Nutr Res Pract.  2015 Apr;9(2):144-149. 10.4162/nrp.2015.9.2.144.

Effects of excessive dietary methionine on oxidative stress and dyslipidemia in chronic ethanol-treated rats

• Kim SY
• Kim H
• Min H

• KMID: 2313822
• DOI: http://doi.org/10.4162/nrp.2015.9.2.144

Abstract

BACKGROUND
/OBJECTIVE: The aim of this study was to examine the effect of high dietary methionine (Met) consumption on plasma and hepatic oxidative stress and dyslipidemia in chronic ethanol fed rats.
MATERIALS/METHODS
Male Wistar rats were fed control or ethanol-containing liquid diets supplemented without (E group) or with DL-Met at 0.6% (EM1 group) or 0.8% (EM2 group) for five weeks. Plasma aminothiols, lipids, malondialdehyde (MDA), alanine aminotransferase (ALT), and aspartate aminotransferase were measured. Hepatic folate, S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) were measured.
RESULTS
DL-Met supplementation was found to increase plasma levels of homocysteine (Hcy), triglyceride (TG), total cholesterol (TC), and MDA compared to rats fed ethanol alone and decrease plasma ALT. However, DL-Met supplementation did not significantly change plasma levels of HDL-cholesterol, cysteine, cysteinylglycine, and glutathione. In addition, DL-Met supplementation increased hepatic levels of folate, SAM, SAH, and SAM:SAH ratio. Our data showed that DL-Met supplementation can increase plasma oxidative stress and atherogenic effects by elevating plasma Hcy, TG, and TC in ethanol-fed rats.
CONCLUSION
The present results demonstrate that Met supplementation increases plasma oxidative stress and atherogenic effects by inducing dyslipidemia and hyperhomocysteinemia in ethanol-fed rats.

Keyword

Ethanol; DL-Methionine supplementation; oxidative stress; plasma lipids; aminothiols

MeSH Terms

Alanine Transaminase
Animals
Aspartate Aminotransferases
Cholesterol
Cysteine
Diet
Dyslipidemias*
Ethanol
Folic Acid
Glutathione
Homocysteine
Humans
Hyperhomocysteinemia
Male
Malondialdehyde
Methionine*
Oxidative Stress*
Plasma
Rats*
Rats, Wistar
S-Adenosylhomocysteine
S-Adenosylmethionine
Triglycerides
Alanine Transaminase
Aspartate Aminotransferases
Cholesterol
Cysteine
Ethanol
Folic Acid
Glutathione
Homocysteine
Malondialdehyde
Methionine
S-Adenosylhomocysteine
S-Adenosylmethionine

Figure

• 

  Fig. 1 Effects of methionine supplementation on plasma and liver MDA in chronic ethanol-treated rats. Data are presented as mean ± SE (n = 8). Statistical significance of means was determined using one-way ANOVA followed by Duncan's multiple-range post hoc test. Values not sharing a common superscript letter are significantly different at P < 0.05. Control, no ethanol; E, ethanol; EM1, ethanol + 0.6% DL-Met; EM2, ethanol + 0.8% DL-Met

• 

  Fig. 2 Effects of methionine supplementation on liver SAM and SAH in chronic ethanol-treated rats. Data are presented as mean ± SE (n = 8). Statistical significance of means was determined using one-way ANOVA followed by Duncan's multiple-range post hoc test. Values not sharing a common superscript letter are significantly different at P < 0.05. Control, no ethanol; E, ethanol; EM1, ethanol + 0.6% DL-Met; EM2, ethanol + 0.8% DL-Met

Reference

1. Barak AJ, Beckenhauer HC, Tuma DJ. Methionine synthase. a possible prime site of the ethanolic lesion in liver. Alcohol. 2002; 26:65–67.

2. Halsted CH, Villanueva J, Chandler CJ, Stabler SP, Allen RH, Muskhelishvili L, James SJ, Poirier L. Ethanol feeding of micropigs alters methionine metabolism and increases hepatocellular apoptosis and proliferation. Hepatology. 1996; 23:497–505.

