Folic Acid Alleviates Oxidative Stress and Hyperhomocysteinemia Involved in Liver Dysfunction of Hypothyroid Rats

Ehab Tousson^1, , Wafaa Ibrahim², Afrah F. Salama³ and Wesam M. Hussein³

¹Department of Zoology, Faculty of Science, Tanta University, Egypt

²Department of medical Biochemistry, Faculty of Medicine, Tanta University, Egypt

³Biochemistry Section, Department of Chemistry, Faculty of Science, Tanta University, Egypt

Cite this paper:
Ehab Tousson, Wafaa Ibrahim, Afrah F. Salama and Wesam M. Hussein. Folic Acid Alleviates Oxidative Stress and Hyperhomocysteinemia Involved in Liver Dysfunction of Hypothyroid Rats. American Journal of Biomedical Research. 2014; 2(4):70-76. doi: 10.12691/ajbr-2-4-3

Abstract

Thyroid hormones are essential for growth and development of the liver. This study evaluated some biochemical alterations in post-pubertal hypothyroidism and its impact on liver functions. Additionally, the ameliorating role of folic acid supplementation was investigated. Fifty male albino rats were randomly divided into five groups (group I, control; group II, folic acid; group III, 0.05% propylthiouracil-induced hypothyroid rats; group IV, Co-treatment; group V post-treatment). There was a significant decrease in plasma T₃, body weight, fluid and food intakes, folic acid, ALT, total thiol and tFRAP in hypothyroid rats as compared to control group. On the other hand, a significant increase in TSH, relative liver weight, plasma of total homocysteine, serum total protein, AST, total serum bilirubin, cholesterol and tMDA in hypothyroid rats as compared to control group. This reflects hyperhomocysteinemia and oxidative stress associated with hypothyroid state. Folic acid supplemented after restoration of the euthyroid state presented better amelioration over its concurrent supplementation. If confirmed in human beings, our results could propose that folic acid can be used as an adjuvant therapy in hypothyroidism disorders with thyroxin replacement therapy.

Keywords:
hypothyroidism liver oxidative stress folic acid PTU

This work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

References:

