Silimarin’in Paklitaksel Kaynaklı Nefrotoksisiteye Karşı Koruyucu Etkileri

Kanser tedavisinde kullanılan ilaçların etkileri yalnızca kanser hücrelerine özgü olmayıp sağlıklı hücreleri de olumsuz etkilemektedir. Bu çalışmada antikanser bir ilaç olan paklitaksel’in (PAX) böbrek dokusundaki olası zararlı etkilerine karşı antioksidan etkileriyle öne çıkan silimarin’in (SLY) olası koruyucu etkilerinin ortaya konulması amaçlandı. Toplam 28 adet Sprague-Dawley cinsi dişi sıçandan rastgele bir seçimle: Kontrol, PAX, SLY ve PAX + SLY olmak üzere dört grup (n=7) oluşturuldu. PAX grubuna 2 mg/kg intraperitoneal yolla PAX, SLY grubuna oral gavaj sonda ile 100 mg/kg SLY, PAX + SLY grubuna ise önceki gruplarla aynı doz ve yolla PAX ve SLY uygulandı. Deneysel işlemlerin sonunda hayvanlardan alınan kan ve böbrek dokularında yapılan biyokimyasal analizlerde PAX’ın, böbrek dokusunda oksidatif stresi, serumda ise kreatinin (Cr) ve kan üre azotu (blood urea nitrogen, BUN) seviyelerini artırdığı tespit edildi. Böbrek dokusunda yapılan histopatolojik incelemelerde PAX’ın renal korpüskül atrofisi, fırçamsı kenarda hasar, vakuolar dejenerasyon ve deskuamasyon gibi patolojik değişikliklere yol açtığı gözlendi. Antienflamatuar, antiapoptotik ve antioksidan etkilere sahip bir farmakolojik ajan olan SLY uygulanması ise, PAX kullanımı sonucu meydana bu gelen patolojik değişiklikleri büyük oranda engelledi. Mevcut çalışmada elde edilen sonuçlar PAX ile yapılacak tedavilerde böbrek dokusunda şekillenecek zararlı etkilere karşı koruyucu olarak SLY’nin kullanılabileceğini gösterdi.

Silymarin Protects Kidneys from Paclitaxel-Induced Nephrotoxicity

The effects of drugs used in cancer treatment are not only specific to cancer cells but also negatively affect healthy cells. This study, it was aimed to investigate the protective effects of silymarin (SLY), which stands out with its antioxidant effects, against the possible harmful effects of paclitaxel (PAX), an anticancer drug, on kidney tissue. A total of 28 Sprague-Dawley female rats were randomly selected into four groups (n=7): Control, PAX, SLY, and PAX + SLY. PAX was administered 2 mg/kg to the PAX group by intraperitoneally (i.p.); SLY was administered 100 mg/kg to the SLY group by oral gavage. Also, The PAX + SLY group was administered the same dose and route of PAX and SLY as the previous groups. In the biochemical analyzes performed in blood and kidney tissues taken from animals at the end of the experimental procedures, it was determined that PAX increased oxidative stress in kidney tissue and creatinine (Cr) and blood urea nitrogen (BUN) levels in serum. In the histopathological examinations of the kidney tissue, it was observed that PAX caused pathological changes such as renal corpuscle atrophy, damage to the brush border, vacuolar degeneration, and desquamation. The administration of SLY, a pharmacological agent with antiinflammatory, anti-apoptotic, and antioxidant effects, largely prevented these pathological changes that occurred as a result of PAX use. The results obtained in the current study showed that SLY can be used as a protective agent against harmful effects on kidney tissue in treatments with PAX.

