Skip to main content
SpringerLink
Log in

Palm tocotrienol-rich fraction inhibits methionine-induced cystathionine β-synthase in rat liver

  • Original Paper
  • Published:
Journal of Physiology and Biochemistry Aims and scope Submit manuscript

Abstract

Oxidative stress plays an important role in cardiovascular diseases. The study investigated the effects of dietary palm tocotrienol-rich fraction on homocysteine metabolism in rats fed a high-methionine diet. Forty-two male Wistar rats were randomly assigned to six groups. Five groups were fed with high-methionine diet (1 %) for 10 weeks. Groups 2 to 5 were also given dietary folate (8 mg/kg) and three doses of palm tocotrienol-rich fraction (30, 60 and 150 mg/kg) from week 6 to week 10. The last group was only given basal rat chow. High-methionine diet increased plasma homocysteine after 10 weeks, which was prevented by the supplementations of folate and high-dose palm tocotrienol-rich fraction. Hepatic S-adenosyl methionine (SAM) content was unaffected in all groups but S-adenosyl homocysteine (SAH) content was reduced in the folate group. Folate supplementation increased the SAM/SAH ratio, while in the palm tocotrienol-rich fraction groups, the ratio was lower compared with the folate. Augmented activity of hepatic cystathionine β-synthase and lipid peroxidation content by high-methionine diet was inhibited by palm tocotrienol-rich fraction supplementations (moderate and high doses), but not by folate. The supplemented groups had lower hepatic lipid peroxidation than the high-methionine diet. In conclusion, palm tocotrienol-rich fraction reduced high-methionine-induced hyperhomocysteinaemia possibly by reducing hepatic oxidative stress in high-methionine-fed rats. It may also exert a direct inhibitory effect on hepatic cystathionine β-synthase.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Amaral CL, Bueno Rde B, Burim RV, Queiroz RH, Bianchi Mde L, Antunes LM (2011) The effects of dietary supplementation of methionine on genomic stability and p53 gene promoter methylation in rats. Mutat Res 722:78–83

    Article  CAS  PubMed  Google Scholar 

  2. Asmadi AY, Adam A, Wan Ngah WZ, Norazlina M, Kamisah Y, Nur-Azlina MF, Qodriyah MS, Ahmad NS, Gapor MT, Marzuki A (2005) Tocotrienols and α-tocopherol reduced acute and chronic lung lipid peroxidation induced by paraquat in rats. Pakistan J Nutr 4:97–100

    Article  Google Scholar 

  3. Cao L, Lou X, Zou Z, Mou N, Wu W, Huang X, Tan H (2013) Folic acid attenuates hyperhomocysteinemia-induced glomerular damage in rats. Microvasc Res 89:146–152

    Article  CAS  PubMed  Google Scholar 

  4. de Rezende MM, D’Almeida V (2014) Central and systemic responses to methionine-induced hyperhomocysteinemia in mice. PLoS One 9, e105704

    Article  PubMed Central  PubMed  Google Scholar 

  5. Dicker-Brown A, Fonseca VA, Fink LM, Kern PA (2001) The effect of glucose and insulin on the activity of methylene tetrahydrofolate reductase and cystathionine-beta-synthase: studies in hepatocytes. Atherosclerosis 158:297–301

    Article  CAS  PubMed  Google Scholar 

  6. Duthie SJ, Grant G, Pirie LP, Watson AJ, Margison GP (2010) Folate deficiency alters hepatic and colon MGMT and OGG-1 DNA repair protein expression in rats but has no effect on genome-wide DNA methylation. Cancer Prev Res 3:92–100

    Article  CAS  Google Scholar 

  7. Fowler B, Kraus J, Packman S, Rosenberg LE (1978) Homocystinuria. Evidence for three distinct classes of cystathionine beta-synthase mutants in cultured fibroblasts. J Clin Invest 61:645–653

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Fukada S, Shimada Y, Morita T, Sugiyama K (2006) Suppression of methionine-induced hyperhomocysteinemia by glycine and serine in rats. Biosci Biotechnol Biochem 70:2403–2409

