The Effect of Chlorogenic Acid on 5-Fluorouracil-Induced Oxidative Damage in Rat Ovarian Tissue

Year 2022, Volume: 1 Issue: 1, 1 - 7, 30.12.2022

Ahmet Mentese , Selim Demir , Nihal Türkmen , Yüksel Aliyazıcıoğlu , Orhan Değer

Abstract

5-fluorouracil (5-FU) is a potent anticancer agent, but its significant tissue toxicity associated with increased oxidative stress and inflammation may limit its clinical use. Chlorogenic acid (CGA) is a dietary polyphenol found in a variety of foods and beverages, including coffee, apples, pears, strawberries, and grapes. It was aimed to evaluate the therapeutic effects of CGA on 5-FU-induced ovotoxicity through oxidative stress and inflammation parameters in this study. Thirty female Sprague-Dawley rats were divided into 5 groups with equal numbers of subjects (n=6): control, 5-FU (100 mg/kg), 5-FU+CGA (1.5 mg/kg), 5-FU+CGA (mg/kg) and CGA (3 mg/kg). The ovarian tissue levels of malondialdehyde (MDA), total oxidant status (TOS), total antioxidant status (TAS), 8-hydroxy-2' -deoxyguanosine (8-OHdG), catalase (CAT) and interleukin-6 (IL-6) were determined using commercial spectrophotometric kits. While 5-FU treatment increased MDA, TOS, 8-OHdG and IL-6 levels in ovarian tissue, it significantly decreased TAS and CAT levels (p<0.05). These parameters, indicating 5-FU-induced toxicity, were significantly reversed with CGA administrations in a dose-dependent manner. The results support the view that CGA may be a useful modulator in attenuating 5-FU-induced ovotoxicity.

Keywords

5-fluorouracil, Chlorogenic acid, Inflammation, Ovotoxicity, Oxidative stress

Klorojenik Asidin Sıçan Yumurtalık Dokusunda 5-Florourasil ile İndüklenen Oksidatif Hasar Üzerine Etkisi

Abstract

5-fluorourasil (5-FU) güçlü bir antikanser ajandır, ancak artan oksidatif stres ve inflamasyon ile ilişkili önemli doku toksisitesi klinik kullanımını sınırlayabilmektedir. Klorojenik asit (CGA) kahve, elma, armut, çilek ve üzüm dahil olmak üzere çeşitli yiyecek ve içeceklerde bulunan bir diyet polifenolüdür. Bu çalışmada, CGA'nın 5-FU ile indüklenen yumurtalık dokusu toksisitesi üzerine terapötik etkilerinin oksidatif stres ve inflamasyon parametreleri üzerinden değerlendirilmesi amaçlandı. Otuz Sprague-Dawley ırkı dişi sıçan eşit sayıda denek (n=6) içeren 5 gruba ayrıldı: kontrol, 5-FU (100 mg/kg), 5-FU+CGA (1.5 mg/kg), 5-FU+CGA (mg/kg) ve CGA (3 mg/kg). Yumurtalık dokularında malondialdehit (MDA), toplam oksidan durum (TOS), toplam antioksidan durum (TAS), 8-hidroksi-2'-deoksiguanozin (8-OHdG), katalaz (CAT) ve interlökin-6 (IL-6) seviyeleri ticari spektrofotometrik kitler kullanılarak belirlendi. 5-FU uygulaması yumurtalık dokusunda MDA, TOS, 8-OHdG ve IL-6 düzeylerini artırırken, TAS ve CAT düzeylerini anlamlı olarak azalttı (p<0.05). 5-FU ile indüklenen toksisiteyi gösteren bu parametreler, CGA tedavisi ile doza bağlı bir şekilde anlamlı derecede tersine çevrildi (p<0.05). Sonuçlar, CGA'nın 5-FU ile indüklenen yumurtalık dokusu toksisitesini azaltmada faydalı bir modülatör olabileceği görüşünü desteklemektedir.