___

  • Adikwu E, Ebinyo NC, Orakpor DO. 2021. Coenzyme Q10 and resveratrol protect against paclitaxel-induced nephrotoxicity in rats. Trends in Pharmaceutical Sciences, 7(1):49-58. https://doi.org/10.30476/TIPS.2021.90346.1082
  • Aebi H. 1984. Catalase in vitro. Methods Enzymology, 105:121- 126. https://doi.org/10.1016/s0076-6879(84)05016-3
  • Ahmed S, Mohammed M, Mahmoud A. 2018. The role of gold nanoparticles on taxol-induced renal cortex damage in adult male albino rats. Egyptian Journal of Histology, 41(3):1-13. https://doi.org/10.21608/EJH.2019.25412
  • Aktas I, Gur FM. 2022. Hepato-protective effects of thymoquinone and beta-aminoisobutyric acid in streptozocin induced diabetic rats. Biotechnic & Histochemistry, 97(1):67- 76. https://doi.org/10.1080/10520295.2021.1949041
  • Aktas I, Ozgocmen M. 2020. The treatment effect of silymarin on heart damage in rats. Annals of Medical Research, 27(3):948. https://doi.org/10.5455/annalsmedres.2019.10.643
  • Aktaş İ, Gür FM. 2021. Investigation of the protective and therapeutic effects of β-aminoisobutyric acid (BAIBA) and Thymoquinone in the diabetic nephropathy. Boletin Latinoamericano Y Del Caribe de Plantas Medicinales Y Aromatica, 20(3):303 - 314
  • Aktaş İ, Gür FM, Özgöçmen M. 2020. Silymarin Ameliorates Valproic Acid-Induced Pancreas Injury by Decreasing Oxidative Stress. International Journal of Veterinary and Animal Research, 3(2):34-38.
  • Arany I, Clark JS, Reed D, Szabo I, Ember I, Juncos LA. 2013. The role of p66shc in taxol- and dichloroacetic aciddependent renal toxicity. Anticancer Research, 33(8):3119- 3122.
  • Arora MK, Singh UK. 2014. Oxidative stress: meeting multiple targets in pathogenesis of diabetic nephropathy. Current Drug Targets, 15(5):531-538. https://doi.org/10.2174/138945011 5666140321120635
  • Baek JS, Kim JH, Park JS, Cho CW. 2015. Modification of paclitaxel-loaded solid lipid nanoparticles with 2- hydroxypropyl-beta-cyclodextrin enhances absorption and reduces nephrotoxicity associated with intravenous injection. International Journal of Nanomedicine, 10:5397-5405. https://doi.org/10.2147/IJN.S86474
  • Balcioglu E, Gur FM, Gur HE, Bilgici P, Kankılıç T. 2021. Histological structure of Nannospalax xanthodon cochlea tissue. Biologia, 76, pages2543–2548. https://doi.org/10. 1007/s11756-021-00746-5
  • Bang KH, Na YG, Huh HW, Hwang SJ, Kim MS, Kim M, Lee HK, Cho CW. 2019. The Delivery Strategy of Paclitaxel Nanostructured Lipid Carrier Coated with Platelet Membrane. Cancers (Basel), 11(6). https://doi.org/10.3390/ cancers11060807
  • Bilgic S, Armagan I. 2020. Effects of misoprostol treatment on doxorubicin induced renal injury in rats. Biotechnic & Histochemistry, 95(2):113-120. https://doi.org/10.1080/1052 02952019.1645356
  • Bilgic S, Korkmaz DT, Azirak S, Güvenc AN, Kocaman N, Ozer MK. 2018. Olanzapine-induced renal damages and metabolic side effects: the protective effects of thymoquinone. Journal of Turgut Ozal Medical Center. 25(1):70-5. https://doi.org/ 10.5455/jtomc.2017.10.133
  • Bilgic S, Ozgocmen M. 2019. The protective effect of misoprostol against doxorubicin induced liver injury. Biotechnic & Histochemistry, 94(8):583-591. https://doi. org10. 1080/10520295.2019.1605457
  • Bilgic S, Ozgocmen M, Ozer MK, Asci H. 2020. Misoprostol ameliorates doxorubicin induced cardiac damage by decreasing oxidative stress and apoptosis in rats. Biotechnic & Histochemistry, 95(7):514-521. https://doi.org/10.1080/ 10520295.2020.1727013
  • Birben E, Sahiner UM, Sackesen C, Erzurum S, Kalayci O. 2012. Oxidative stress and antioxidant defense. World Allergy Organization Journal, 5(1):9-19. https://doi.org/10.1097/ WOX.0b013e3182439613
