The effects of acute hyperhomocysteinemia induced by DL-homocysteine or DL-homocysteine thiolactone on serum biochemical parameters, plasma antioxidant enzyme and cardiac acetylcholinesterase activities in the rat
Keywords:acetylcholinesterase, antioxidant enzymes, DL-homocysteine, DL-homocysteine thiolactone, rat
The aim of this study was to assess the effects of DL-homocysteine (DL-Hcy) and DL-homocysteine thiolactone (DL-Hcy TLHC) on selected serum biochemical parameters, markers of oxidative stress and the activities of antioxidant enzymes (catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD)) in the plasma, as well as on acetylcholinesterase (AChE) activity in the cardiac tissue homogenate in the rat. Male Wistar rats were divided into three groups as follows: control group (1 mL 0.9% NaCl, intraperitoneal (i.p.) injection), DL-Hcy group (8 mmol/kg body mass (b.m.), i.p.) or DL-Hcy TLHC group (8 mmol/kg b.m., i.p.). One hour after administration, the rats were euthanized, whole blood was collected for biochemical analysis, and the heart was excised. Following the i.p. administration of DL-Hcy and DL-Hcy TLHC, the activities of antioxidant enzymes were mostly significantly increased, while plasma malondialdehyde (MDA) was decreased. Administration of DL-Hcy and DL-Hcy TLHC significantly inhibited AChE activity in rat cardiac tissue. Our findings suggest that DL-Hcy and DL-Hcy TLHC exerted prooxidant effects; however, the decrease in MDA points to an inverse response to the increase in antioxidant enzyme activities. While both substances inhibited AChE activity in rat cardiac tissue, DL-Hcy TLHC induced stronger effects than DL-Hcy.
Received: July 31; Revised: October 23, 2017; Accepted: October 23, 2017; Published online: October 30, 2017
How to cite this article: Kornjača D, Živković V, Krstić D, Čolović M, Đurić M, Stanković S, Mutavdžin S, Jakovljević V, Đurić D. The effects of acute hyperhomocysteinemia induced by DL-homocysteine or DL-homocysteine thiolactone on serum biochemical parameters, plasma antioxidant enzyme and cardiac acetylcholinesterase activities in the rat. Arch Biol Sci. 2018;70(2):241-8.
Ganguly P, Alam SF. Role of homocysteine in the development of cardiovascular disease. Nutr J. 2015;14:6.
Malinowska J, Kolodziejczyk J, Olas B. The disturbance of hemostasis induced by hyperhomocysteinemia; the role of antioxidants. Acta Biochim Pol. 2012;59(2):185-94.
Shenov V, Mehendale V, Prabhu K, Shetty R, Rao P. Correlation of serum homocysteine levels with the severity of coronary artery disease. Indian J Clin Biochem. 2014;29(3):339-44.
Jakubowski H. The pathophysiological hypothesis of homocysteine thiolactone-mediated vascular disease. J Physiol Pharmacol. 2008;59(9):155-67.
Schaffer A, Verdoia M, Cassetti E, Marino P, Suryapranata H, De Luca G. Novara Atherosclerosis Study Group (NAS). Relationship between homocysteine and coronary artery disease. Results from a large prospective cohort study. Thromb Res. 2014;134(2):288-93.
Baszczuk A, Kopczyński Z, Thielemann A. Endothelial dysfunction in patients with primary hypertension and hyperhomocysteinemia. Postepy Hig Med Dosw. 2014;68:91-100.
Chen C, Halkos ME, Surowiec SM, Conklin BS, Lin PH, Lumsden AB. Effects of homocysteine on smooth muscle cell proliferation in both cell culture and artery perfusion culture models. J Surg Res. 2000;88(1):26-33.
Toohey JI. Homocysteine toxicity in connective tissue: theories, old and new. Connect Tissue Res. 2008;49(2):57-61.
Derouiche F, Bôle-Feysot C, Naïmi D, Coëffier M. Hyperhomocysteinemia-induced oxidative stress differentially alters proteasome composition and activities in heart and aorta. Biochem Biophys Res Commun. 2014;452(3):740-5.
Liu HH, Shih TS, Huang HR, Huang SC, Lee LH, Huang YC. Plasma homocysteine is associated with increased oxidative stress and antioxidant enzyme activity in welders. Sci World J. 2013;e370487.
da Cunha AA, Scherer E, da Cunha MJ, Schmitz F, Machado FR, Lima DD, Delwing D, Wyse AT. Acute hyperhomocysteinemia alters the coagulation system and oxidative status in the blood of rats. Mol Cell Biochem. 2012;360(1-2):205-14.
Kerkeni M, Added F, Ben Farhat M, Miled A, Trivin F, Maaroufi K. Hyperhomocysteinaemia and parameters of antioxidative defence in Tunisian patients with coronary heart disease. Ann Clin Biochem. 2008;45(2):193-8.
