Ratlarda Methotrexate Kaynaklı Karaciğer Toksisitesine Karşı Silymarin ve Naringin’in Yararlı Etkileri

KANDEMİR, Fatih Mehmet; caglayan, cuneyt; KÜÇÜKLER, Sefa

Ratlarda Methotrexate Kaynaklı Karaciğer Toksisitesine Karşı Silymarin ve Naringin’in Yararlı Etkileri

Fatih Mehmet KANDEMİR, (Atatürk Üniversitesi, Veteriner Fakültesi, Biyokimya Ana Bilim Dalı, Erzurum, Türkiye)

Sefa KÜÇÜKLER, (Atatürk Üniversitesi, Veteriner Fakültesi, Biyokimya Ana Bilim Dalı, Erzurum, Türkiye)

Cüneyt ÇAĞLAYAN (Bingöl Üniversitesi, Veteriner Fakültesi, Biyokimya Anabilim Dalı, Bingöl, tÜRKİYE)

Atatürk Üniversitesi Veteriner Bilimleri Dergisi

14 2

Yıl: 2017 Cilt: 12 Sayı: 2 Sayfa Aralığı: 167 - 177 Metin Dili: Türkçe İndeks Tarihi: 29-07-2022

Ratlarda Methotrexate Kaynaklı Karaciğer Toksisitesine Karşı Silymarin ve Naringin’in Yararlı Etkileri

Öz:

Karaciğer toksisitesi, kemoterapötik bir ilaç olan methotrexate (MTX) terapisinin komplikasyonlarının sonucunda oluşur. Silymarin (SLY) ve naringin (NRG) antioksidant, anti-inflamatuvar ve anti-hiperlipidemik gibi birçok farmakolojik özelliklere sahip biyoflavonoidlerdir. Bu çalışma ratlarda MTX kaynaklı karaciğer toksisitesi üzerine SLY ve NRG'in yararlı etkilerinin araştırılması için yapılmıştır. Ratlara (20 mg/kg) tek doz periton içi MTX verildikten sonra 7 gün boyunca (25 ve 50 mg/kg) SLY ve (50 ve 100 mg/kg) NRG tedavisi oral yoldan gavaj ile verilmiştir. MTX; süperoksit dismutaz (SOD), katalaz (KAT) ve glutatyon peroksidaz (GPx) gibi antioksidan enzim aktivitelerini ve glutatyon (GSH) seviyesini azaltıp, lipid peroksidasyonunu artırarak oksidatif hasarı tetiklediği belirlenmiştir. Üstelik MTX toksikasyonu aspartat amino transferaz (AST), alanin amino transferaz (ALT) ve alkalin fosfataz (ALP) gibi karaciğer enzim aktivitelerini artırmıştır. Diğer taraftan SLY ve NRG tedavisi GSH seviyesini ve antioksidan enzim aktivitelerini artırıp, lipid peroksidasyonunu inhibe etmiştir. Ayrıca SLY ve NRG tedavisi, MTX grubu ile karşılaştırıldığında karaciğer enzim aktivitelerini azalttığı belirlenmiştir. Bu çalışmada SLY ve NRG, MTX'ın neden olduğu karaciğer toksisitesine karşı yararlı etki sağlamıştır

Anahtar Kelime:

Konular: Biyokimya ve Moleküler Biyoloji

Beneficial Effects of Silymarin and Naringin Against Methotrexate-induced Hepatotoxicity in Rats

Öz:

Hepatotoxicity occurs as a result of the complications of methotrexate (MTX) therapy, which is a chemotherapeutic drug. Silymarin (SLY) and naringin (NRG) are bioflavonoids possess multiple pharmacological properties such as antioxidant, anti-inflammatory and anti-hyperlipidemic activity. This study was undertaken to investigate the beneficial effects of SLY and NRG on MTX-induced liver toxicity in rats. After a single dose of intraperitoneal MTX (20 mg/kg) was given to rats, SLY (25 and 50 mg/kg) and NRG (50 and 100 mg/kg) treatment was given by oral gavage for 7 days. It has been determined that MTX induces oxidative stress by increasing lipid peroxidation, decreased in glutathione (GSH) level and antioxidant enzyme activities such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx). Moreover, MTX toxication has increased liver enzyme activities such as aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP). On the other hand, SLY and NRG treatment increased the level of glutathione (GSH) and antioxidant enzyme activities and inhibited lipid peroxidation. It has also been determined that SLY and NRG treatment reduces liver enzyme activities when compared to the MTX group. In this study, SLY and NRG provided a beneficial effect against MTXinduced liver toxicity