  • Choudhury H, Gorain B, Tekade RK, Pandey M, Karmakar S, Pal TK. 2017. Safety against nephrotoxicity in paclitaxel treatment: Oral nanocarrier as an effective tool in preclinical evaluation with marked in vivo antitumor activity. Regulatory Toxicology and Pharmacology, 91:179-189. https://doi.org/ 10.1016/j.yrtph.2017.10.023
  • Da Costa R, Passos GF, Quintao NLM, Fernandes ES, Maia J, Campos MM, Calixto JB. 2020. Taxane-induced neurotoxicity: Pathophysiology and therapeutic perspectives. British Journal of Pharmacology, 177(14):3127-3146. https://doi.org/10.1111/bph.15086
  • Dashti-Khavidaki S, Shahbazi F, Khalili H, Lessan-Pezeshki M. 2012. Potential renoprotective effects of silymarin against nephrotoxic drugs: a review of literature. Journal of Pharmacy and Pharmaceutical Sciences, 15(1):112-123. https://doi.org/10.18433/j3f88s
  • Ding T, Tian S, Zhang Z, Gu D, Chen Y, Shi Y, Sun Z. 2001. Determination of active component in silymarin by RP-LC and LC/MS. Journal of Pharmaceutical and Biomedical Analysis, 26(1):155-161. https://doi.org/10.1016/s0731-7085 (01)00364-8
  • Draper HH, Hadley M. 1990. Malondialdehyde determination as index of lipid peroxidation. Methods in Enzymology, 186:421- 431. https://doi.org/10.1016/s0731-7085(01)00364-8 Ellman GL. 1959. Tissue sulfhydryl groups. Archives of Biochemistry and Biophysics, 82(1):70-77.
  • Federico A, Dallio M, Loguercio C. 2017. Silymarin/Silybin and Chronic Liver Disease: A Marriage of Many Years. Molecules, 22(2). https://doi.org/10.3390/molecules22020191
  • Ghosh S, Sarkar A, Bhattacharyya S, Sil PC. 2016. Silymarin Protects Mouse Liver and Kidney from Thioacetamide Induced Toxicity by Scavenging Reactive Oxygen Species and Activating PI3K-Akt Pathway. Frontiers in Pharmacology, 7:481. https://doi.org/10.3389/fphar.2016. 00481
  • Giribabu N, Karim K, Kilari EK, Salleh N. 2017. Phyllanthus niruri leaves aqueous extract improves kidney functions, ameliorates kidney oxidative stress, inflammation, fibrosis and apoptosis and enhances kidney cell proliferation in adult male rats with diabetes mellitus. Journal of Ethnopharmacology, 205:123-137. https://doi.org/10.1016/j. jep.2017.05.002
  • Guo W, Johnson JL, Khan S, Ahmad A, Ahmad I. 2005. Paclitaxel quantification in mouse plasma and tissues containing liposome-entrapped paclitaxel by liquid chromatography-tandem mass spectrometry: application to a pharmacokinetics study. Analytical Biochemistry, 336(2):213-220. https://doi.org/10.1016/j.ab.2004.09.046
  • Gur FM, Aktas I. 2021. The ameliorative effects of thymoquinone and beta-aminoisobutyric acid on streptozotocin-induced diabetic cardiomyopathy. Tissue and Cell, 71:101582. https://doi.org/10.1016/j.tice.2021.101582
  • Gür FM, Aktaş İ, Bilgic S, Pekince M. 2022. Misoprostol alleviates paclitaxel‑induced liver damage through its antioxidant and anti‑apoptotic efects. Molecular & Cellular Toxicology, https://doi.org/10.1007/s13273-021-00210-0
  • Gur FM, Timurkaan S. 2014. The effects of prepubertal epididymal ligation upon the rat testis. Iran Journal of Reproductive Medicine 12 (10): 673-680.
  • Huizing MT, Misser VH, Pieters RC, ten Bokkel Huinink WW, Veenhof CH, Vermorken JB, Pinedo HM, Beijnen JH. 1995. Taxanes: a new class of antitumor agents. Cancer Investigation, 13(4):381-404. https://doi.org/10.3109/07357 909509031919
  • Jagiela J, Bartnicki P, Rysz J. 2021. Nephrotoxicity as a Complication of Chemotherapy and Immunotherapy in the Treatment of Colorectal Cancer, Melanoma and Non-Small Cell Lung Cancer. International Journal of Molecular Sciences, 22(9). https://doi.org/10.3390/ijms22094618
