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Published in: BMC Complementary Medicine and Therapies 1/2016

Open Access 01-12-2016 | Research article

Rutin attenuates intestinal toxicity induced by Methotrexate linked with anti-oxidative and anti-inflammatory effects

Published in: BMC Complementary Medicine and Therapies | Issue 1/2016

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Abstract

Background

Methotrexate (MTX) is recognized as an anti-metabolite in cancer chemotherapy and is associated with various toxicities assigned to inflammation and oxidative stress. Rutin has been reported to have significant anti-inflammatory, antioxidant along with antiulcer properties. The present study was undertaken to corroborate the effect of rutin against MTX induced intestinal toxicity in experimental animals.

Method

Six groups of rats (n = 6) were dosed with normal saline (3 ml/kg,i.p.); MTX (2.5 mg/kg,i.p.); rutin (50 and 100 mg/kg,i.p.); rutin + MTX (50 mg/kg + 2.5 mg/kg,i.p.); rutin + MTX (100 mg/kg + 2.5 mg/kg,i.p.) for seven consecutive days and sacrificed on eighth day. The intestinal contents were scrutinized physiologically (pH, total acidity, free acidity, CMDI), biochemically (TBARS, protein carbonyl, SOD, catalase and GSH) and for immunoregulatory cytokines (IL-2, IL-4 and IL-10).

Results and Discussion

The administration of rutin demonstrated significant protection against intestinal lesions damaged by MTX. The treatment with rutin elicited noticeable inhibition of free acidity (26.20 %), total acidity (22.05 %) and CMDI (1.16 %) in the experimental animals similar to control. In MTX treated toxic group, the levels of oxidative markers and immunoregulatory cytokines significantly increased in comparison to control, which was subsequently restored after rutin treatment. Rutin also demonstrated 75.63, 81.00 and 80.43 % inhibition of cyclooxygenase-1 and 2, and 15-lipoxygenase respectively.