[1]	Strait KA, Kinlaw WB, Mariash, CN, Oppenheimer JH. Kinetics of induction by thyroid hormone of the two hepatic mRNAs coding for cytosolic malic enzyme in the hypothyroid and euthyroid states. Evidence against an obligatory role of S14 protein in malic enzyme gene expression. J Biol Chem 1989; 264; 19784-9.
[2]	Morrison WL, Gibson JN, Jung RT. Skeletal muscle and whole body protein turnover in thyroid disease. Eur. J. Clin, 1988; 18; 62-8.
[3]	Rochon C, Tauveron I, Dejax C. Response of glucose disposal to hyperinsulinaemia in human hypothyroidism and hyperthyroidism. Clin Sci 2003; 104; 7-15.
[4]	Ibrahim W, Tousson E, Ali EM, Mansour MA. Folic acid alleviates oxidative stress and hyperhomocysteinemia involved in testicular dysfunction of hypothyroid rats. General and Comparative Endocrinology 2011; 174; 143-9.
[5]	Ibrahim W, Tousson E, El-Masery T, Arafa N, Akela M. The effect of folic acid as an antioxidant on the hypothalamic monoamines in experimentally induced hypothyroid rat. Toxicology and Industrial Health 2012; 28; 253-61.
[6]	Tousson E, Ali EM, Ibrahim W, Mansour MA. Treatment with folic acid ameliorated the histopathological alterations caused by propylthiouracil-induced hypothyroid rat testes. Toxicology and Industrial Health 2012b; 28; 566-76.
[7]	Tousson E, Ibrahim W, Arafa N and Akela MA. Monoamine concentrations changes in the PTU induced hypothyroid rat brain and the ameliorating role of folic acid. Human & Experimental Toxicology 2012a; 31; 282-9.
[8]	Salama AF, Tousson E, Ibrahim W and Hussein MW. Biochemical and histopathological studies in the PTU-induced hypothyroid rat kidney with reference to the ameliorating role of folic acid. Toxicology and Industrial Health 2013; 29 (7); 600-8.
[9]	Nair CP, Viswanathan G, Noronha JM. Folate mediated incorporation of ring-2-carbon of histidine into nucleic acids: influence of thyroid hormone. Metabolism 1994; 43; 1575-8.
[10]	Tousson E, Ali EM, Ibrahim W and Ashraf RM (2012): Histopathological and immunohistochemical alterations in rat heart after thyroidectomy and the role of hemin and ketoconazole in treatment. Biomedicine & Pharmacotherapy. 66 (2012) 627-632.
[11]	Tousson E, Ali EM, Ibrahim W, Mansour MA. Proliferating Cell Nuclear Antigen as a Molecular Biomarker for Spermatogenesis in PTU-Induced Hypothyroidism of Rats. Reprod Sci 2011; 18; 679-86.
[12]	Tousson E, Hafez E, Massoud A, Sweef O, Atta N. Protective role of folic acid in thyroxine-induced cardiac hypertrophy in hyperthyroid rat. Biomedicine & Aging Pathology 2013; 3; 89-95.
[13]	Tousson E and Hafez E. Thyroxine-induced cardiac hypertrophy: Role of ascorbic acid in treatment. Biomedicine & Aging Pathology 2014; 4.
[14]	Tan KC, Shiu SW, Kung AW. Effect of thyroid dysfunction on high-density lipoprotein sub fraction metabolism: roles of hepatic lipase and cholesteryl ester transfer protein. J Clin Endocrinol Metab 1998; 83; 2921-4.
[15]	Liverini G, Iossa S, Barletta A. Relationship between resting metabolism and hepatic metabolism: effect of hypothyroidism and 24 hours fasting. Hor Res 1992; 38; 154-8.
[16]	Comte B, Vidal H, Laville M, et al. Influence of thyroid hormones on gluconeogenesis from glycerol in rat hepatocytes: a dose-response study. Metabolism 1990; 39; 259-63.
[17]	Marchesini G, Fabbri A, Bianchi GP, et al. Hepatic conversion of amino nitrogen to urea nitrogen in hypothyroid patients and upon L-thyroxine therapy. Metabolism 1993; 42; 1263-6.
[18]	Balasubramaniam S, Mitropoulous KA, Myant NB. Hormonal Control of the Activities of Cholesterol-7hydroxylase and Hydroxy Methylglutaryl-Coa Reductase in Rats. In: Advances in bile acid research. Matern, S, Hachenschmidt, J, Back, P, et al, (eds). Stuttgart: Schattauer Verlag. P 61; 1975.
[19]	Lin-Lee YC, Strobl W, Soyal S, et al. Role of thyroid hormone in the expression of apo lipoprotein A-IV and C-III Genes in rat liver. J Lipid Res 1993; 34; 249-55.
[20]	Gebhart RL, Stone BG, Andreini JP, et al. Thyroid hormone differentially augments biliary sterol secretion in the rat. J Lipid Res 1992; 33; 1459-64.
[21]	Inkinen J, Sand J, Nordback I. Association between common bile duct stones and treated hypothyroidism. Hepatogastroenterology 2000; 47; 919-21.
[22]	Au-Yeung KW, Yip JCW, Siow YL, Karmin O. Folic acid inhibits homocysteine-induced superoxide anion production and nuclear factor kappa B activation in macrophages. Can J Physiol Pharmacol 2006; 84; 141-7.
[23]	Chopra IJ, Solomon DH, Ho RS. A radioimmunoassay of triiodothyronine. J Clin Endocrinol 1971; 33; 865-8.
[24]	Engall E. Methods in Enzymology. In: Methods in Enzymology. Van Vunakis H. and Langone J.J. (eds.), Vol. 70, Academic press, New York. pp 419-92; 1980.
