Protective effect of rutin on the antioxidant genes expression in hypercholestrolemic male Westar rat

BMC Complementary and Alternative Medicine

Mohamed M Hafez¹  Khaled A Al-Hosaini¹  Mohammed M Ahmed¹  Hatem M Abuohashish¹  Othman A AL-Shabanah¹  Mohamed M Sayed-Ahmed¹  Abdulaziz M Aleisa¹  Salem S Al-Rejaie¹ 

[1] Department of pharmacology and toxicology; College of pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia

关键词: Real time PCR;    Oxidative stress genes;    Rutin;    Hypercholesterolemic liver;   

Others  :  1229848
DOI  :  10.1186/1472-6882-13-136

 received in 2013-01-25, accepted in 2013-06-13,  发布年份 2013

【 摘 要 】

Background

High-cholesterol diet (HCD) increases the oxidative stress in different tissues leading to many diseases. Rutin (RT) is a natural flavonoid (vitamin p), which possesses an antioxidant activity with protective potential. The present study aimed to examine the potential effects of rutin on hypercholesterolemia-induced hepatotoxicity in rat.

Methods

Male Wistar rats were divided into four groups: GI) control (Rat chow), GII) Rutin (0.2% in rat chow), GIII) HCD (1% cholesterol and 0.5% cholic acid in rat chow) and GIV) rutin (0.2%) + HCD.

Results

Rutin in combination with HCD induced a significant protective effect against the hepatotoxicity by reducing the plasma level of alanine transaminase (ALT), aspartate aminotransferase (AST), triglyceride (TG), total cholesterol (TC), and low-density lipoprotein (LDL). The HCD (GII) showed a decrease in glutathione peroxidase (GPx), glutathione reductase (GR) and increase in glutathione S transferase α (GSTα), sulfiredoxin-1(Srx1), glutamate-cysteine ligase (GCL) and paraoxonase-1(PON-1) genes expression levels.

Conclusion

Treatment with rutin reversed all the altered genes induced by HCD nearly to the control levels. The present study concluded that the HCD feedings altered the expression levels of some genes involved in the oxidative stress pathway resulting in DNA damage and hepatotoxicity. Rutin have a hepatoprotective effect through the mechanism of enhancing the antioxidant effect via amelioration of oxidative stress genes.