Conclusion

The positive modulation of MTX toxicity could be attributed to the free radical scavenging and anti-inflammatory (dual inhibition of arachidonic acid pathways) potential of rutin.
Literature
1.
go back to reference Leitao RFC, Brito GAC, Oria RB, Neto MBB, Bellaguarda EAL, Silva JV, Gomes A S, G, Júnior R CPL, Siqueira FJWS, Freire R S, Vale ML, Ribeiro RA. Role of inducible nitric oxide synthase pathway on methotrexate-induced intestinal mucositis in rodents. BMC Gastroenterol. 2011;16:11–90. Leitao RFC, Brito GAC, Oria RB, Neto MBB, Bellaguarda EAL, Silva JV, Gomes A S, G, Júnior R CPL, Siqueira FJWS, Freire R S, Vale ML, Ribeiro RA. Role of inducible nitric oxide synthase pathway on methotrexate-induced intestinal mucositis in rodents. BMC Gastroenterol. 2011;16:11–90.
2.
go back to reference Hashkes PJ, Becker ML, Cabral DA, Laxer RM, Paller AS, Rabinovich CE, Turner D, Zulian F. Methotrexate: new uses for an old drug. J Pediat. 2014;164(2):231–6. Hashkes PJ, Becker ML, Cabral DA, Laxer RM, Paller AS, Rabinovich CE, Turner D, Zulian F. Methotrexate: new uses for an old drug. J Pediat. 2014;164(2):231–6.
3.
go back to reference Cronstein BN. Low-dose Methotrexate: a mainstay in the treatment of rheumatoid arthritis. Pharmacol Rev. 2005;57(2):163–72.CrossRefPubMed Cronstein BN. Low-dose Methotrexate: a mainstay in the treatment of rheumatoid arthritis. Pharmacol Rev. 2005;57(2):163–72.CrossRefPubMed
5.
go back to reference Sonis ST, Elting LS, Keefe D, Peterson DE, Schubert M, Bekele BN, Raber-Durlacher J, Donnelly JP, Rubenstein EB. Perspective on cancer therapy induced mucosal injury: pathogenesis, measurements, epidemiology and consequences for patient. Cancer. 2004;100(9 Suppl):1995–2025. Sonis ST, Elting LS, Keefe D, Peterson DE, Schubert M, Bekele BN, Raber-Durlacher J, Donnelly JP, Rubenstein EB. Perspective on cancer therapy induced mucosal injury: pathogenesis, measurements, epidemiology and consequences for patient. Cancer. 2004;100(9 Suppl):1995–2025.
6.
go back to reference Kolli VK, Abraham P, Isaac B, Kasthuri N. Preclinical efficacy of melatonin to reduce methotrexate-induced oxidative stress and small intestinal damage in rats. Dig Dis Sci. 2013;58(4):959–69.CrossRefPubMed Kolli VK, Abraham P, Isaac B, Kasthuri N. Preclinical efficacy of melatonin to reduce methotrexate-induced oxidative stress and small intestinal damage in rats. Dig Dis Sci. 2013;58(4):959–69.CrossRefPubMed
7.
go back to reference Manach C, Morand C, Demigne C, Texier O, Regerat F, Remesy C. Bioavailability of rutin and quercetin in rats. FEBS Lett. 1997;409(1):12–6.CrossRefPubMed Manach C, Morand C, Demigne C, Texier O, Regerat F, Remesy C. Bioavailability of rutin and quercetin in rats. FEBS Lett. 1997;409(1):12–6.CrossRefPubMed
8.
go back to reference Hussain TH, Verma AR, Vijayakumar M, Sharma A, Mathela CS, Rao CV. Rutin, a natural flavonoid, protects against gastric mucosal damage in experimental animals. Asian J Trop Med. 2009;4(5):188–97. Hussain TH, Verma AR, Vijayakumar M, Sharma A, Mathela CS, Rao CV. Rutin, a natural flavonoid, protects against gastric mucosal damage in experimental animals. Asian J Trop Med. 2009;4(5):188–97.
9.
go back to reference Kaithwas G, Majumdar DK. Evaluation of antiulcer and antisecretory potential of L. Usitatissimum fixed oil and possible mechanism of action. Inflammo pharmacol. 2010;18(3):137–45.CrossRef Kaithwas G, Majumdar DK. Evaluation of antiulcer and antisecretory potential of L. Usitatissimum fixed oil and possible mechanism of action. Inflammo pharmacol. 2010;18(3):137–45.CrossRef
10.
go back to reference Kurisawa M, Chung JE, Uyama H, Kobayashi S. Enzymatic synthesis and antioxidant properties of poly(rutin). Biomacromolecules. 2003;4(5):1394–9.CrossRefPubMed Kurisawa M, Chung JE, Uyama H, Kobayashi S. Enzymatic synthesis and antioxidant properties of poly(rutin). Biomacromolecules. 2003;4(5):1394–9.CrossRefPubMed
11.
