The hepatoprotective effects of sitagliptin against cyclophosphamide-induced hepatotoxicity in rat

Document Type : Original article

Authors

1 Department of Basic Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran

2 Molecular Department of Central Laboratory, School of Veterinary Medicine, Shiraz University, Shiraz, Iran

3 Department of Pathobiology, School of Veterinary Medicine, Shiraz University, Shiraz, Iran

4 Department of Clinical Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Iran

Abstract

Hepatotoxicity is a serious side effects of cyclophosphamide. Thus, the present research investigates the protective properties of sitagliptin against cyclophosphamide-induced hepatotoxicity. Fifty male rats were randomly divided into five groups. They were pre-treated with either sitagliptin or normal saline once a day for the first ten days of the study. To induce acute hepatotoxicity, cyclophosphamide (200 mg/kg, i.p) was injected only one time and 45 min after the last dose of sitagliptin. The rats were sacrificed on the 11th day, and their blood and liver were collected for biochemical, gene expression, and histopathological assessments. Our results showed that cyclophosphamide induced obvious liver toxicity as marked by an increase in serum levels of alanine transaminase and aspartate transaminase, reduced serum albumin and total protein levels, in addition to histopathological changes. The malondialdehyde, tumor necrosis factor-, and interleukin-6 levels were also elevated and total antioxidant capacity declined in serum and hepatic homogenates. Sitagliptin magnificently attenuated the cylophosphamide-induced histological alterations, improved liver function tests, enhanced total antioxidant capacity, and decreased malondialdehyde, tumor necrosis factor-α, and interleukin-6 in the blood and hepatic tissues. These findings suggest that sitagliptin has hepatoprotective activity against cyclophosphamide toxicity, which may be due to its antioxidant and anti-inflammatory effects.

Keywords

References

  1. Doustimotlagh AH, Kokhdan EP, Vakilpour H, Khalvati B, Barmak MJ, Sadeghi H, Asfaram A. Protective effect of Nasturtium officinale R. Br and quercetin against cyclophosphamide-induced hepatotoxicity in rats. Mol Biol Rep 2020;47:5001-5012.
  2. Lehmann F, Wennerberg J. Evolution of nitrogen-based alkylating anticancer agents. Processes 2021;9:377.
  3. Sherif IO. The effect of natural antioxidants in cyclophosphamide-induced hepatotoxicity: Role of Nrf2/HO-1 pathway. Int immunopharmacol 2018;61:29-36.
  4. Zhai X, Zhang Z, Liu W, Liu B, Zhang R, Wang W, Zheng W, Xu F, JWang J, Chen Y. Protective effect of ALDH2 against cyclophosphamide-induced acute hepatotoxicity via attenuating oxidative stress and reactive aldehydes. Biochem Biophys Res Commun 2018; 499:93-98.
  5. Akamo AJ, Rotimi SO, Akinloye DI, Ugbaja RN, Adeleye OO, Dosumu OA, Eteng OE, Amah G, Obijeku A, Cole OE. Naringin prevents cyclophosphamide-induced hepatotoxicity in rats by attenuating oxidative stress, fibrosis, and inflammation. Food Chem Toxico 2021; 153:112266.
  6. Aladaileh SH, Abukhalil MH, Saghir SA, Hanieh H, Alfwuaires MA, Almaiman AA, Bin-Jumah M, Mahmoud AM. Galangin activates Nrf2 signaling and attenuates oxidative damage, inflammation, and apoptosis in a rat model of cyclophosphamide-induced hepatotoxicity. Biomolecules 2019;9:346.
  7. Cuce G, Çetinkaya S, Koc T, Esen HH, Limandal C, Balcı T, Kalkan S, Akoz M. Chemoprotective effect of vitamin E in cyclophosphamide-induced hepatotoxicity in rats. Chem Biol Interact 2015;232:7-11.
  8. Fouad AA, Qutub HO, Al-Melhim WN. Punicalagin alleviates hepatotoxicity in rats challenged with cyclophosphamide. Environ Toxicol Pharmacol 2016;45:158-162.
  9. Germoush MO, Mahmoud AM. Berberine mitigates cyclophosphamide-induced hepato-toxiccity by modulating antioxidant status and inflammatory cytokines. J Cancer Res Clin Oncol 2014;140:1103-1109.
  10. Shruthi S, Shenoy KB. Gallic acid: A promising genoprotective and hepatoprotective bioactive compound against cyclophosphamide induced toxicity in mice. Environ Toxicol 2021;36:123-131.
  11. Abo-Haded HM, Elkablawy MA, Al-Johani Z, Al-Ahmadi O, El-Agamy DS. Hepato-protective effect of sitagliptin against methotrexate induced liver toxicity. PLoS One 2017; 12:e0174295.
  12. El-Kashef DH, Serrya MS. Sitagliptin ameliorates thioacetamide-induced acute liver injury via modulating TLR4/NF-KB signaling pathway in mice. Life Sci 2019;228:266-273.
  13. Hazman Ö, Çelik S. Effects of oral anti-diabetic agent sitagliptin on total antioxidant and oxidant status in rats with type 2 diabetes mellitus. J Appl Biol Sci 2014;8:31-37.
  14. Hu X, Liu S, Liu X, Zhang J, Liang Y, Li Y. DPP-4 (CD26) inhibitor sitagliptin exerts anti-inflammatory effects on rat insulinoma (RINm) cells via suppressing NF-κB activation. Endocrine 2017;55:754-763.
  15. Khedr R, Ahmed A, Kamel R, Rafaat E. Antioxidant effects of sitagliptin in a rat model of intestinal ischemia/reperfusion injury. JAPR 2021;5:234-240.
  16. Ji Y, Nyamagoud SB, SreeHarsha N, Mishra A, Gubbiyappa SK, Singh Y. Sitagliptin protects liver against aflatoxin B1‐induced hepatotoxicity through upregulating Nrf2/ARE/ HO‐1 pathway. Biofactors 2020;46:76-82.
  17. Tveden-Nyborg P, Bergmann TK, Jessen N, Simonsen U, Lykkesfeldt J. BCPT policy for experimental and clinical studies. Basic Clin Pharmacol Toxicol 2021;128:4-8
  18. Ayza MA, Zewdie KA, Yigzaw EF, Ayele SG, Tesfaye BA, Tafere GG, Gebreyohannes Abrha M. Potential protective effects of antioxidants against cyclophosphamide-induced nephrotoxicity. Int J Nephrol 2022;2022:5096825.
  19. Hamzeh M, Hosseinimehr SJ, Khalatbary AR, Mohammadi HR, Dashti A, Talebpour Amiri F. Atorvastatin mitigates cyclophosphamide-induced hepatotoxicity via suppression of oxidative stress and apoptosis in rat model. Res Pharm Sci 2018;13:440-449.
  20. El-Kholy AA, Elkablawy MA, El-Agamy DS. Lutein mitigates cyclophosphamide induced lung and liver injury via NF-κB/MAPK dependent mechanism. Biomed Pharmacother 2017;92:519-527.
  21. Mahmoud AM, Al Dera HS. 18β-Glycyrrhetinic acid exerts protective effects against cyclophosphamide-induced hepatotoxicity: potential role of PPARγ and Nrf2 upregulation. Genes Nutr 2015;10:41.
  22. Hewedy WA. Effects of treatment with sitagliptin on hepatotoxicity induced by acetamino-phen in mice. Braz J Pharm Sci 2021;56:e18482.

Files

Share

How to cite

Statistics