【 授权许可】

   
2013 Al-Rejaie et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Farrell GC, Teoh NC, McCuskey RS: Hepatic microcirculation in fatty liver disease. Anat Rec (Hoboken) 2008, 291:684-692.
• [2]Trauner M, Arrese M, Wagner M: Fatty liver and lipotoxicity. Biochim Biophys Acta 1801, 2010:299-310.
• [3]Bellentani S, Saccoccio G, Masutti F, Croce LS, Brandi G, Sasso F, Cristanini G, Tiribelli C: Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med 2000, 132:112-117.
• [4]Vitaglione P, Morisco F, Mazzone G, Amoruso DC, Ribecco MT, Romano A, Fogliano V, Caporaso N, D'Argenio G: Coffee reduces liver damage in a rat model of steatohepatitis: the underlying mechanisms and the role of polyphenols and melanoidins. Hepatology 2010, 52:1652-1661.
• [5]Araya J, Rodrigo R, Videla LA, Thielemann L, Orellana M, Pettinelli P, Poniachik J: Increase in long-chain polyunsaturated fatty acid n - 6/n - 3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease. Clin Sci (Lond) 2004, 106:635-643.
• [6]Araya J, Rodrigo R, Pettinelli P, Araya AV, Poniachik J, Videla LA: Decreased liver fatty acid delta-6 and delta-5 desaturase activity in obese patients. Obesity (Silver Spring) 2010, 18:1460-1463.
• [7]Videla LA, Rodrigo R, Araya J, Poniachik J: Insulin resistance and oxidative stress interdependency in non-alcoholic fatty liver disease. Trends Mol Med 2006, 12:555-558.
• [8]Tomofuji T, Azuma T, Kusano H, Sanbe T, Ekuni D, Tamaki N, Yamamoto T, Watanabe T: Oxidative damage of periodontal tissue in the rat periodontitis model: effects of a high-cholesterol diet. FEBS Lett 2006, 580:3601-3604.
• [9]Fried M, Hainer V, Basdevant A, Buchwald H, Dietel M, Finer N, Greve JW, Horber F, Mathus-Vliegen E, Scopinaro N, et al.: Interdisciplinary European guidelines on surgery for severe obesity. Rozhl Chir 2008, 87:468-476.
• [10]Preiss D, Sattar N: Non-alcoholic fatty liver disease: an overview of prevalence, diagnosis, pathogenesis and treatment considerations. Clin Sci (Lond) 2008, 115:141-150.
• [11]Al-Nozha MM, Al-Mazrou YY, Al-Maatouq MA, Arafah MR, Khalil MZ, Khan NB, Al-Marzouki K, Abdullah MA, Al-Khadra AH, Al-Harthi SS, et al.: Obesity in Saudi Arabia. Saudi Med J 2005, 26:824-829.
• [12]Al-hamoudi W, El-Sabbah M, Ali S, Altuwaijri M, Bedewi M, Adam M, Alhammad A, Sanai F, Alswat K, Abdo A: Epidemiological, clinical, and biochemical characteristics of Saudi patients with nonalcoholic fatty liver disease: a hospital-based study. Ann Saudi Med 2012, 32:288-292.
• [13]Jump DB: N-3 polyunsaturated fatty acid regulation of hepatic gene transcription. Curr Opin Lipidol 2008, 19:242-247.
• [14]Clarke SD, Jump DB: Polyunsaturated fatty acid regulation of hepatic gene transcription. Lipids 1996, 31(Suppl):S7-S11.
• [15]Pegorier JP, Le May C, Girard J: Control of gene expression by fatty acids. J Nutr 2004, 134:2444S-2449S.
• [16]Nguyen P, Leray V, Diez M, Serisier S, Le Bloc'h J, Siliart B, Dumon H: Liver lipid metabolism. J Anim Physiol Anim Nutr 2008, 92:272-283.
• [17]Ikonen E: Mechanisms for cellular cholesterol transport: defects and human disease. Physiol Rev 2006, 86:1237-1261.
• [18]Ho YK, Brown MS, Goldstein JL: Hydrolysis and excretion of cytoplasmic cholesteryl esters by macrophages: stimulation by high density lipoprotein and other agents. J Lipid Res 1980, 21:391-398.
• [19]Sonta T, Inoguchi T, Tsubouchi H, Sekiguchi N, Kobayashi K, Matsumoto S, Utsumi H, Nawata H: Evidence for contribution of vascular NAD(P)H oxidase to increased oxidative stress in animal models of diabetes and obesity. Free Radic Biol Med 2004, 37:115-123.