3. Waly MI, Kharbanda KK, Deth RC. Ethanol lowers glutathione in rat liver and brain and inhibits methionine synthase in a cobalamin-dependent manner. Alcohol Clin Exp Res. 2011; 35:277–283.

4. Stipanuk MH. Sulfur amino acid metabolism: pathways for production and removal of homocysteine and cysteine. Annu Rev Nutr. 2004; 24:539–577.

5. Selhub J. Homocysteine metabolism. Annu Rev Nutr. 1999; 19:217–246.

6. Brosnan JT, Brosnan ME. The sulfur-containing amino acids: an overview. J Nutr. 2006; 136:1636S–1640S.

7. Wang H, Jiang X, Yang F, Gaubatz JW, Ma L, Magera MJ, Yang X, Berger PB, Durante W, Pownall HJ, Schafer AI. Hyperhomocysteinemia accelerates atherosclerosis in cystathionine beta-synthase and apolipoprotein E double knock-out mice with and without dietary perturbation. Blood. 2003; 101:3901–3907.

8. Finkelstein JD. Methionine metabolism in mammals. J Nutr Biochem. 1990; 1:228–237.

9. Lieber CS, Casini A, DeCarli LM, Kim CI, Lowe N, Sasaki R, Leo MA. S-adenosyl-L-methionine attenuates alcohol-induced liver injury in the baboon. Hepatology. 1990; 11:165–172.

10. Mato JM, Alvarez L, Ortiz P, Mingorance J, Durán C, Pajares MA. S-adenosyl-L-methionine synthetase and methionine metabolism deficiencies in cirrhosis. Adv Exp Med Biol. 1994; 368:113–117.

11. Bailey SM, Robinson G, Pinner A, Chamlee L, Ulasova E, Pompilius M, Page GP, Chhieng D, Jhala N, Landar A, Kharbanda KK, Ballinger S, Darley-Usmar V. S-adenosylmethionine prevents chronic alcoholinduced mitochondrial dysfunction in the rat liver. Am J Physiol Gastrointest Liver Physiol. 2006; 291:G857–G867.

12. Lieber CS. S-adenosyl-L-methionine: its role in the treatment of liver disorders. Am J Clin Nutr. 2002; 76:1183S–1187S.

13. Lu SC, Huang ZZ, Yang H, Mato JM, Avila MA, Tsukamoto H. Changes in methionine adenosyltransferase and S-adenosylmethionine homeostasis in alcoholic rat liver. Am J Physiol Gastrointest Liver Physiol. 2000; 279:G178–G185.

14. Albano E. Alcohol, oxidative stress and free radical damage. Proc Nutr Soc. 2006; 65:278–290.

15. Deneke SM. Thiol-based antioxidants. Curr Top Cell Regul. 2000; 36:151–180.

16. Munday R. Toxicity of thiols and disulphides: involvement of free-radical species. Free Radic Biol Med. 1989; 7:659–673.

17. Finkelstein JD, Martin JJ. Methionine metabolism in mammals. Adaptation to methionine excess. J Biol Chem. 1986; 261:1582–1587.

18. Toborek M, Kopieczna-Grzebieniak E, Drózdz M, Wieczorek M. Increased lipid peroxidation and antioxidant activity in methionine-induced hepatitis in rabbits. Nutrition. 1996; 12:534–537.

19. Yalçinkaya S, Unlüçerçi Y, Uysal M. Methionine-supplemented diet augments hepatotoxicity and prooxidant status in chronically ethanol-treated rats. Exp Toxicol Pathol. 2007; 58:455–459.

20. Lieber CS, DeCarli LM. Animal models of chronic ethanol toxicity. Methods Enzymol. 1994; 233:585–594.

21. Nolin TD, McMenamin ME, Himmelfarb J. Simultaneous determination of total homocysteine, cysteine, cysteinylglycine, and glutathione in human plasma by high-performance liquid chromatography: application to studies of oxidative stress. J Chromatogr B Analyt Technol Biomed Life Sci. 2007; 852:554–561.