Anahtar Kelime:

Konular: Biyokimya ve Moleküler Biyoloji

Belge Türü: Makale Makale Türü: Araştırma Makalesi Erişim Türü: Erişime Açık

1. Khan ZA., Tripathi R., Mishra B., 2012. Methotrexate: a detailed review on drug delivery and clinical aspects. Expert Opin Drug Deliv, 9, 151-169.
2. Ali N., Rashid S., Nafees S., Hasan SK., Sultana S., 2014. Beneficial effects of Chrysin against Methotrexate-induced hepatotoxicity via attenuation of oxidative stress and apoptosis. Mol Cell Biochem, 385, 215-223.
3. Mukherjee S., Ghosh S., Choudhury S., Adhikary A., Manna K., Dey S., Chattopadhyay S., 2013. Pomegranate reverses methotrexate-induced oxidative stress and apoptosis in hepatocytes by modulating Nrf2-NF-κB pathways. J Nutr Biochem, 24, 2040-2050.
4. Şener G., Ekşioğlu-Demiralp, E., Cetiner M., Ercan F., Şirvancı S., Gedik N., Yeğen BC., 2006. LCarnitine ameliorates methotrexate-induced oxidative organ injury and inhibits leukocyte death. Cell Biol Toxicol, 22, 47-60.
5. Uraz S., Tahan V., Aygun C., Eren F., Unluguzel G., Yuksel M., Hulagu S., 2008. Role of ursodeoxycholic acid in prevention of methotrexate-induced liver toxicity. Dig Dis Sci, 53, 1071-1077.
6. Olayinka ET., Ore A., Adeyemo OA., Ola OS., 2016. Ameliorative effect of gallic acid on methotrexate-induced hepatotoxicity and nephrotoxicity in rat. J Xenobiotics, 6(1).
7. Vardi N., Parlakpinar H., Ates B., 2012. Beneficial effects of chlorogenic acid on methotrexateinduced cerebellar Purkinje cell damage in rats. J Chem Neuroanat, 43, 43-47.
8. Ueki M., Ueno M., Morishita J., Maekawa N., 2013. Curcumin ameliorates cisplatin-induced nephrotoxicity by inhibiting renal inflammation in mice. J Biosci Bioeng, 115, 547-551.
9. Kiruthiga PV., Karutha PS., Pandima DK., 2014. Silymarin prevents the toxicity induced by benzo (a) pyrene in human erythrocytes by preserving its membrane integrity: An in vitro study. Environ. Toxicol, 29, 165-175.
10. Köksal E., Gülçin İ., Beyza S., Sarikaya Ö., Bursal E., 2009. In vitro antioxidant activity of silymarin. J Enzyme Inhib Med Chem, 24, 395-405.
11. Al-Rasheed N., Faddah L., Al-Rasheed N., Bassiouni YA., Hasan IH., Mahmoud AM., Yacoub HI., 2016. Protective effects of silymarin, alone or in combination with chlorogenic acid and/or melatonin, against carbon tetrachloride-induced hepatotoxicity. Pharmacogn Mag, 12(Suppl 3), S337.
12. Pari L., Amudha K., 2011. Hepatoprotective role of naringin on nickel-induced toxicity in male Wistar rats. Eur J Pharmacol, 650, 364-370.
13. Gürsul C., Ekinci Akdemir FN., Akkoyun T., Can İ., Gül M., Gülçin İ., 2016. Protective effect of Naringin on experimental hindlimb ischemia/reperfusion injury in rats. J Enzyme Inhib Med Chem, 31, 56-61.
14. Erboga M., Aktas C., Erboga ZF., Donmez YB., Gurel A., 2015. Quercetin ameliorates methotrexate-induced renal damage, apoptosis and oxidative stress in rats. Renal Failure, 37, 1492-1497.
15. Ghaznavi H., Mehrzadi S., Dormanesh B., Tabatabaei SM., Vahedi H., Hosseinzadeh A., Pazoki-Toroudi H., Rashidian A., 2016. Comparison of the protective effects of melatonin and silymarin against gentamicininduced nephrotoxicity in rats. J Evid Based Complementary Altern Med, 21, NP49-55.
16. Sahu BD., Tatireddy S., Koneru M., Borkar RM., Kumar JM., Kuncha M., Sistla R. 2014. Naringin ameliorates gentamicin-induced nephrotoxicity and associated mitochondrial dysfunction, apoptosis and inflammation in rats: possible mechanism of nephroprotection. Toxicol Appl Pharmacol, 277, 8-20.
17. Placer ZA., Cushmanni LL., Johnson BC., 1966. Estimation of products of lipid peroxidation (as malondialdehyde) in biochemical systems. Anal. Biochem, 16, 359-364.