go back to reference Yang C, Hsiu S, Yuan J. In vitro antioxidant properties of rutin. LWT - Food SciTechnol. 2008;41(6):1060–6.CrossRef Yang C, Hsiu S, Yuan J. In vitro antioxidant properties of rutin. LWT - Food SciTechnol. 2008;41(6):1060–6.CrossRef
12.
go back to reference Yang C, Hsiu S, Wen K, Lin S, Tsai S. Bioavailability and metabolic pharmacokinetics of rutin and quercetin in Rats. J Food Drug Anal. 2005;13(3):244–50. Yang C, Hsiu S, Wen K, Lin S, Tsai S. Bioavailability and metabolic pharmacokinetics of rutin and quercetin in Rats. J Food Drug Anal. 2005;13(3):244–50.
13.
go back to reference Casa CL, Villegas I, Lasta AD, Motilva V, Calero MJM. Evidence for protective and antioxidant properties of rutin, a natural flavone, against ethanol induced gastric lesions. J Ethnopharmacol. 1999;71(1–2):45–53. Casa CL, Villegas I, Lasta AD, Motilva V, Calero MJM. Evidence for protective and antioxidant properties of rutin, a natural flavone, against ethanol induced gastric lesions. J Ethnopharmacol. 1999;71(1–2):45–53.
14.
go back to reference Shukla K, Raj P, Kumar A, Kumar M, Kaithwas G. Effect of monotherapy and combination therapy of pantoprazole and aprepitant in gastric esophageal reflux disease in albino rats. Sci World J. 2014;23:183147. Shukla K, Raj P, Kumar A, Kumar M, Kaithwas G. Effect of monotherapy and combination therapy of pantoprazole and aprepitant in gastric esophageal reflux disease in albino rats. Sci World J. 2014;23:183147.
15.
go back to reference Khinchi P, Saha S, Saraf SA, Kaithwas G. Combination therapy of gamma-amino butyric acid derivative promotes proton pump inhibitors based healing of reflux esophagitis in animal model. Pharmacol Rep. 2014;66(1):165–8.CrossRefPubMed Khinchi P, Saha S, Saraf SA, Kaithwas G. Combination therapy of gamma-amino butyric acid derivative promotes proton pump inhibitors based healing of reflux esophagitis in animal model. Pharmacol Rep. 2014;66(1):165–8.CrossRefPubMed
16.
go back to reference Patel MA, Patel PK, Patel MB. Effect of ethanol extracts of Ficusbengalensis (bark) on inflammatory bowel disease. Indian J Pharmacol. 2010;42(4):214–8.CrossRefPubMedPubMedCentral Patel MA, Patel PK, Patel MB. Effect of ethanol extracts of Ficusbengalensis (bark) on inflammatory bowel disease. Indian J Pharmacol. 2010;42(4):214–8.CrossRefPubMedPubMedCentral
17.
go back to reference Ohkawa H, Ohishi N, Yagi K. Assay of lipid peroxide in animal tissue by thiobarbituric acid reaction. Anal Biochem. 1979;95(2):351–8.CrossRefPubMed Ohkawa H, Ohishi N, Yagi K. Assay of lipid peroxide in animal tissue by thiobarbituric acid reaction. Anal Biochem. 1979;95(2):351–8.CrossRefPubMed
18.
go back to reference Marklund S, Marklund G. Involvement of super oxide anion radical in the autoxidation of pyrogallol and a convenient assay of super oxide dismutase. Eur J Biochemistry. 1974;47(3):469–74.CrossRef Marklund S, Marklund G. Involvement of super oxide anion radical in the autoxidation of pyrogallol and a convenient assay of super oxide dismutase. Eur J Biochemistry. 1974;47(3):469–74.CrossRef
19.
go back to reference Ellaman GL. Tissue sulphydryl groups. Arch Biochem Biophy. 1958;82(1):70–7.CrossRef Ellaman GL. Tissue sulphydryl groups. Arch Biochem Biophy. 1958;82(1):70–7.CrossRef
20.
go back to reference Claiborne A. Catalase activity. In: Greenwald RA, editor. CRS. Handbook of Methods for Oxygen Radical Research. Boca Raton: CRC Press; 1985. p. 283–4. Claiborne A. Catalase activity. In: Greenwald RA, editor. CRS. Handbook of Methods for Oxygen Radical Research. Boca Raton: CRC Press; 1985. p. 283–4.
21.
go back to reference Dalle-Donne I, Rossi R, Giustarini D, Milzani A, Colombo R. Protein carbonyl groups as biomarkers of oxidative stress. Clin Chim Acta. 2003;329(1–2):23–38.CrossRefPubMed Dalle-Donne I, Rossi R, Giustarini D, Milzani A, Colombo R. Protein carbonyl groups as biomarkers of oxidative stress. Clin Chim Acta. 2003;329(1–2):23–38.CrossRefPubMed
22.
go back to reference Rossi, S. Australian Medicines Handbook. Adelaide: The Australian medicines handbook unit trust. 2013 ISBN 978-0-9805790-9-3. Rossi, S. Australian Medicines Handbook. Adelaide: The Australian medicines handbook unit trust. 2013 ISBN 978-0-9805790-9-3.