    Article  CAS  PubMed  Google Scholar 

  9. Gapor MT, Leong WL, Ong ASH, Kawada T, Watanabe H, Tsuchiya N (1993) Production of high concentration tocopherols and tocotrienols from palm oil byproducts. US Patent No. 5,190,618. 2 March 1993; Malaysian Patent No. MY-110779-A

  10. Huang RFS, Hsu YC, Lin HL, Yang FL (2001) Folate depletion and elevated plasma homocysteine promote oxidative stress in rat livers. J Nutr 131:33–38

    CAS  PubMed  Google Scholar 

  11. Hwang SY, Siow YL, Au-Yeung KK, House J, Karmin O (2011) Folic acid supplementation inhibits NADPH oxidase-mediated superoxide anion production in the kidney. Am J Physiol Renal Physiol 300:F189–F198

    Article  CAS  PubMed  Google Scholar 

  12. Janosik M, Kery V, Gaustadnes M, Maclean KN, Kraus JP (2001) Regulation of human cystathionine β-synthase by S-adenosyl-l-methionine: evidence for two catalytically active conformations involving an autoinhibitory domain in the C-terminal region. Biochemistry 40:10625–10633

    Article  CAS  PubMed  Google Scholar 

  13. Jeeja MC, Jayakrishnan T, Narayanan PV, Kumar MS, Thejus T, Anilakumari VP (2014) Folic acid supplementation on homocysteine levels in children taking antiepileptic drugs: a randomized controlled trial. J Pharmacol Pharmacother 5:93–99

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Joseph J, Loscalzo J (2013) Methoxistasis: integrating the roles of homocysteine and folic acid in cardiovascular pathobiology. Nutrients 5:3235–3256

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Kamisah Y, Norhayati MY, Zakri B, Asmadi AY (2009) The effects of palmvitee on δ-aminolevulinic acid-induced hyperbilirubinaemia in suckling rats. Arch Med Sci 5:329–334

    CAS  Google Scholar 

  16. Kamisah Y, Lim JJ, Lim CL, Asmadi AY (2014) Inhibitory effects of palm tocotrienol-rich fraction on bilirubin-metabolizing enzymes in hyperbilirubinemic adult rats. Plos One 9, e89248

    Article  PubMed Central  PubMed  Google Scholar 

  17. Kirac D, Negis Y, Ozer NK (2013) Vitamin E attenuates homocysteine and cholesterol induced damage in rat aorta. Cardiovasc Pathol 22465–472

  18. Kolling J, Scherer EB, da Cunha AA, da Cunha MJ, Wyse AT (2010) Homocysteine induces oxidative-nitrative stress in heart of rats: prevention by folic acid. Cardiovasc Toxicol 11:67–73

    Article  Google Scholar 

  19. Ledwozyw A, Michalak J, Stepien A, Kadziolka A (1986) The relationship between plasma triglycerides, cholesterol, total lipids and lipid peroxidation products during human atherosclerosis. Clin Chem Acta 155:275–284

    Article  CAS  Google Scholar 

  20. Lee SJ, Kim SY, Min H (2013) Effects of vitamin C and E supplementation on oxidative stress and liver toxicity in rats fed a low-fat ethanol diet. Nutr Res Pract 7:109–114

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Liu YQ, Liu Y, Morita T, Mori M, Sugiyama K (2012) Factors contributing to the resistivity of a higher casein diet against choline deficiency-induced hyperhomocysteinemia in rats. J Nutr Sci Vitaminol 58:78–87

    Article  CAS  PubMed  Google Scholar 

  22. Liu YQ, Jia Z, Han F, Inakuma T, Miyashita T, Sugiyama K, Sun LC, Xiang XS, Huang ZW (2014) Suppression effects of betaine-enriched spinach on hyperhomocysteinemia induced by guanidinoacetic acid and choline deficiency in rats. Sci World J 2014:904501

    Google Scholar 

  23. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  24. Maron BA, Loscalzo J (2009) The treatment of hyperhomocysteinemia. Annu Rev Med 60:39–54

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Mato JM, Corrales FJ, Lu SC, Avila MA (2002) S-Adenosylmethionine: a control switch that regulates liver function. FASEB J 16:5–26