Keywords

5-florourasil, İnflamasyon, Klorojenik asit, Yumurtalık dokusu toksisitesi, Oksidatif stres

References

• 1. Jurczyk M, Król M, Midro A, Kurnik-Łucka M, Poniatowski A, Gil K. Cardiotoxicity of fluoropyrimidines: Epidemiology, mechanisms, diagnosis, and management. J Clin Med. 2021; 10(19): 4426. DOI: 10.3390/jcm10194426.
• 2. Naren G, Guo J, Bai Q, Fan N, Nashun B. Reproductive and developmental toxicities of 5-fluorouracil in model organisms and humans. Expert Rev Mol Med. 2022; 24: e9. DOI: 10.1017/erm.2022.3.
• 3. Zeng D, Wang Y, Chen Y, et al. Angelica polysaccharide antagonizes 5-FU-induced oxidative stress injury to reduce apoptosis in the liver through Nrf2 pathway. Front Oncol. 2021; 11: 720620. DOI: 10.3389/fonc.2021.720620.
• 4. Al-Asmari AK, Khan AQ, Al-Masri N. Mitigation of 5-fluorouracil-induced liver damage in rats by vitamin C via targeting redox-sensitive transcription factors. Hum Exp Toxicol. 2016; 35(11): 1203-1213. DOI: 10.1177/0960327115626583.
• 5. Alkis I, Ekin S, Yildirim S, Bakir A, Eser G, Firat M. Evaluation of the protective effect of chlorogenic acid and Rhabdosciadium anatolyi against cyclophosphamide-induced ovarian toxicity in the rat with histopathological and immunohistochemical findings. Kafkas Univ Vet Fak Derg. 2020; 26(6): 757-763. DOI: 10.9775/kvfd.2020.24305.
• 6. Naveed M, Hejazi V, Abbas M, et al. Chlorogenic acid (CGA): A pharmacological review and call for further research. Biomed Pharmacother. 2018; 97: 67-74. DOI: 10.1016/j.biopha.2017.10.064.
• 7. Lu H, Tian Z, Cui Y, Liu Z, Ma X. Chlorogenic acid: A comprehensive review of the dietary sources, processing effects, bioavailability, beneficial properties, mechanisms of action, and future directions. Compr Rev Food Sci Food Saf. 2020; 19(6): 3130-3158. DOI: 10.1111/1541-4337.12620.
• 8. Vardi N, Parlakpinar H, Ates B, Otlu A. The preventive effects of chlorogenic acid against to testicular damage caused by methotrexate. Turkiye Klinikleri J Med Sci. 2010; 30(2): 507-513.
• 9. Rashid S, Sultana S. Chlorogenic acid represses 5-fluorouracil induced renal oxidative stress, apoptosis and inflammation in murine model. Free Radic Biol Med. 2016; 100: S128-S129. DOI: 10.1016/j.freeradbiomed.2016.10.336.
• 10. Mentese A, Alemdar NT, Livaoglu A, Demir EA, Aliyazicioglu Y, Demir S. Suppression of cisplatin-induced ovarian injury in rats by chrysin: An experimental study. J Obstet Gynaecol. 2022; DOI: 10.1080/01443615.2022.2130201, In Press.
• 11. Domitrović R, Cvijanović O, Šušnić V, Katalinić N. Renoprotective mechanisms of chlorogenic acid in cisplatin-induced kidney injury. Toxicology. 2014; 324: 98-107. DOI: 10.1016/j.tox.2014.07.004.
• 12. Park SH, Baek SI, Yun J, et al. IRAK4 as a molecular target in the amelioration of innate immunity-related endotoxic shock and acute liver injury by chlorogenic acid. J Immunol. 2015; 194(3): 1122-1130. DOI: 10.4049/jimmunol.1402101.
• 13. Zhang S, Liu Y, Xiang D, et al. Assessment of dose-response relationship of 5-fluorouracil to murine intestinal injury. Biomed Pharmacother. 2018; 106: 910-916. DOI: 10.1016/j.biopha.2018.07.029.
• 14. Narayana K, D'Souza UJ, Sanyal AK, Rao KP. 5-fluorouracil (5-FU) induces the formation of giant cells and sloughing of seminiferous epithelium in the rat testis. Indian J Physiol Pharmacol. 2000; 44(3): 317-322.
• 15. Demir EA, Mentese A, Livaoglu A, Alemdar NT, Demir S. Ameliorative effect of gallic acid on cisplatin-induced ovarian toxicity in rats. Drug Chem Toxicol. 2021; DOI: 10.1080/01480545.2021.2011312, In Press.
• 16. Mihara M, Uchiyama M. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 1978; 86(1): 271-278. DOI: 10.1016/0003-2697(78)90342-1.