  • Karimi G, Ramezani M, Tahoonian Z. 2005. Cisplatin nephrotoxicity and protection by milk thistle extract in rats. Evidence Based Complementary Alternative Medicine, 2(3):383-386. https://doi.org/10.1093/ecam/neh103
  • Khalilpour J, Roshan-Milani S, Gharalari FH, Fard AA. 2019. Macrophage migration inhibitory factor antagonist (p425) ameliorates kidney histopathological and functional changes in diabetic rats. Brazilian Journal of Nephrology, 41(3):315- 322. https://doi.org/10.1590/2175-8239-JBN-2018-0184
  • Khatri H, Chokshi N, Rawal S, Patel BM, Badanthadka M, Patel MM. 2020. Fabrication and in vivo evaluation of ligand appended paclitaxel and artemether loaded lipid nanoparticulate systems for the treatment of NSCLC: A nanoparticle assisted combination oncotherapy. International Journal of Pharmaceutics, 583:119386. https://doi.org/10. 1016/j.ijpharm.2020.119386
  • Kim MJ, Kim DU, Choi JW, Kim DG, Song HJ, Bae GS, Park SJ. 2020. Silymarin Attenuates the Severity of Cerulein- Induced Acute Pancreatitis. Pancreas, 49(1):89-95. https://doi.org/10.1097/MPA.0000000000001453
  • Kocaman N, Dabak DÖ. 2015. Hepatoprotektif bir ajan: Silymarin. Fırat Tıp Derg, 20(3):128-132.
  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. 1951. Protein measurement with the Folin phenol reagent. Journal of Biological Chemistry, 193(1):265-275. Journal of Biological Chemistry
  • Marklund S, Marklund G. 1974. Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Journal of Cellular Physiology, 47(3):469-474. https://doi.org/10.1111/ j.1432-1033.1974.tb03714.x
  • Massey AE, Sikander M, Chauhan N, Kumari S, Setua S, Shetty AB, Mandil H, Kashyap VK, Khan S, Jaggi M ve ark., 2019. Next-generation paclitaxel-nanoparticle formulation for pancreatic cancer treatment. Nanomedicine, 20:102027. https://doi.org/10.1016/j.nano.2019.102027
  • Ohkawa H, Ohishi N, Yagi K. 1979. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Analytical Biochemistry, 95(2):351-358. https://doi.org/10.1016/0003- 2697(79)90738-3
  • Omran OM. 2014. Effects of thymoquinone on STZ-induced diabetic nephropathy: an immunohistochemical study. Ultrastructural Pathology, 38(1):26-33. https://doi.org/10. 3109/01913123.2013.830166
  • Ozer MK, Bilgic S, Armagan I, Savran M. 2020. Thymoquinone protection from amikacin induced renal injury in rats. Biotechnic & Histochemistry, 95:(2):129-136. https://doi.org/10.1080/ 10520295.2019.1650957
  • Padmavathi R, Senthilnathan P, Chodon D, Sakthisekaran D. 2006. Therapeutic effect of paclitaxel and propolis on lipid peroxidation and antioxidant system in 7,12 dimethyl benz(a)anthracene-induced breast cancer in female Sprague Dawley rats. Life Sciences, 78(24):2820-2825. https://doi.org/10.1016/j.lfs.2005.11.005
  • Park JH, Davis KR, Lee G, Jung M, Jung Y, Park J, Yi SY, Lee MA, Lee S, Yeom CH ve ark., 2012. Ascorbic acid alleviates toxicity of paclitaxel without interfering with the anticancer efficacy in mice. Nutrition Research, 32(11):873-883. https://doi.org/10.1016/j.nutres.2012.09.011
  • Perazella MA. 2009. Renal vulnerability to drug toxicity. Clinical Journal of the American Society of Nephrology 4(7):1275- 1283. https://doi.org/10.2215/CJN.02050309
  • Rabah SO. 2010. Acute Taxol nephrotoxicity: Histological and ultrastructural studies of mice kidney parenchyma. Saudi Journal of Biological Sciences, 17(2):105-114. https://doi.org/10.1016/j.sjbs.2010.02.003
  • Rafieian-Kopaie M, Nasri H. 2012. Silymarin and diabetic nephropathy. Journal of Renal Injury Prevention, 1(1):3-5. https://doi.org/10.12861/jrip.2012.02.
