Rutin Attenuates Methotrexate-Induced Hepatic Oxidative Stress in Rats

Year 2021, , 291 - 297, 30.12.2021

Sueda Türk , Filiz Kazak , Pinar Peker , Mehmet Ali Kısaçam

https://doi.org/10.17094/ataunivbd.982438

Cited By: 3

Abstract

This study aimed to assess the antioxidant effects of rutin on methotrexate-induced hepatic oxidative stress. Wistar Albino rats (n=24) were separated into 4 groups: control group (C); methotrexate (M, 20 mg/kg, single dose) group; rutin (R, 50 mg/kg/day, for fifteen days) group; and methotrexate + rutin [MR, methotrexate (20 mg/kg, single dose) + rutin (50 mg/kg/day, for fifteen days)] group. Rats were sacrificed on the sixteenth day and liver tissues were removed. The liver glucose-6-phosphate dehydrogenase (G6PD), glutathione peroxidase (GPx), malondialdehyde (MDA), nicotinamide adenine dinucleotide phosphate (NADPH), total glutathione (tGSH), and vitamin C were determined colorimetrically. Malondialdehyde increased and vitamin C decreased in the M group compared to the others (P<0.001). Total glutathione reduced in both M and MR groups compared to C group (P<0.05). An important decrease in M group NADPH and GPx compared to C group (P<0.001) was observed. Nicotinamide adenine dinucleotide phosphate of R group were determined to be higher than M group (P<0.001). In this study, it might demonstrate that methotrexate caused oxidative stress in the liver and rutin had antioxidant effects on methotrexate-induced hepatic oxidative stress. Consequently, it can be suggested that rutin may be useful in attenuating the side effects of methotrexate on the liver.

Keywords

Liver, Methotrexate, Nicotinamide adenine dinucleotide phosphate, Rutin, Vitamin C

Supporting Institution

Hatay Mustafa Kemal University Coordinatorship of Scientific Research Projects

Project Number

19.YL.067

Rutin Ratlarda Metotreksata Bağlı Hepatik Oksidatif Stresi Hafifletir

Abstract

Bu çalışma, rutinin ratlarda metotreksata bağlı hepatik oksidatif stres üzerindeki potansiyel antioksidan etkilerini değerlendirmeyi amaçlamıştır. Wistar Albino ratlar (n=24) dört gruba ayrıldı: Kontrol grubu (K); metotreksat (M, 20 mg/kg, tek doz) grubu; rutin (R, 50 mg/kg/gün, 15 gün) grubu; ve metotreksat + rutin [MR, metotreksat (20 mg/kg, tek doz) + rutin (50 mg/kg/gün, 15 gün)] grubu. Ratlar onaltıncı gün sakrifiye edildi. Karaciğer dokuları alındı. Malondialdehit (MDA), vitamin C, total glutatyon (tGSH), nikotinamid adenin dinükleotid fosfat (NADPH) seviyeleri ve glutatyon peroksidaz (GPx) ve glukoz-6-fosfat dehidrojenaz (G6PD) aktiviteleri kolorimetrik olarak belirlendi. M grubunda diğer gruplara göre MDA düzeyleri artmış ve C vitamini düzeyleri azalmıştır (P<0.001). tGSH düzeyleri, hem M hem de MR gruplarında K grubuna göre azaldı (P<0.05). M grubu NADPH düzeylerinde ve GPx aktivitesinde K grubuna kıyasla önemli azalma (P<0.001) gözlendi. R grubunun NADPH düzeyleri M grubuna kıyasla daha yüksek belirlendi (P<0.001). Bu çalışma, metotreksatın karaciğerde oksidatif strese neden olduğunu ve rutinin de metotreksata bağlı hepatik oksidatif stres üzerine antioksidan etkisinin olduğunu göstermektedir. Sonuç olarak rutinin metotreksatın karaciğer üzerindeki yan etkilerini hafifletmede faydalı olabileceği düşünülmektedir.