• 17. Demir S, Kazaz IO, Kerimoglu G, et al. Astaxanthin protects testicular tissue against torsion/detorsion-induced injury via suppressing endoplasmic reticulum stress in rats. J Invest Surg. 2022; 35(5): 1044-1049. DOI: 10.1080/08941939.2021.1995540.
• 18. Lambouras M, Liew SH, Horvay K, Abud HE, Stringer JM, Hutt KJ. Examination of the ovotoxicity of 5-fluorouracil in mice. J Assist Reprod Genet. 2018; 35: 1053-1060. DOI: 10.1007/s10815-018-1169-6.
• 19. Stringer JM, Swindells EOK, Zerafa N, Liew SH, Hutt KJ. Multidose 5-fluorouracil is highly toxic to growing ovarian follicles in mice. Toxicol Sci. 2018; 166(1): 97-107. DOI: 10.1093/toxsci/kfy189.
• 20. Zhang QY, Wang FX, Jia KK, Kong LD. Natural product interventions for chemotherapy and radiotherapy-induced side effects. Front Pharmacol. 2018; 9: 1253. DOI: 10.3389/fphar.2018.01253.
• 21. Rashid S, Ali N, Nafees S, Ahmad ST, Hasan SK, Sultana S. Abrogation of 5-flourouracil induced renal toxicity by bee propolis via targeting oxidative stress and inflammation in Wistar rats. J Pharm Res. 2013; 7(2): 189-194.
• 22. Kazaz IO. Demir S, Kerimoglu G, et al. Chlorogenic acid ameliorates torsion/detorsion-induced testicular injury via decreasing endoplasmic reticulum stress. J Pediatr Urol. 2022; 18(3): 289.e1-289.e7. DOI: 10.1016/j.jpurol.2022.02.013.
• 23. Kazaz IO, Demir S, Kerimoglu G, et al. Effect of chrysin on endoplasmic reticulum stress in a rat model of testicular torsion. J Invest Surg. 2022; 35(5): 1106-1111. DOI: 10.1080/08941939.2021.2015489.
• 24. Al-Asmari AK, Khan AQ, Al-Qasim AM, Al-Yousef Y. Ascorbic acid attenuates antineoplastic drug 5-fluorouracil induced gastrointestinal toxicity in rats by modulating the expression of inflammatory mediators. Toxicol Rep. 2015; 2: 908-916. DOI: 10.1016/j.toxrep.2015.06.006.
• 25. Gelen V, Şengül E, Yıldırım S, Senturk E, Tekin S, Kükürt A. The protective effects of hesperidin and curcumin on 5-fluorouracil-induced nephrotoxicity in mice. Environ Sci Pollut Res Int. 2021; 28(34): 47046-47055. DOI: 10.1007/s11356-021-13969-5.
• 26. Ali N, Rashid S, Nafees S, et al. Protective effect of chlorogenic acid against methotrexate induced oxidative stress, inflammation and apoptosis in rat liver: An experimental approach. Chem Biol Interact. 2017; 272: 80-91. DOI: 10.1016/j.cbi.2017.05.002.
• 27. Demir EA, Mentese A, Kucuk H, Alemdar NT, Demir S. p-Coumaric acid alleviates cisplatin-induced ovarian toxicity in rats. J Obstet Gynaecol Res. 2022; 48(2): 411-419. DOI: 10.1111/jog.15119.
• 28. Arab HH, Salama SA, Maghrabi IA. Camel milk ameliorates 5-fluorouracil-induced renal injury in rats: Targeting MAPKs, NF-κB and PI3K/Akt/eNOS pathways. Cell Physiol Biochem. 2018; 46(4): 1628-1642. DOI: 10.1159/000489210.
• 29. Liang N, Kitts DD. Role of chlorogenic acids in controlling oxidative and inflammatory stress conditions. Nutrients 2016; 8: 16. DOI: 10.3390/nu8010016.
• 30. Rodrigues D, de Souza T, Coyle L, et al. New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids. Arch Toxicol. 2021; 95: 2691-2718. DOI: 10.1007/s00204-021-03092-2.
• 31. Xue Y, Huang F, Tang R, et al. Chlorogenic acid attenuates cadmium-induced intestinal injury in Sprague-Dawley rats. Food Chem Toxicol. 2019; 133: 110751. DOI: 10.1016/j.fct.2019.110751.
• 32. Gao W, Wang C, Yu L, et al. Chlorogenic acid attenuates dextran sodium sulfate-induced ulcerative colitis in mice through MAPK/ERK/JNK pathway. Biomed Res Int. 2019; 2019: 6769789. DOI: 10.1155/2019/6769789.
• 33. Shi H, Dong L, Jiang J, et al. Chlorogenic acid reduces liver inflammation and fibrosis through inhibition of toll-like receptor 4 signaling pathway. Toxicology. 2013; 303: 107-114. DOI: 10.1016/j.tox.2012.10.025.
• 34. Guo Z, Li J. Chlorogenic acid prevents alcohol-induced brain damage in neonatal rat. Transl Neurosci. 2017; 8: 176-181. DOI: 10.1515/tnsci-2017-0024.