23.
go back to reference Sirotnak FM, Moccio DM, Dorick DM. Optimization of high-dose methotrexate with leucovorin rescue therapy in the L1210 leukemia and sarcoma 180 murine tumor models. Cancer Res. 1978;38(2):345–53.PubMed Sirotnak FM, Moccio DM, Dorick DM. Optimization of high-dose methotrexate with leucovorin rescue therapy in the L1210 leukemia and sarcoma 180 murine tumor models. Cancer Res. 1978;38(2):345–53.PubMed
24.
go back to reference Widemann BC, Balis FM, Kempf-Bielack B, Bielack S, Pratt CB, Ferrari S, Bacci G, Craft AW, Adamson PC. High dose MTX- induced nephrotoxicity in patients with osteosarcoma. Cancer. 2004;100(10):2222–32. Widemann BC, Balis FM, Kempf-Bielack B, Bielack S, Pratt CB, Ferrari S, Bacci G, Craft AW, Adamson PC. High dose MTX- induced nephrotoxicity in patients with osteosarcoma. Cancer. 2004;100(10):2222–32.
25.
go back to reference Verdia AP, Angulo F, Hardwicke FL, Nugent KL. Acute cardiac toxicity associated with high dose intravenous MTX therapy: case report and review of the literature. J Inv Cardiol. 2005;25(9):1271–6. Verdia AP, Angulo F, Hardwicke FL, Nugent KL. Acute cardiac toxicity associated with high dose intravenous MTX therapy: case report and review of the literature. J Inv Cardiol. 2005;25(9):1271–6.
26.
go back to reference Huang C, Hsu P, Hung Y, Liao Y, Liu C, Hour C, Kao M, Tsay GJ, Hung H, Liu GY. Ornithine decarboxylase prevents methotrexate-induced apoptosis by reducing intracellular reactive oxygen species production. Apoptosis. 2005;10(4):895–907. Huang C, Hsu P, Hung Y, Liao Y, Liu C, Hour C, Kao M, Tsay GJ, Hung H, Liu GY. Ornithine decarboxylase prevents methotrexate-induced apoptosis by reducing intracellular reactive oxygen species production. Apoptosis. 2005;10(4):895–907.
27.
go back to reference Dubey S, Ganeshpurkar A, Shrivastava A, Bansal D, Dubey N. Rutin exerts antiulcer effect by inhibiting the gastric proton pump. Indian J Pharmacol. 2013;45(4):415–7.CrossRefPubMedPubMedCentral Dubey S, Ganeshpurkar A, Shrivastava A, Bansal D, Dubey N. Rutin exerts antiulcer effect by inhibiting the gastric proton pump. Indian J Pharmacol. 2013;45(4):415–7.CrossRefPubMedPubMedCentral
28.
go back to reference Atashfaraz E, Farokhi F, Najafi G. Protective effect of ethyl pyruvate on epididymal sperm characteristics, oxidative stress and testosterone level in methotrexate treated mice. J Report Infertile. 2013;14(4):190–6. Atashfaraz E, Farokhi F, Najafi G. Protective effect of ethyl pyruvate on epididymal sperm characteristics, oxidative stress and testosterone level in methotrexate treated mice. J Report Infertile. 2013;14(4):190–6.
29.
go back to reference Kolli VK, Natarajan K, Isaac B, Selvakumar D, Abraham P. Mitochondrial dysfunction and respiratory chain defects in a rodent model of methotrexate-induced enteritis. Hum Exp Toxicol. 2014;33(10):1051–65.CrossRefPubMed Kolli VK, Natarajan K, Isaac B, Selvakumar D, Abraham P. Mitochondrial dysfunction and respiratory chain defects in a rodent model of methotrexate-induced enteritis. Hum Exp Toxicol. 2014;33(10):1051–65.CrossRefPubMed
30.
go back to reference De Groot H. Reactive oxygen species in tissue injury. Hepatogastroenterol. 1994;41(4):328–32. De Groot H. Reactive oxygen species in tissue injury. Hepatogastroenterol. 1994;41(4):328–32.
31.
32.
go back to reference Barlett BS, Stadtman ER. Protein oxidation in aging, disease and oxidative stress. J Biol Chem. 1997;272(33):20313–6.CrossRef Barlett BS, Stadtman ER. Protein oxidation in aging, disease and oxidative stress. J Biol Chem. 1997;272(33):20313–6.CrossRef
33.
go back to reference Leszczyńska BA, Pfaff E. Effect of depletion of cellular glutathione on methotrexate influx, efflux and retention in hepatocytes. Biochem Pharmacol. 1985;34(10):1627–34.CrossRef Leszczyńska BA, Pfaff E. Effect of depletion of cellular glutathione on methotrexate influx, efflux and retention in hepatocytes. Biochem Pharmacol. 1985;34(10):1627–34.CrossRef