    Article  Google Scholar 

  26. McAnulty SR, McAnulty LS, Nieman DC, Morrow JD, Shooter LA, Holmes S, Heward C, Henson DA (2005) Effect of alpha-tocopherol supplementation on plasma homocysteine and oxidative stress in highly trained athletes before and after exhaustive exercise. J Nutr Biochem 16:530–537

    Article  CAS  PubMed  Google Scholar 

  27. Miller JW, Nadeau MR, Smith J, Smith D, Selhub J (1994) Folate-deficiency-induced homocysteinaemia in rats: disruption of S-adenosylmethionine’s co-ordinate regulation of homocysteine metabolism. Biochem J 298:415–419

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Min H (2009) Effects of dietary supplementation of high-dose folic acid on biomarkers of methylating reaction in vitamin B12-deficient rats. Nutr Res Pract 3:122–127

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Mosharov E, Cranford MR, Banerjee R (2000) The quantitatively important relationship between homocysteine metabolism and glutathione synthesis by the transsulfuration pathway and its regulation by redox changes. Biochemistry 39:13005–13011

    Article  CAS  PubMed  Google Scholar 

  30. Norsidah KZ, Asmadi AY, Azizi A, Faizah O, Kamisah Y (2013) Palm tocotrienol-rich fraction improves vascular proatherosclerotic changes in hyperhomocysteinemic rats. Evid Based Complement Alternat Med 2013:976967

    Article  PubMed Central  PubMed  Google Scholar 

  31. Norsidah KZ, Asmadi AY, Azizi A, Faizah O, Kamisah Y (2013) Palm tocotrienol-rich fraction reduced plasma homocysteine and heart oxidative stress in rats fed with a high-methionine diet. J Physiol Biochem 69:441–449

    Article  CAS  PubMed  Google Scholar 

  32. Partearroyo T, Ubeda N, Alonso-Aperte E, Varela-Moreiras G (2010) Moderate or supranormal folic acid supplementation does not exert a protective effect for homocysteinemia and methylation markers in growing rats. Ann Nutr Metab 56:143–151

    Article  CAS  PubMed  Google Scholar 

  33. Pizzolo F, Blom HJ, Choi SW, Girelli D, Guarini P, Martinelli N, Stanzial AM, Corrocher R, Olivieri O, Friso S (2011) Folic acid effects on s-adenosylmethionine, s-adenosylhomocysteine, and DNA methylation in patients with intermediate hyperhomocysteinemia. J Am Coll Nutr 30:11–18

    Article  CAS  PubMed  Google Scholar 

  34. Qureshi AA, Pearce BC, Nor RM, Gapor A, Peterson DM, Elson CE (1996) Dietary alpha-tocopherol attenuates the impact of gamma-tocotrienol on hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in chickens. J Nutr 126:389–394

    CAS  PubMed  Google Scholar 

  35. Racek J, Rusnakova H, Trefil L, Siala KK (2005) The influence of folate and antioxidants on homocysteine levels and oxidative stress in patients with hyperlipidemia and hyperhomocysteinemia. Physiol Res 54:87–95

    CAS  PubMed  Google Scholar 

  36. Sarna LK, Wu N, Wang P, Siow YL, Karmin O (2012) Folic acid supplementation attenuates high fat diet induced hepatic oxidative stress via regulation of NADPH oxidase. Can J Physiol Pharmacol 90:155–165

    Article  CAS  PubMed  Google Scholar 

  37. Selhub J (1999) Homocysteine metabolism. Annu Rev Nutr 19:217–246

    Article  CAS  PubMed  Google Scholar 

  38. Stipanuk MH (1979) Effect of excess dietary methionine on the catabolism of cysteine in rats. J Nutr 109:2126–2139

    CAS  PubMed  Google Scholar 

  39. Sugiyama A, Awaji H, Horie K, Kim M, Nakata R (2012) The beneficial effect of folate-enriched egg on the folate and homocysteine levels in rats fed a folate- and choline-deficient diet. J Food Sci 77:H268–H272