• [20]Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I: Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 2004, 114:1752-1761.
• [21]Faienza MF, Francavilla R, Goffredo R, Ventura A, Marzano F, Panzarino G, Marinelli G, Cavallo L, Di Bitonto G: Oxidative stress in obesity and metabolic syndrome in children and adolescents. Horm Res Paediatr 2012, 78:158-164.
• [22]Park S, Kim M, Paik JK, Jang YJ, Lee SH, Lee JH: Oxidative stress is associated with C-reactive protein in non-diabetic postmenopausal women, independent of obesity and insulin resistance. Clin Endocrinol (Oxf) 2012, 79:65-70.
• [23]Mishra KP: Cell membrane oxidative damage induced by gamma-radiation and apoptotic sensitivity. J Environ Pathol Toxicol Oncol 2004, 23:61-66.
• [24]Bravo E, Palleschi S, Aspichueta P, Buque X, Rossi B, Cano A, Napolitano M, Ochoa B, Botham KM: High fat diet-induced non alcoholic fatty liver disease in rats is associated with hyperhomocysteinemia caused by down regulation of the transsulphuration pathway. Lipids Health Dis 2011, 10:60. BioMed Central Full Text
• [25]Koc A, Duru M, Ciralik H, Akcan R, Sogut S: Protective agent, erdosteine, against cisplatin-induced hepatic oxidant injury in rats. Mol Cell Biochem 2005, 278:79-84.
• [26]Blokhina O, Virolainen E, Fagerstedt KV: Antioxidants, oxidative damage and oxygen deprivation stress: a review. Ann Bot 2003, 91:Spec No:179-Spec No:194.
• [27]Yagmurca M, Bas O, Mollaoglu H, Sahin O, Nacar A, Karaman O, Songur A: Protective effects of erdosteine on doxorubicin-induced hepatotoxicity in rats. Arch Med Res 2007, 38:380-385.
• [28]Sayed-Ahmed AMA MM, Al-Rejaie SS, Al-Yahya AA, Al-Shabanah OA, Hafez MM, Nagi MN: Thymoquinone attenuates diethylnitrosamine induction of hepatic carcinogenesis through antioxidant signaling. Oxidative Medicine and Cellular Longevity 2010, 3:254-261.
• [29]Danz ED, Skramsted J, Henry N, Bennett JA, Keller RS: Resveratrol prevents doxorubicin cardiotoxicity through mitochondrial stabilization and the Sirt1 pathway. Free Radic Biol Med 2009, 46:1589-1597.
• [30]Fisher-Wellman K, Bell HK, Bloomer RJ: Oxidative stress and antioxidant defense mechanisms linked to exercise during cardiopulmonary and metabolic disorders. Oxid Med Cell Longev 2009, 2:43-51.
• [31]Senti M, Tomas M, Fito M, Weinbrenner T, Covas MI, Sala J, Masia R, Marrugat J: Antioxidant paraoxonase 1 activity in the metabolic syndrome. J Clin Endocrinol Metab 2003, 88:5422-5426.
• [32]Peltoniemi MJ, Rytila PH, Harju TH, Soini YM, Salmenkivi KM, Ruddock LW, Kinnula VL: Modulation of glutaredoxin in the lung and sputum of cigarette smokers and chronic obstructive pulmonary disease. Respir Res 2006, 7:133. BioMed Central Full Text
• [33]Lu W, Chen Z, Zhang H, Wang Y, Luo Y, Huang P: ZNF143 transcription factor mediates cell survival through upregulation of the GPX1 activity in the mitochondrial respiratory dysfunction. Cell Death Dis 2012, 3:e422.
• [34]Potter JD: Cancer prevention: epidemiology and experiment. Cancer Lett 1997, 114:7-9.
• [35]Aleksandrov PN, Speranskaia TV, Bobkov Iu G, Zagorevskii VA, Zykov DA: [Effect of rutin and esculamine on models of aseptic inflammation]. Farmakol Toksikol 1986, 49:84-86.
• [36]Deschner EE, Ruperto J, Wong G, Newmark HL: Quercetin and rutin as inhibitors of azoxymethanol-induced colonic neoplasia. Carcinogenesis 1991, 12:1193-1196.