Matté C, Mackedanz V, Stefanello FM, Scherer EB, Andreazza AC, Zanotto C, Moro AM, Garcia SC, Gonçalves CA, Erdtmann B, Salvador M, Wyse AT. Chronic hyperhomocysteinemia alters antioxidant defenses and increases DNA damage in brain and blood of rats: protective effect of folic acid. Neurochem Int. 2009;54(1):7-13.
Wilcken DE, Wang XL, Adachi T, Hara H, Duarte N, Green K, Wilcken B. Relationship between homocysteine and superoxide dismutase in homocystinuria: possible relevance to cardiovascular risk. Arterioscler Thromb Vasc Biol. 2000;20(5):1199-202.
Hrnčić D, Rašić-Marković A, Stojković T, Velimirović M, Puškaš N, Obrenović R, Macut D, Sušić V, Jakovljević V, Djuric D, Petronijević N, Stanojlović O. Hyperhomocysteinemia induced by methionine dietary nutritional overload modulates acetylcholinesterase activity in the rat brain. Mol Cell Biochem. 2014;396(1-2):99-105.
Scherer EB, Loureiro SO, Vuaden FC, da Cunha AA, Schmitz F, Kolling J, Savio LE, Bogo MR, Bonan CD, Netto CA, Wyse AT. Mild hyperhomocysteinemia increases brain acetylcholinesterase and proinflammatory cytokine levels in different tissues. Mol Neurobiol. 2014;50(2):589-96.
Darvesh S, Walsh R, Martin E. Homocysteine thiolactone and human cholinesterases. Cell Mol Neurobiol. 2007;27(1):33-48.
Kučera M, Hrabovská A. Cholinergic system of the heart. Ceska Slov Farm. 2015;64(6):254-63.
Aruoma OI, Halliwell B, Laughton MJ, Quinlan GJ, Gutteridge JMC. The mechanism of initiation of lipid peroxidation. Evidence against a requirement for an iron (II)- iron (III) complex. Biochem J. 1989;258:617-20.
Beutler E. Red Cell Metabolism: A manual of biochemical methods. 3rd ed. New York: Grune Startton; 1984. 133 p.
Misra HP, Fridovich I. The role of superoxide-anion in the autooxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem. 1972;247:3170-5.
Wendel A. Enzymatic basis of detoxication. Vol. 1. New York: Academic Press; 1980. 333 p.
Ellman GL, Courtney KD, Andres VJr, Feather-Stone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol. 1961;7:88-95.
de Andrade CR, Tirapelli CR, Haddad R, Eberlin MN, Ramalho LN, Iyomasa MM, Uyemura SA, de Oliveira AM. Hyperhomocysteinemia induced by feeding rats diets rich in DL-homocysteine thiolactone promotes alterations on carotid reactivity independent of arterial structure. Vascul Pharmacol. 2009;51(4):291-8.
Werstuck GH, Lentz SR, Dayal S, Hossain GS, Sood SK, Shi YY, Zhou J, Maeda N, Krisans SK, Malinow MR, Austin RC. Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways. J Clin Invest. 2001;107(10):1263-73.
Pushpakumar S, Kundu S, Narayanan N, Sen U. DNA hypermethylation in hyperhomocysteinemia contributes to abnormal extracellular matrix metabolism in the kidney. FASEB J. 2015;29(11):4713-25.
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 M. Methionine excess in diet induces acute lethal hepatitis in mice lacking cystathionine γ-lyase, an animal model of cystathioninuria. Free Radic Biol Med. 2012;52(9):1716-26.
Mendes RH, Mostarda C, Candido GO, Moraes-Silva IC, D'Almeida V, Belló-Klein A, Irigoyen MC, Rigatto K. Moderate hyperhomocysteinemia provokes dysfunction of cardiovascular autonomic system and liver oxidative stress in rats. Auton Neurosci. 2014;180:43-7.
Golbahar J, Aminzadeh MA, Kassab SE, Omrani GR. Hyperhomocysteinemia induces insulin resistance in male Sprague-Dawley rats. Diabetes Res Clin Pract. 2007;76(1):1-5.
Lee H, Kim JM, Kim HJ, Lee I, Chang N. Folic acid supplementation can reduce the endothelial damage in rat brain microvasculature due to hyperhomocysteinemia. J Nutr. 2005;135(3):544-8.
Kolling J, Scherer EB, da Cunha AA, da Cunha MJ, Wyse AT. Homocysteine induces oxidative-nitrative stress in heart of rats: prevention by folic acid. Cardiovasc Toxicol. 2011;11(1):67-73.
Zivkovic V, Jakovljevic V, Djordjevic D, Vuletic M, Barudzic N, Djuric D. The effects of homocysteine-related compounds on cardiac contractility, coronary flow, and oxidative stress markers in isolated rat heart. Mol Cell Biochem. 2012;370(1-2):59-67.
Lubos E, Loscalzo J, Handy DE. Homocysteine and glutathione peroxidase-1. Antioxid Redox Signal. 2007;9(11):1923-40.
Jakubowski H. Protein homocysteinylation: possible mechanism underlying pathological consequences of elevated homocysteine levels. FASEB J. 1999;13(15):2277-83.