22. Wong SH, Knight JA, Hopfer SM, Zaharia O, Leach CN Jr, Sunderman FW Jr. Lipoperoxides in plasma as measured by liquid-chromatographic separation of malondialdehyde-thiobarbituric acid adduct. Clin Chem. 1987; 33:214–220.

23. 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; 140:108–116.

24. Tamura T. Microbiological assay of folates. In : Picciano MF, Stokstad EL, Gregory JF, editors. Folic Acid Metabolism in Health and Disease. New York (NY): Wiley-Liss;1990. p. 121–137.

25. Song Z, Zhou Z, Chen T, Hill D, Kang J, Barve S, McClain C. S-adenosylmethionine (SAMe) protects against acute alcohol induced hepatotoxicity in mice. J Nutr Biochem. 2003; 14:591–597.

26. Toue S, Kodama R, Amao M, Kawamata Y, Kimura T, Sakai R. Screening of toxicity biomarkers for methionine excess in rats. J Nutr. 2006; 136:1716S–1721S.

27. Benevenga NJ, Harper AE. Alleviation of methionine and homocystine toxicity in the rat. J Nutr. 1967; 93:44–52.

28. Zhang R, Ma J, Xia M, Zhu H, Ling W. Mild hyperhomocysteinemia induced by feeding rats diets rich in methionine or deficient in folate promotes early atherosclerotic inflammatory processes. J Nutr. 2004; 134:825–830.

29. Yang CM, Carlson GP. Effects of ethanol on glutathione conjugation in rat liver and lung. Biochem Pharmacol. 1991; 41:923–929.

30. Aykaç G, Uysal M, Yalçin AS, Koçak-Toker N, Sivas A, Oz H. The effect of chronic ethanol ingestion on hepatic lipid peroxide, glutathione, glutathione peroxidase and glutathione transferase in rats. Toxicology. 1985; 36:71–76.

31. Meister A. Glutathione metabolism and its selective modification. J Biol Chem. 1988; 263:17205–17208.

32. Barak AJ, Beckenhauer HC, Tuma DJ. S-adenosylmethionine generation and prevention of alcoholic fatty liver by betaine. Alcohol. 1994; 11:501–503.

33. Avila MA, García-Trevijano ER, Martínez-Chantar ML, Latasa MU, Pérez-Mato I, Martínez-Cruz LA, del Pino MM, Corrales FJ, Mato JM. S-Adenosylmethionine revisited: its essential role in the regulation of liver function. Alcohol. 2002; 27:163–167.

34. Cederbaum AI. Hepatoprotective effects of S-adenosyl-L-methionine against alcohol- and cytochrome P450 2E1-induced liver injury. World J Gastroenterol. 2010; 16:1366–1376.

35. García-Ruiz C, Morales A, Colell A, Ballesta A, Rodés J, Kaplowitz N, Fernández-Checa JC. Feeding S-adenosyl-L-methionine attenuates both ethanol-induced depletion of mitochondrial glutathione and mitochondrial dysfunction in periportal and perivenous rat hepatocytes. Hepatology. 1995; 21:207–214.

36. Colell A, García-Ruiz C, Morales A, Ballesta A, Ookhtens M, Rodés J, Kaplowitz N, Fernández-Checa JC. Transport of reduced glutathione in hepatic mitochondria and mitoplasts from ethanol-treated rats: effect of membrane physical properties and S-adenosyl-L-methionine. Hepatology. 1997; 26:699–708.

37. Lapenna D, de Gioia S, Ciofani G, Mezzetti A, Ucchino S, Calafiore AM, Napolitano AM, Di Ilio C, Cuccurullo F. Glutathione-related antioxidant defenses in human atherosclerotic plaques. Circulation. 1998; 97:1930–1934.

38. Kugiyama K, Ohgushi M, Motoyama T, Hirashima O, Soejima H, Misumi K, Yoshimura M, Ogawa H, Sugiyama S, Yasue H. Intracoronary infusion of reduced glutathione improves endothelial vasomotor response to acetylcholine in human coronary circulation. Circulation. 1998; 97:2299–2301.