18. Aebi H., 1983. Catalase. In: Bergmeyer HU, ed. Methods in Enzymatic Analysis. New York: Academic Press, 276-286.
19. Lowry OH., Rosebrough NJ., Farr AL., Randall RJ. 1951. Protein measurement with the folin phenol reagent. J. Biol. Chem, 193, 265-275.
20. Sun Y., Larry WO., Ying LA., 1988. Simple method for clinical assay of superoxide dismutase. Clinical Chemistry, 34, 497-500.
21. Sedlak J., Lindsay RHC., 1965. Estimation of total protein bound and nonprotein sulfhydryl groups in tissue with Ellmann’s reagent. Anal Biochem, 25, 192-205.
22. Lawrence RA., Burk RF., 1976. Glutathione peroxidase activity in selenium-deficient rat liver. Biochem Biophys Res Commun, 71, 952-958.
23. Sathiavelu J., Senapathy GJ., Devaraj R., 2009. Hepatoprotective effect of chrysin on prooxidantantioxidant status during ethanol-induced toxicity in female albino rats. J Pharm Pharmacol, 61, 809-817.
24. Prey S., Paul C., 2008. Effect of folic or folinic acid supplementation on methotrexate associated safety and efficacy in inflammatory disease: a systematic review. Br. J. Dermatol, 160, 622-628.
25. Hadi NR., Al-Amran FG., Swadi A., 2012. Metformin ameliorates methotrexate-induced hepatotoxicity. J Pharmacol Pharmacother, 3, 248-253.
26. Hafez HM., Ibrahim MA., Ibrahim SA., Amin EF., Goma W., Abdelrahman AM., 2015. Potential protective effect of etanercept and aminoguanidine in methotrexate-induced hepatotoxicity and nephrotoxicity in rats. Eur J Pharmacol, 768, 1-12.
27. Dalaklioglu S., Genc GE., Aksoy NH., Akcit F., Gumuslu S., 2013. Resveratrol ameliorates methotrexate-induced hepatotoxicity in rats via inhibition of lipid peroxidation. Hum Exp Toxicol, 32, 662-671.
28. Kelleni MT., Ibrahim SA., Abdelrahman AM., 2016. Effect of captopril and telmisartan on methotrexate-induced hepatotoxicity in rats: impact of oxidative stress, inflammation and apoptosis. Toxicol Mech Methods, 26, 371-377.
29. Hamza RZ., Al-Harbi MS., 2015. Amelioration of paracetamol hepatotoxicity and oxidative stress on mice liver with silymarin and Nigella sativa extract supplements. Asian Pac J Trop Biomed, 5, 521-531.
30. Dong D., Xu L., Yin L., Qi Y., Peng J., 2015. Naringin prevents carbon tetrachloride-induced acute liver injury in mice. J Funct Food, 12, 179-191.
31. Çakır T., Özkan E., Dulundu E., Topaloğlu Ü., Şehirli AÖ., Ercan F., Şener G., 2011. Caffeic acid phenethyl ester (CAPE) prevents methotrexate‐ induced hepatorenal oxidative injury in rats. J Pharm Pharmacol, 63, 1566-1571.
32. Abdel-Raheem IT., Khedr NF., 2014. Renoprotective effects of montelukast, a cysteinyl leukotriene receptor antagonist, against methotrexate-induced kidney damage in rats. Naunyn Schmiedebergs Arch Pharmacol, 387, 341-353.
33. Nagi MN., Almakki HA., 2009. Thymoquinone supplementation induces quinone reductase and glutathione transferase in mice liver: possible role in protection against chemical carcinogenesis and toxicity. Phytother Res, 23, 1295-1298.
34. Ince S., Keles H., Erdogan M., Hazman O., Kucukkurt I., 2012. Protective effect of boric acid against carbon tetrachloride–induced hepatotoxicity in mice. Drug Chem Toxicol, 35, 285-292.
35. Sukhotnik I., Nativ O., Roitburt A., 2013. Methotrexate induces germ cell apoptosis and impairs spermatogenesis in a rat. Pediatr Surg Int, 29, 179-184.
36. Das SK., Vasudevan DM., 2006. Protective effects of silymarin, a milk thistle (Silybium marianum) derivative on ethanolinduced oxidative stress in liver. Indian J Biochem Biophys, 43, 306-311.
37. Pari L., Amudha K., 2011. Hepatoprotective role of naringin on nickel-induced toxicity in male Wistar rats. Eur J Pharmacol, 650, 364-370.

