinary folate excretion in rats. Biochem. Pharm. 33, 2549- 2555 (1983)
  24. McMartin, K.E. & Collins, T.D. Bairnsfather, L. Cumulative excess urinary excretion of folate in rats after repeated ethanol treatment. J. Nutr. 116, 1316- 1325 (1986) https://doi.org/10.1093/jn/116.7.1316
  25. Shaw, S., Jayatilleke, E., Herbert, V. & Colman, N. Cleavageof folates during ethanol metabolism. Biochem. J. 257, 277-280 (1989) https://doi.org/10.1042/bj2570277
  26. Health and social welfare review. Korean Institute for health and social affairs (1996)
  27. Naughton, C.A., Chandler, C.J., Duplantier, R.B. & Halsted, C.H. Folate absorption in alcoholic pigs: In vitro hydrolysis and transport at the intestinal brush border membrane. Am. J. Clin. Nutr. 50, 1436-1441 (1989) https://doi.org/10.1093/ajcn/50.6.1436
  28. Tamura, T., Romero, J.J., Watson, J.E., Gong, E.J. & Halsted, C.H. Hepatic folate metabolism in the chronic alcoholic monkey. J. Lab. Clin. Med. 97, 654 (1981)
  29. Mezey, E. Alcoholic liver disease: Roles of alcohol and metabolism. Am. J. Clin. Nutr. 33, 2709-2718 (1980) https://doi.org/10.1093/ajcn/33.12.2709
  30. Chang, N.S. & Kim, K.N. Effect of alcohol administration on folate metabolism in rats Korean J. Nutr. 31, (1998)
  31. Verhoef, P. et al. Homocysteine metabolism and risk of myocardial infarction. Relation with vitamins B6, B12, and folate. Am. J. Epidemiol. 143, 845-859 (1996)
  32. Lin, J.Y., Kang, S.S., Zhou, J. & Wong, P,W. Homocysteinemia in rats induced by folic acid deficiency. Life Sci. 44, 319-325 (1993) https://doi.org/10.1016/0024-3205(89)90225-7
  33. Miller, J.M., Nadeau, M.R., Smith, D. & Selhub, J. Vitamin B-6 deficiency vs folate deficiency: Comparison of responses to methionine loading in rats. Am. J. Clin. Nutr. 59, 1033-1039 (1993)
  34. Pancharuniti, N. et al. Plasma homocysteine, folate and vitamin B-12 concentrations and risk for early-onset coronary artery disease. Am. J. Clin. Nutr. 59, 940- 948 (1994) https://doi.org/10.1093/ajcn/59.4.940
  35. Selhub. J., Jacques, P.F., Wilson, P.W.F., Rush, D. & Rosenberg, I.H. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. J.A.M.A. 270, 2693-2698 (1993) https://doi.org/10.1001/jama.270.22.2693
  36. Hultberg, B., Gerlund, M., Andersson, A. & Frank, A. Elevated plasma homocysteine in alcoholics. Alcohol. Clin. Exp. Res. 17, 687-689 (1993) https://doi.org/10.1111/j.1530-0277.1993.tb00820.x
  37. Cravo, M.L. et al. Hyperhomocysteinemia in chronic alcoholism: Correlation with folate, vitamin B-12, and vitamin B-6 status. Am. J. Clin. Nutr. 63, 220-224 (1996) https://doi.org/10.1093/ajcn/63.2.220
  38. Ueland, P.M. & Refsum, H. Plasma homocysteine, a risk factor for vascular disease: Plasma homocyseine, a risk factor for vascular disease: Plasma levels in health, disease, and drug therapy. J. Lab. Clin. Med. 473-501 (1989)
  39. Selhub, J., Rosenberg, I.H. Folic Acid Ziegler, E.E. & Filer, L.J. Present knowledge in Nutrition pp. 206- 219, ILSI Press, New York (1996)
  40. Westermann, J., Schwinzer, R., Jecker, P. & Pabst, R. Lyphocyte subsets in the blood. Scand. J. Immunol. 31, 327-334 (1990) https://doi.org/10.1111/j.1365-3083.1990.tb02775.x
  41. Halsted, C.H. Ethanol feeding of micropigs alters methionine metabolism and increases hepatocellualr apoptosis and proliferation. Hepatol. 23, 497-505 (1996) https://doi.org/10.1002/hep.510230314