[25]	Rietman S, Frankel S. A colorimetric method for determination of serum glutamic oxaloacetic and glutamic pyruvic transaminase. Amer J Clin Pathol 1957; 28; 56-61.
[26]	Jendrassik L, Gróf P. Vereinfachte photometrische Methoden zur Bestimmung des Blutbilirubins. Biochem Zeitschrift 1938; 297; 82-9.
[27]	Bowers L, Wong E. Kinetic serum creatinine assays. A critical evaluation and review. Clin Chem 1980; 26; 555-61.
[28]	Allain C, Poon L, Chan G, Richmond W, Fu C. Enzymatic determination of total serum cholesterol. Clin Chem 1974; 20 (4); 470-5.
[29]	Amidzic R, Brboric J, Cudina O, Vladimirov S. RP-HPLC Determination of vitamins B1, B3, B6, folic acid and B12 in multivitamin tablets. J Serb Chem Soc 2005; 70 (10); 1229-35.
[30]	Jayatilleke E, Shaw S. A high performance liquid chromatographic assay for reduced and oxidized glutathione in biological samples. Ana Biochem 1993; 214; 452-7.
[31]	Placer ZA, Cushmann LL, Johnson BC. Estimation of products of lipid peroxidation in biochemical systems. Anal Biochem 1966; 16; 359-64.
[32]	Benzie IF, Strain JJ. The ferric reducing ability of plasma (FRAP) as a measure of antioxidant power: the FRAP assay. Anal Biochem 1996; 239; 70-6.
[33]	Gilbert ME, Paczkowski C. Propylthiouracil (PTU) induced hypothyroidism in the developing rat impairs synaptic transmission and plasticity in the dentate gyrus of the adult hippocampus. Dev Brain Res 2003; 145; 19-29.
[34]	Brosnan JT, Jacobs RL, Stead LM, Brosnan ME. Methylation demand: a key determinant of homocysteine metabolism. Acta Biochim 2004; 51; 405-13.
[35]	Diekman MJ, Harms MP, Endert E. Endocrine factors related to changes in total peripheral vascular resistance after treatment of thyrotoxic and hypothyroid patients. Eur J Endocrinol 2001; 144; 339-42.
[36]	Adrees M, Gibney J, El-Saeity N, Boran G. Effects of 18 months of L-T4 replacement in women with subclinical hypothyroidism. Clin Endocrinol (Oxf) 2001; 71 (2); 298-303.
[37]	Turhan S, Sezer S, Erden G, Guctekin A, Ucar F, Ginis Z, Ozturk O, Bingol S. Plasma homocysteine concentrations and serum lipid profile as atherosclerotic risk factors in subclinical hypothyroidism. Annu Saudi Med 2008; 28 (2); 96-101.
[38]	Parameswaran F, Nair CP, Viswanathan G, Noronha, JM. Folate mediated incorporation of ring-2-carbon of histidine into nucleicacids: influence of thyroid hormone. Metabolism 1994; 43; 1575-8.
[39]	39 Simon-Giavarotti KA, Giavarotti L, Gomes, LF, Lima AF, Veridiano AM, Garcia EA. Enhancement of lindane induced liver oxidative stress and hepatotoxicity by thyroid hormone is reduced by gadolinium chloride. Free Radic Res 2002; 36; 1033-9.
[40]	Malik R, Hodgson H. The relationship between the thyroid gland and the liver. Q J Med 2002; 95; 559-69.
[41]	Dory L, Roheim P. Rat plasma lipoproteins and apolipoproteins in experimental hypothyroidism. J Lipid Res 1981; 22 (2); 287-96.
[42]	Varghese, S, Shameena, B, Oommen, OV. Thyroid hormones regulate lipid peroxidation and antioxidant enzyme activities in Anabas testudinens (Bloch). Comp Biochem Physiol 2001; 128; 165-71.
[43]	Al-Tonsi AA, Abdel-Gayoum AA, Saad M. The secondary dyslipidemia and deranged serum phosphate concentration in thyroid disorders. Exp Mol Pathol 2004; 76; 182-7.
[44]	Sheridan MA, His Kao Y. Regulation of metamorphosis associated changes in the lipid metabolism of selected vertebrates. Amer Zoolo 1998; 38; 350-68.
[45]	Morris M, Bostom A, Jacques P, Selhub J, Rosenberg I. Hyperhomocysteinemia and hypercholesterolemia associated with hypothyroidism in the third US National Health and Nutrition Examination Survey. Atherosclerosis 2001; 155; 195-200.
[46]	Karmin O, Lynn EG, Chung YH, Siow YL, Man RY, Choy PC. Homocysteine stimulates the production and secretion of cholesterol in hepatic cells. Biochim Biophys Acta 1998; 1393; 317-24.
[47]	Layden TJ, Boyer JL. The effect of thyroid hormone on bile salt-independent bile flow and Na+, K+-ATPase activity in liver plasma membranes enriched in bile canaliculi. J Clin Invest 1976; 57; 1009-18.
[48]	Arora S, Chawla R, Tayal D, Gupta V, Sohi J, Mallika V. Biochemical markers of liver and kidney function are influenced by thyroid function a case-controlled follow up study in indian hypothyroid subjects. Indian J Clinic Biochem 2009; 24 (4); 370-4.
[49]	Messarah M, Boulakoud MS, Boumendjel A, El Feki A. The impact of thyroid activity variations on some oxidizing-stress parameters in rats. C R Biol 2007; 330; 107-12.
[50]	Yilmaz S, Ozan S, Benzer F, Canatan H. Oxidative damage an antioxidant enzyme activities in experimental hypothyroidism. Cell Biochem Funct 2003; 21; 325-30.