  • Ramakrishnan G, Lo Muzio L, Elinos-Baez CM, Jagan S, Augustine TA, Kamaraj S, Anandakumar P, Devaki T. 2009. Silymarin inhibited proliferation and induced apoptosis in hepatic cancer cells. Cell Proliferation, 42(2):229-240. https://doi.org/10.1111/j.1365-2184.2008.00581.x
  • Rowinsky EK, Eisenhauer EA, Chaudhry V, Arbuck SG, Donehower RC. 1993. Clinical toxicities encountered with paclitaxel (Taxol). Seminars in Oncology, 20(4 Suppl 3):1- 15.
  • Salahshoor MR, Roshankhah S, Jalili C. 2019. Antioxidative properties of Thymus vulgaris on liver rats induced by paclitaxel. Pharmacognosy Research, 11:315-320. https://doi.org/10.4103/pr.pr_45_19
  • Sarosy G, Reed E. 1993. Taxol dose intensification and its clinical implications. Journal of the National Medical Association, 85(6):427-431.
  • Shaker E, Mahmoud H, Mnaa S. 2010. Silymarin, the antioxidant component and Silybum marianum extracts prevent liver damage. Food and Chemical Toxicology, 48(3):803-806. https://doi.org/10.1016/j.fct.2009.12.011
  • Shoji H, Koletzko B. 2007. Oxidative stress and antioxidant protection in the perinatal period. Current Opinion in Clinical Nutrition & Metabolic Care, 10(3):324-328.
  • https://doi.org/10.1097/MCO.0b013e3280a94f6d Singla AK, Garg A, Aggarwal D. 2002. Paclitaxel and its formulations. International Journal of Pharmaceutics, 235(1- 2):179-192. https://doi.org/10.1016/s0378-5173(01)00986-3
  • Soto C, Mena R, Luna J, Cerbon M, Larrieta E, Vital P, Uria E, Sanchez M, Recoba R, Barron H ve ark., 2004. Silymarin induces recovery of pancreatic function after alloxan damage in rats. Life Sciences, 75(18):2167-2180. https://doi.org/10.1016/j.lfs.2004.04.019
  • Stage TB, Bergmann TK, Kroetz DL. 2018. Clinical pharmacokinetics of paclitaxel monotherapy: An updated literature review. Clinical Pharmacokinetics, 57(1):7-19. https://doi.org/10.1007/s40262-017-0563-z
  • Stephen Robert JM, Peddha MS, Srivastava AK. 2021. Effect of silymarin and quercetin in a miniaturized scaffold in wistar rats against non-alcoholic fatty liver disease. American Chemical Society Omega, 6(32):20735-20745. https://doi.org/10.1021/acsomega.1c00555
  • Thornton LM, Carson WE, 3rd, Shapiro CL, Farrar WB, Andersen BL. 2008. Delayed emotional recovery after taxane-based chemotherapy. Cancer, 113(3):638-647. https://doi.org/10.1002/cncr.23589
  • Varbiro G, Veres B, Gallyas F46Jr, Sumegi B. 2001. Direct effect of Taxol on free radical formation and mitochondrial permeability transition. Free Radical Biology and Medicine, 31(4):548-558. https://doi.org/10.1016/s0891- 5849(01)00616-5
  • Xie JD, Huang Y, Chen DT, Pan JH, Bi BT, Feng KY, Huang W, Zeng WA. 2015. Fentanyl enhances hepatotoxicity of paclitaxel via inhibition of CYP3A4 and ABCB1 transport activity in mice. PLoS One, 10(12):e0143701.
  • Xie QM, Chen JQ, Shen WH, Bian RL. 2002. Correlative changes of interferon-gamma and interleukin-4 between cortical layer and pulmonary airway of sensitized rats. Acta Pharmacologica Sinica, 23(3):248–252.
  • Zang X, Kagan L. 2018. Physiologically-based modeling and interspecies prediction of paclitaxel pharmacokinetics. Journal of Pharmacokinetics and Pharmacodynamics, 45(4):577-592. https://doi.org/10.1007/s10928-018-9586-9
  • Zasadil LM, Andersen KA, Yeum D, Rocque GB, Wilke LG, Tevaarwerk AJ, Raines RT, Burkard ME, Weaver BA. 2014. Cytotoxicity of paclitaxel in breast cancer is due to chromosome missegregation on multipolar spindles. Science Translational Medicine, 6(229):229ra243. https://doi.org/10. 1126/scitranslmed.3007965
Türk Tarım - Gıda Bilim ve Teknoloji dergisi-Cover
  • ISSN: 2148-127X
  • Yayın Aralığı: Aylık
  • Başlangıç: 2013
  • Yayıncı: Turkish Science and Technology Publishing (TURSTEP)
Sayıdaki Diğer Makaleler