• [37]Bear WL, Teel RW: Effects of citrus flavonoids on the mutagenicity of heterocyclic amines and on cytochrome P450 1A2 activity. Anticancer Res 2000, 20:3609-3614.
• [38]Chen S, Gong J, Liu F, Mohammed U: Naturally occurring polyphenolic antioxidants modulate IgE-mediated mast cell activation. Immunology 2000, 100:471-480.
• [39]Khan RA, Khan MR, Sahreen S: CCl4-induced hepatotoxicity: protective effect of rutin on p53, CYP2E1 and the antioxidative status in rat. BMC Complement Altern Med 2012, 12:178. BioMed Central Full Text
• [40]Lopez-Revuelta A, Sanchez-Gallego JI, Hernandez-Hernandez A, Sanchez-Yague J, Llanillo M: Membrane cholesterol contents influence the protective effects of quercetin and rutin in erythrocytes damaged by oxidative stress. Chem Biol Interact 2006, 161:79-91.
• [41]Takashi N, Nobuaki T, Yoshiaki I, Naoyuki N: Suppression of early and advanced glycation by dietary water-soluble rutin derivative in diabetic rats. Int Congr Ser 2002, 1245:403-405.
• [42]Al-Rejaie SS, Abuohashish HM, Alkhamees OA, Aleisa AM, Alroujayee AS: Gender difference following high cholesterol diet induced renal injury and the protective role of rutin and ascorbic acid combination in Wistar albino rats. Lipids Health Dis 2012, 11:41. BioMed Central Full Text
• [43]Ohkawa H, Ohishi N, Yagi K: Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979, 95:351-358.
• [44]Sedlak J, Lindsay RH: Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman's reagent. Anal Biochem 1968, 25:192-205.
• [45]Sayed-Ahmed MM, Al-Shabanah OA, Hafez MM, Aleisa AM, Al-Rejaie SS: Inhibition of gene expression of heart fatty acid binding protein and organic cation/carnitine transporter in doxorubicin cardiomyopathic rat model. Eur J Pharmacol 2010, 640:143-149.
• [46]Artham SM, Lavie CJ, Milani RV, Ventura HO: The obesity paradox: impact of obesity on the prevalence and prognosis of cardiovascular diseases. Postgrad Med 2008, 120:34-41.
• [47]Madsen AN, Hansen G, Paulsen SJ, Lykkegaard K, Tang-Christensen M, Hansen HS, Levin BE, Larsen PJ, Knudsen LB, Fosgerau K, et al.: Long-term characterization of the diet-induced obese and diet-resistant rat model: a polygenetic rat model mimicking the human obesity syndrome. J Endocrinol 2010, 206:287-296.
• [48]Lopez IP, Marti A, Milagro FI, Zulet Md Mde L, Moreno-Aliaga MJ, Martinez JA, De Miguel C: DNA microarray analysis of genes differentially expressed in diet-induced (cafeteria) obese rats. Obes Res 2003, 11:188-194.
• [49]Tan M, Schmidt RH, Beier JI, Watson WH, Zhong H, States JC, Arteel GE: Chronic subhepatotoxic exposure to arsenic enhances hepatic injury caused by high fat diet in mice. Toxicol Appl Pharmacol 2011, 257:356-364.
• [50]Song HY, Mao ZM, Yang LL, Liu T, Li DF, Zhang L, Ge YL, Zheng PY, Liu P, Zhang XQ, et al.: Dangfei liganning capsules attenuate the susceptibility of rat nonalcoholic fatty liver to carbon tetrachloride toxicity. J Tradit Chin Med 2011, 31:327-333.
• [51]Kamalakkannan N, Prince PS: Antihyperglycaemic and antioxidant effect of rutin, a polyphenolic flavonoid, in streptozotocin-induced diabetic wistar rats. Basic Clin Pharmacol Toxicol 2006, 98:97-103.
• [52]Kamalakkannan N, Stanely Mainzen Prince P: Rutin improves the antioxidant status in streptozotocin-induced diabetic rat tissues. Mol Cell Biochem 2006, 293:211-219.
• [53]Tsimikas S, Miller YI: Oxidative modification of lipoproteins: mechanisms, role in inflammation and potential clinical applications in cardiovascular disease. Curr Pharm Des 2011, 17:27-37.
