Research Article
Ratlarda Methotrexate Kaynaklı Karaciğer Toksisitesine Karşı Silymarin ve Naringin’in Yararlı Etkileri
Abstract
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.
References
- 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. L-Carnitine 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 methotrexate-induced 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 gentamicin-induced 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 prooxidant-antioxidant 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.
Year 2017,
Volume: 12 Issue: 2, 167 - 177, 30.10.2017
Abstract
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 MTX-induced liver toxicity.
References
- 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. L-Carnitine 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 methotrexate-induced 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 gentamicin-induced 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 prooxidant-antioxidant 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.
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Details
| Journal Section | Araştırma Makaleleri |
|---|---|
| Authors | |
| Publication Date | October 30, 2017 |
| Published in Issue | Year 2017 Volume: 12 Issue: 2 |