Bıldırcın Büyütme Rasyonlarında Elekaltı Fasulye Kullanımının Performans, Karkas Özellikleri ve Serum Parametrelerine Etkisi

Alpönder YILDIZ, Cevher Şamil ÇALDAĞI

Samsun İlinde Hayvansal Üretimin 2010-2020 Yılları Arasındaki Değişimi

Savaş ATASEVER

Üniversite Öğrencilerinin Algılanan Stres Düzeylerinin Beden-Kitle İndeksi Kategorileri ve Cinsiyet Açısından Karşılaştırılması

Burcu KÖKSAL

Farklı Seviyelerde Aspir (Carthamus tinctorius L.) Küspesi İçeren Bıldırcın Rasyonlarına Enzim İlavesinin Performans, Yumurta Kalitesi ve Serum Parametrelerine Etkisi

Rukiye DOĞAN, Yusuf CUFADAR

Fitoplazma: Taşınması, Hastalık Gelişimi ve Fonksiyonel Genomları

Zehra MEZRELİ

Silimarin’in Paklitaksel Kaynaklı Nefrotoksisiteye Karşı Koruyucu Etkileri

Fatih Mehmet GÜR, İbrahim AKTAŞ

Polietilen Torbalarındaki Farklı Orandaki Açıklıkların ‘Sultani Çekirdeksiz’ Üzüm Çeşidinin Depolanmasına Etkileri

Fatih ŞEN, Ayşe BAYRAMOĞLU

Tüketicilerin Dana Eti Tüketim Hedonizminin Risk Faktörlü Aracılık Etki Modeli ile Değerlendirilmesi

Yavuz TOPÇU

Rasyona Ham ve Kavrulmuş Elekaltı Fasulye İlavesinin Yumurtlayan Bıldırcınlarda Performansa, Yumurta Kalitesine ve Serum Biyokimyasal Parametrelerine Etkisi

Osman OLGUN, Ayşe Süeda ÖZÇALIK

Broyler Rasyonuna İlave Edilen Resveratrol ve Kurkumin Ekstraktlarının Serumda Biyokimyasal Parametreler ve Karaciğer Enzimleri Üzerine Etkileri

Recep GÜMÜŞ, Abdullah ÖZBİLGİN