34.
go back to reference Kaithwas G, Singh P, Bhatia D. Evaluation of in vitro and in vivo antioxidant potential of polysaccharides from Aloe vera (Aloe barbadensis Miller) gel. Drug Chem Toxicol. 2014;37(2):135–43.CrossRefPubMed Kaithwas G, Singh P, Bhatia D. Evaluation of in vitro and in vivo antioxidant potential of polysaccharides from Aloe vera (Aloe barbadensis Miller) gel. Drug Chem Toxicol. 2014;37(2):135–43.CrossRefPubMed
35.
go back to reference Kaithwas G, Dubey K, Pillai KK. Effect of aloe vera (Aloe barbadensis Miller) gel on doxorubicin induced myocardial oxidative stress and calcium overload in albino rats. Indian J Exp Biol. 2011;49(4):260–8.PubMed Kaithwas G, Dubey K, Pillai KK. Effect of aloe vera (Aloe barbadensis Miller) gel on doxorubicin induced myocardial oxidative stress and calcium overload in albino rats. Indian J Exp Biol. 2011;49(4):260–8.PubMed
36.
go back to reference Rivarola A, Friedman M, Lawrence Jr W. Methotrexate and the immune response. Transplantation. 1967;5(4):1223–30.CrossRefPubMed Rivarola A, Friedman M, Lawrence Jr W. Methotrexate and the immune response. Transplantation. 1967;5(4):1223–30.CrossRefPubMed
37.
go back to reference Sokol CL, Barton GM, Farr AG, Medzhitov R. A mechanism for the initiation of allergen-induced T helper type 2 responses. Nat Immunol. 2008;9(3):310–8.CrossRefPubMedPubMedCentral Sokol CL, Barton GM, Farr AG, Medzhitov R. A mechanism for the initiation of allergen-induced T helper type 2 responses. Nat Immunol. 2008;9(3):310–8.CrossRefPubMedPubMedCentral
38.
go back to reference Cantrell DA, Smith KA. The interleukin-2 T-cell system: a new cell growth model. Science. 1984;224(4655):1312–6.CrossRefPubMed Cantrell DA, Smith KA. The interleukin-2 T-cell system: a new cell growth model. Science. 1984;224(4655):1312–6.CrossRefPubMed
39.
40.
go back to reference Afanasev IB, Dorozhko AI, Brodskii AV, Kostyuk VA, Potapovitch AI. Chelating and free radical scavenging mechanisms of inhibitory action of rutin and quercetin in lipid peroxidation. Biochem Pharmacol. 1989;38(11):1763–9.CrossRef Afanasev IB, Dorozhko AI, Brodskii AV, Kostyuk VA, Potapovitch AI. Chelating and free radical scavenging mechanisms of inhibitory action of rutin and quercetin in lipid peroxidation. Biochem Pharmacol. 1989;38(11):1763–9.CrossRef
41.
go back to reference Argentieri DC, Ritchie DM, Ferro MP, Kirchner T, Wachter MP, Anderson DW, Rosenthale ME, Capetola RJ. Tepoxalin: a dual cyclooxygenase/5-lipoxygenase inhibitor of arachidonic acid metabolism with potent anti-inflammatory activity and a favorable gastrointestinal profile. J Pet. 1994;271(3):1399–408. Argentieri DC, Ritchie DM, Ferro MP, Kirchner T, Wachter MP, Anderson DW, Rosenthale ME, Capetola RJ. Tepoxalin: a dual cyclooxygenase/5-lipoxygenase inhibitor of arachidonic acid metabolism with potent anti-inflammatory activity and a favorable gastrointestinal profile. J Pet. 1994;271(3):1399–408.
42.
go back to reference Li S, Wang C, Peng X, Wu X. Effects of aqueous extracts and essential oil from cinnamomum cassia on rat colonic mucosal morphology and bacteroidales. J Nutr. 2003;133(10):32555–615. Li S, Wang C, Peng X, Wu X. Effects of aqueous extracts and essential oil from cinnamomum cassia on rat colonic mucosal morphology and bacteroidales. J Nutr. 2003;133(10):32555–615.
43.
go back to reference Widemann BC, Adamson PC. Understanding and managing methotrexate nephrotoxicity. Oncologist. 2006;11(6):694–703.CrossRefPubMed Widemann BC, Adamson PC. Understanding and managing methotrexate nephrotoxicity. Oncologist. 2006;11(6):694–703.CrossRefPubMed
Metadata
Title
Rutin attenuates intestinal toxicity induced by Methotrexate linked with anti-oxidative and anti-inflammatory effects
Publication date
01-12-2016
Published in
BMC Complementary Medicine and Therapies / Issue 1/2016
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-016-1069-1

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