Keywords

Karaciğer, Metotreksat, Nikotinamid adenin dinükleotid fosfat, Rutin, Vitamin C

Project Number

19.YL.067

References

• 1. Adikwu E., Deo O., 2013. Hepatoprotective effect of vitamin c (ascorbic acid). J Pharm Pharmacol, 4, 84-92.
• 2. Yuan L., Kaplowitz N., 2013. Mechanisms of drug-induced liver injury. Clin Liver Dis, 17, 50.
• 3. Mahmoud AM., Hozayen WG., Ramadan SM., 2017. Berberine ameliorates methotrexate-induced liver injury by activating Nrf2/HO-1 pathway and PPARγ, and suppressing oxidative stress and apoptosis in rats. Biomed Pharmacother, 94, 280-291.
• 4. Olayinka ET., Ore A., Adeyemo OA., Ola OS., 2016. Ameliorative effect of gallic acid on methotrexate-induced hepatotoxicity and nephrotoxicity in rat. J Xenobiot, 6, 6092.
• 5. King PD., Perry MC., 2001. Hepatotoxicity of chemotherapy. Oncologist, 6, 162-176.
• 6. Holmboe L., Andersen AM., Morkrid L., Slordal L., Hall KS., 2012. High dose methotrexate chemotherapy: pharmacokinetics, folate and toxicity in osteosarcoma patients. Br J Clin Pharmacol, 73, 106-114.
• 7. Mulder RL., Bresters D., Van den HM., Koot BG., Castellino SM., Loke YKK., Post PN., Postma A., Szonyi LP., Levitt GA., Bardi E., Skinner R., van Dalen EC., 2019. Hepatic late adverse effects after antineoplastic treatment for childhood cancer. Cochrane Database Syst Rev, 4, CD008205.
• 8. Ali N., Rashid S., Nafees S., Hasan SK., Shahid A., Majed F., Sultana S., 2017. Protective effect of Chlorogenic acid against methotrexate induced oxidative stress, inflammation and apoptosis in rat liver: An experimental approach. Chem Biol Interact, 272, 80-91.
• 9. Mehrzadi S., Fatemi I., Esmaeilizadeh M., Ghaznavi H., Kalantar H., Goudarzi M., 2018. Hepatoprotective effect of berberine against methotrexate induced liver toxicity in rats. Biomed Pharmacother, 97, 233-239.
• 10. Pinar N., Kaplan M., Özgür T., Özcan O., 2018. Ameliorating effects of tempol on methotrexate-induced liver injury in rats. Biomed Pharmacother, 102, 758-764.
• 11. Hoshyar R., Sebzari A., Balforoush M., Valavi M., Hosseini M., 2019. The impact of Crocus sativus stigma against methotrexate-induced liver toxicity in rats. J Complement Integr Med, 17,1.
• 12. Malayeri A., Badparva R., Mombeini MA., Khorsandi L., Goudarzi M., 2020. Naringenin: a potential natural remedy against methotrexate-induced hepatotoxicity in rats. Drug Chem Toxicol, 28, 1-8.
• 13. Cetin A., Kaynar L., Kocyigit I., Hacioglu SK., Saraymen R., Ozturk A., Sari I., Sagdic O., 2008. Role of grape seed extract on methotrexate induced oxidative stress in rat liver. J Trace Elem Med Biol, 36, 861-872.
• 14. Savran M., Cicek E., Doguc DK., Asci H., Yesilot S., Candan IA., Dagdeviren B., Cankara FN., Oncu M., Uğuz AC., Ozer MK., 2017. Vitamin C attenuates methotrexate-induced oxidative stress in kidney and liver of rats. Physiol Int, 1-11.
• 15. Kalantari H., Asadmasjedi N., Abyaz MR., Mahdavinia M., Mohammadtaghvaei N., 2019. Protective effect of inulin on methotrexate-induced liver toxicity in mice. Biomed Pharmacother, 110, 943-950.
• 16. Shenbagam M., Nalini N., 2011. Dose response effect of rutin a dietary antioxidant on alcohol-induced prooxidant and antioxidant imbalance - a histopathologic study. Fundam Clin Pharmacol, 25, 493-502.