    Article  PubMed  Google Scholar 

  40. Tawfik A, Markand S, Al-Shabrawey M, Mayo JN, Reynolds J, Bearden SE, Ganapathy V, Smith SB (2014) Alterations of retinal vasculature in cystathionine-β-synthase heterozygous mice: a model of mild to moderate hyperhomocysteinemia. Am J Pathol 184:2573–2585

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Topal G, Brunet A, Millanvoye E, Boucher JL, Rendu F, Devynck MA, David-Dufilho M (2004) Homocysteine induces oxidative stress by uncoupling of NO synthase activity through reduction of tetrahydrobiopterin. Free Radic Biol Med 36:1532–1541

    Article  CAS  PubMed  Google Scholar 

  42. Vitvitsky V, Mosharov E, Tritt M, Ataullakhanov F, Banerjee R (2003) Redox regulation of homocysteine- dependent glutathione synthesis. Redox Rep 8:57–63

    Article  CAS  PubMed  Google Scholar 

  43. Wang W, Kramer PM, Yang S, Pereira MA, Tao L (2001) Reversed-phase high-performance liquid chromatography procedure for the simultaneous determination of S-adenosyl-l-methionine and S-adenosyl-l-homocysteine in mouse liver and the effect of methionine on their concentrations. J Chromatography B 762:59–65

    Article  CAS  Google Scholar 

  44. Wang H, Tan H, Yang F (2005) Mechanisms in homocysteine-induced vascular disease. Drug Discov Today Dis Mech 2:25–31

    Article  CAS  Google Scholar 

  45. Yamada H, Akahoshi N, Kamata S, Hagiya Y, Hishiki T, Nagahata Y, Matsuura T, Takano N, Mori M, Ishizaki Y, Izumi T, Kumagai Y, Kasahara T, Suematsu M, Ishii I (2012) Methionine excess in diet induces acute lethal hepatitis in mice lacking cystathionine γ-lyase, an animal model of cystathioninuria. Free Radic Biol Med 52:1716–1726

    Article  CAS  PubMed  Google Scholar 

  46. Yang R, Chen RP, Chen H, Zhang H, Cai DH (2014) Folic acid attenuates cognitive dysfunction in streptozotocin-induced diabetic rats. Int J Clin Exp Med 7:4214–4219

    PubMed Central  PubMed  Google Scholar 

  47. Yang XL, Tian J, Liang Y, Ma CJ, Yang AN, Wang J, Ma SC, Cheng Y, Hua X, Jiang YD (2014) Homocysteine induces blood vessel global hypomethylation mediated by LOX-1. Genet Mol Res 13:3787–3799

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The study was financially supported by the Faculty Medicine, Universiti Kebangsaan Malaysia (FF-013-2006). The authors would like to thank Puan Azizah Osman for her technical assistance.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine, UKMMC, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Cheras, 56000, Kuala Lumpur, Malaysia

    Yusof Kamisah & Ku-Zaifah Norsidah

  2. Department of Basic Medical Sciences, Kuliyyah of Medicine, International Islamic University of Malaysia, Kuantan, Pahang, Malaysia

    Ku-Zaifah Norsidah

  3. Division of Pathology, School of Medicine, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia

    Ayob Azizi

  4. Department of Anatomy, Faculty of Medicine, UKMMC, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur, Malaysia

    Othman Faizah

  5. Department of Pathology, Faculty of Medicine, UKMMC, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur, Malaysia

    Mohd Rizal Nonan

  6. Faculty of Traditional and Complementary Medicine, Cyberjaya University College of Medical Sciences, Cyberjaya, Selangor, Malaysia

    Ahmad Yusof Asmadi

Authors
  1. Yusof Kamisah
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ku-Zaifah Norsidah
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ayob Azizi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Othman Faizah
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mohd Rizal Nonan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ahmad Yusof Asmadi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yusof Kamisah.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kamisah, Y., Norsidah, KZ., Azizi, A. et al. Palm tocotrienol-rich fraction inhibits methionine-induced cystathionine β-synthase in rat liver. J Physiol Biochem 71, 659–667 (2015). https://doi.org/10.1007/s13105-015-0431-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13105-015-0431-y

Keywords

Search

Navigation