• [54]Lavie L, Lavie P: Molecular mechanisms of cardiovascular disease in OSAHS: the oxidative stress link. Eur Respir J 2009, 33:1467-1484.
• [55]Noeman SA, Hamooda HE, Baalash AA: Biochemical study of oxidative stress markers in the liver, kidney and heart of high fat diet induced obesity in rats. Diabetol Metab Syndr 2011, 3:17. BioMed Central Full Text
• [56]Amin KA, Nagy MA: Effect of Carnitine and herbal mixture extract on obesity induced by high fat diet in rats. Diabetol Metab Syndr 2009, 1:17. BioMed Central Full Text
• [57]Bloomgarden ZT: Dyslipidemia and the metabolic syndrome. Diabetes Care 2004, 27:3009-3016.
• [58]Kauss T, Moynet D, Rambert J, Al-Kharrat A, Brajot S, Thiolat D, Ennemany R, Fawaz F, Mossalayi MD: Rutoside decreases human macrophage-derived inflammatory mediators and improves clinical signs in adjuvant-induced arthritis. Arthritis Res Ther 2008, 10:R19. BioMed Central Full Text
• [59]Guardia T, Rotelli AE, Juarez AO, Pelzer LE: Anti-inflammatory properties of plant flavonoids. Effects of rutin, quercetin and hesperidin on adjuvant arthritis in rat. Farmaco 2001, 56:683-687.
• [60]Ziaee A, Zamansoltani F, Nassiri-Asl M, Abbasi E: Effects of rutin on lipid profile in hypercholesterolaemic rats. Basic Clin Pharmacol Toxicol 2009, 104:253-258.
• [61]Park S, Park NY, Valacchi G, Lim Y: Calorie restriction with a high-fat diet effectively attenuated inflammatory response and oxidative stress-related markers in obese tissues of the high diet fed rats. Mediators Inflamm 2012, 2012:984643.
• [62]Huisamen B, Dietrich D, Bezuidenhout N, Lopes J, Flepisi B, Blackhurst D, Lochner A: Early cardiovascular changes occurring in diet-induced, obese insulin-resistant rats. Mol Cell Biochem 2012, 368:37-45.
• [63]Vincent HK, Powers SK, Dirks AJ, Scarpace PJ: Mechanism for obesity-induced increase in myocardial lipid peroxidation. Int J Obes Relat Metab Disord 2001, 25:378-388.
• [64]Husain K, Somani SM: Interaction of exercise training and chronic ethanol ingestion on hepatic and plasma antioxidant system in rat. J Appl Toxicol 1997, 17:189-194.
• [65]Ji L, Liu T, Chen Y, Wang Z: Protective mechanisms of N-acetyl-cysteine against pyrrolizidine alkaloid clivorine-induced hepatotoxicity. J Cell Biochem 2009, 108:424-432.
• [66]Chen L, Pan DD, Zhou J, Jiang YZ: Protective effect of selenium-enriched Lactobacillus on CCl4-induced liver injury in mice and its possible mechanisms. World journal of gastroenterology : WJG 2005, 11:5795-5800.
• [67]Sanz N, Diez-Fernandez C, Alvarez A, Cascales M: Age-dependent modifications in rat hepatocyte antioxidant defense systems. J Hepatol 1997, 27:525-534.
• [68]Kim SJ, Jung HJ, Hyun DH, Park EH, Kim YM, Lim CJ: Glutathione reductase plays an anti-apoptotic role against oxidative stress in human hepatoma cells. Biochimie 2010, 92:927-932.
• [69]Tappel AL: Glutathione peroxidase and hydroperoxides. Methods Enzymol 1978, 52:506-513.
• [70]Sekine Y, Osei-Hwedieh D, Matsuda K, Raghavachari N, Liu D, Furuya Y, Koike H, Suzuki K, Remaley AT: High fat diet reduces the expression of glutathione peroxidase 3 in mouse prostate. Prostate 2011, 71:1499-1509.
• [71]De Haan JB, Witting PK, Stefanovic N, Pete J, Daskalakis M, Kola I, Stocker R, Smolich JJ: Lack of the antioxidant glutathione peroxidase-1 does not increase atherosclerosis in C57BL/J6 mice fed a high-fat diet. J Lipid Res 2006, 47:1157-1167.