• 17. Nafees S., Rashid S., Ali N., Hasan SK., Sultana S., 2015. Rutin ameliorates cyclophosphamide induced oxidative stress and inflammation in Wistar rats: role of NFκB/MAPK pathway. Chem Biol Interact, 231, 98-107.
• 18. Singh S., Singh DK., Meena A., Dubey V., Masood N., Luqman S., 2019. Rutin protects t‑butyl hydroperoxide-induced oxidative impairment via modulating the Nrf2 and iNOS activity. Phytomedicine, 55, 92-104.
• 19. Ganeshpurkar A., Saluja AK., 2017. The pharmacological potential of rutin. Saudi Pharm J, 25, 149-164.
• 20. Aziza SA., Azab Mel-S., El-Shall SK., 2014. Ameliorating role of rutin on oxidative stress induced by iron overload in hepatic tissue of rats. Pak J Biol Sci, 17, 964-977.
• 21. Caglayan C., Kandemir FM., Darendelioğlu E., Yıldırım S., Kucukler S., Dortbudak MB., 2019. Rutin ameliorates mercuric chloride-induced hepatotoxicity in rats via interfering with oxidative stress, inflammation and apoptosis. J Trace Elem Med Biol, 56, 60-68.
• 22. Abarikwu SO., Njoku RC., Lawrence CJ., Charles IA., Ikewuchi JC., 2017. Rutin ameliorates oxidative stress and preserves hepatic and renal functions following exposure to cadmium and ethanol. Pharm Biol, 55, 216-219.
• 23. Lowry OH., Rosebrough NJ., Farr AL., Randall RJ., 1951. Protein measurement with pholin phenol reagent. J Biol Chem, 193, 265-275.
• 24. Ohkawa H., Ohishi N., Yagi K., 1979. Assay for lipit peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem, 95, 351-358.
• 25. Haag W., 1985. Zur methodik und praktischen Bedeutung der Vitamin C - Best immung be im Rind in Vergangenheit und Gegenwart. Inaugural Dissertation. Justus Liebig Universitaet, Giessen.
• 26. Beutler E., 1975. Red cell metabolism. In: A Manual of Biochemical Methods. Grune Strottan, New York, 67-69.
• 27. Beutler E., 1971. Red cell metabolism manual of biochemical methods. Academic Press. London, 68-70.
• 28. Moghadam AR., Tutunchi S., Namvaran AAA., Yazdi M., Bonyadi F., Mohajeri D., Mazani M., Marzban H., tos MJ., Ghavami S., 2015. Pre-administration of turmeric prevents methotrexate-induced liver toxicity and oxidative stress. BMC Complement Altern Med, 15, 246.
• 29. Erdogan E., Ilgaz Y., Gurgor PN., Oztas Y., Topal T., Oztas E., 2015. Rutin ameliorates methotrexate induced hepatic injury in rats. Acta Cir Bras, 30, 778-784.
• 30. Traber MG., Buettner GR., Bruno RS., 2019. The relationship between vitamin C status, the gut-liver axis, and metabolic syndrome. Redox Biol, 21, 101091.
• 31. Yamamoto Y., Yamashita S., Fujisawa A., Kokura S., Yoshikawa T., 1998. Oxidative stress in patients with hepatitis, cirrhosis, and hepatoma evaluated by plasma antioxidants. Biochem Biophys Res Commun, 247, 166-170.
• 32. Negre-Salvayre A., Affany A., Hariton C., Salvayre R., 1991. Additional antilipoperoxidant activities of alpha-tocopherol and ascorbic acid on membrane-like systems are potentiated by rutin. Pharmacology, 42, 262-272.
• 33. Corpas FJ., Barroso JB., 2014. NADPH-generating dehydrogenases: their role in the mechanism of protection against nitro-oxidative stress induced by adverse environmental conditions. Front Environ Sci, 5, 1-5.
• 34. Caetano NN., Campello AP., Carnieri EG., Kluppel ML., Oliveira MB., 1997. Effect of methotrexate (MTX) on NAD(P)+ dehydrogenases of HeLa cells: malic enzyme, 2-oxoglutarate and isocitrate dehydrogenases. Cell Biochem Funct, 15, 259-264.