APA	KANDEMİR F, KÜÇÜKLER S, caglayan c (2017). Ratlarda Methotrexate Kaynaklı Karaciğer Toksisitesine Karşı Silymarin ve Naringin’in Yararlı Etkileri. , 167 - 177.
Chicago	KANDEMİR Fatih Mehmet,KÜÇÜKLER Sefa,caglayan cuneyt Ratlarda Methotrexate Kaynaklı Karaciğer Toksisitesine Karşı Silymarin ve Naringin’in Yararlı Etkileri. (2017): 167 - 177.
MLA	KANDEMİR Fatih Mehmet,KÜÇÜKLER Sefa,caglayan cuneyt Ratlarda Methotrexate Kaynaklı Karaciğer Toksisitesine Karşı Silymarin ve Naringin’in Yararlı Etkileri. , 2017, ss.167 - 177.
AMA	KANDEMİR F,KÜÇÜKLER S,caglayan c Ratlarda Methotrexate Kaynaklı Karaciğer Toksisitesine Karşı Silymarin ve Naringin’in Yararlı Etkileri. . 2017; 167 - 177.
Vancouver	KANDEMİR F,KÜÇÜKLER S,caglayan c Ratlarda Methotrexate Kaynaklı Karaciğer Toksisitesine Karşı Silymarin ve Naringin’in Yararlı Etkileri. . 2017; 167 - 177.
IEEE	KANDEMİR F,KÜÇÜKLER S,caglayan c "Ratlarda Methotrexate Kaynaklı Karaciğer Toksisitesine Karşı Silymarin ve Naringin’in Yararlı Etkileri." , ss.167 - 177, 2017.
ISNAD	KANDEMİR, Fatih Mehmet vd. "Ratlarda Methotrexate Kaynaklı Karaciğer Toksisitesine Karşı Silymarin ve Naringin’in Yararlı Etkileri". (2017), 167-177.

APA	KANDEMİR F, KÜÇÜKLER S, caglayan c (2017). Ratlarda Methotrexate Kaynaklı Karaciğer Toksisitesine Karşı Silymarin ve Naringin’in Yararlı Etkileri. Atatürk Üniversitesi Veteriner Bilimleri Dergisi, 12(2), 167 - 177.
Chicago	KANDEMİR Fatih Mehmet,KÜÇÜKLER Sefa,caglayan cuneyt Ratlarda Methotrexate Kaynaklı Karaciğer Toksisitesine Karşı Silymarin ve Naringin’in Yararlı Etkileri. Atatürk Üniversitesi Veteriner Bilimleri Dergisi 12, no.2 (2017): 167 - 177.
MLA	KANDEMİR Fatih Mehmet,KÜÇÜKLER Sefa,caglayan cuneyt Ratlarda Methotrexate Kaynaklı Karaciğer Toksisitesine Karşı Silymarin ve Naringin’in Yararlı Etkileri. Atatürk Üniversitesi Veteriner Bilimleri Dergisi, vol.12, no.2, 2017, ss.167 - 177.
AMA	KANDEMİR F,KÜÇÜKLER S,caglayan c Ratlarda Methotrexate Kaynaklı Karaciğer Toksisitesine Karşı Silymarin ve Naringin’in Yararlı Etkileri. Atatürk Üniversitesi Veteriner Bilimleri Dergisi. 2017; 12(2): 167 - 177.
Vancouver	KANDEMİR F,KÜÇÜKLER S,caglayan c Ratlarda Methotrexate Kaynaklı Karaciğer Toksisitesine Karşı Silymarin ve Naringin’in Yararlı Etkileri. Atatürk Üniversitesi Veteriner Bilimleri Dergisi. 2017; 12(2): 167 - 177.
IEEE	KANDEMİR F,KÜÇÜKLER S,caglayan c "Ratlarda Methotrexate Kaynaklı Karaciğer Toksisitesine Karşı Silymarin ve Naringin’in Yararlı Etkileri." Atatürk Üniversitesi Veteriner Bilimleri Dergisi, 12, ss.167 - 177, 2017.
ISNAD	KANDEMİR, Fatih Mehmet vd. "Ratlarda Methotrexate Kaynaklı Karaciğer Toksisitesine Karşı Silymarin ve Naringin’in Yararlı Etkileri". Atatürk Üniversitesi Veteriner Bilimleri Dergisi 12/2 (2017), 167-177.