• [72]Pradeep K, Mohan CV, Gobianand K, Karthikeyan S: Silymarin modulates the oxidant-antioxidant imbalance during diethylnitrosamine induced oxidative stress in rats. Eur J Pharmacol 2007, 560:110-116.
• [73]Leviev I, Negro F, James RW: Two alleles of the human paraoxonase gene produce different amounts of mRNA. An explanation for differences in serum concentrations of paraoxonase associated with the (Leu-Met54) polymorphism. Arterioscler Thromb Vasc Biol 1997, 17:2935-2939.
• [74]Rodrigo L, Gil F, Hernandez AF, Marina A, Vazquez J, Pla A: Purification and characterization of paraoxon hydrolase from rat liver. Biochem J 1997, 321(Pt 3):595-601.
• [75]Ferre N, Marsillach J, Camps J, Mackness B, Mackness M, Riu F, Coll B, Tous M, Joven J: Paraoxonase-1 is associated with oxidative stress, fibrosis and FAS expression in chronic liver diseases. J Hepatol 2006, 45:51-59.
• [76]Zhang C, Peng W, Jiang X, Chen B, Zhu J, Zang Y, Zhang J, Zhu T, Qin J: Transgene expression of human PON1 Q in mice protected the liver against CCl4-induced injury. J Gene Med 2008, 10:94-100.
• [77]Curin Y, Ritz MF, Andriantsitohaina R: Cellular mechanisms of the protective effect of polyphenols on the neurovascular unit in strokes. Cardiovasc Hematol Agents Med Chem 2006, 4:277-288.
• [78]Panchal SK, Poudyal H, Arumugam TV, Brown L: Rutin attenuates metabolic changes, nonalcoholic steatohepatitis, and cardiovascular remodeling in high-carbohydrate, high-fat diet-fed rats. J Nutr 2011, 141:1062-1069.
• [79]Findlay VJ, Tapiero H, Townsend DM: Sulfiredoxin: a potential therapeutic agent? Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 2005, 59:374-379.
• [80]Rhee SG, Jeong W, Chang TS, Woo HA: Sulfiredoxin, the cysteine sulfinic acid reductase specific to 2-Cys peroxiredoxin: its discovery, mechanism of action, and biological significance. Kidney Int Suppl 2007, S3-S8.
• [81]Biteau B, Labarre J, Toledano MB: ATP-dependent reduction of cysteine-sulphinic acid by S. cerevisiae sulphiredoxin. Nature 2003, 425:980-984.
• [82]Martindale JL, Holbrook NJ: Cellular response to oxidative stress: signaling for suicide and survival. J Cell Physiol 2002, 192:1-15.
• [83]Maher P, Schubert D: Signaling by reactive oxygen species in the nervous system. Cell Mol Life Sci 2000, 57:1287-1305.
• [84]Feinendegen LE: Reactive oxygen species in cell responses to toxic agents. Hum Exp Toxicol 2002, 21:85-90.
• [85]Turella P, Cerella C, Filomeni G, Bullo A, De Maria F, Ghibelli L, Ciriolo MR, Cianfriglia M, Mattei M, Federici G, et al.: Proapoptotic activity of new glutathione S-transferase inhibitors. Cancer Res 2005, 65:3751-3761.
• [86]Burg D, Riepsaame J, Pont C, Mulder G, van de Water B: Peptide-bond modified glutathione conjugate analogs modulate GSTpi function in GSH-conjugation, drug sensitivity and JNK signaling. Biochem Pharmacol 2006, 71:268-277.
• [87]Nishiya T, Mori K, Hattori C, Kai K, Kataoka H, Masubuchi N, Jindo T, Manabe S: The crucial protective role of glutathione against tienilic acid hepatotoxicity in rats. Toxicol Appl Pharmacol 2008, 232:280-291.
• [88]Wu KC, Liu JJ, Klaassen CD: Nrf2 activation prevents cadmium-induced acute liver injury. Toxicol Appl Pharmacol 2012, 263:14-20.
• [89]Wang J, Ji L, Liu H, Wang Z: Study of the hepatotoxicity induced by Dioscorea bulbifera L. rhizome in mice. Biosci Trends 2010, 4:79-85.
• [90]Baek JY, Han SH, Sung SH, Lee HE, Kim YM, Noh YH, Bae SH, Rhee SG, Chang TS: Sulfiredoxin protein is critical for redox balance and survival of cells exposed to low steady-state levels of H2O2. J Biol Chem 2012, 287:81-89.