Cerium Oxide Nanoparticles Attenuate Oxidative Stress and Inflammation in the Liver of Diethylnitrosamine-Treated Mice

  • Olayinka A. Adebayo
  • Oluyemi Akinloye
  • Oluwatosin A. AdaramoyeEmail author


The catalytic activity of cerium oxide nanoparticles (CeO2NPs) is responsible for its application as an antitumor agent. This activity may be due to its ability to switch between III and IV oxidation states thereby conferring pro- and antioxidant properties. This study was designed to assess the hepatoprotective potential of CeO2NPs in male BALB/c mice administered diethylnitrosamine (DEN). Thirty-six mice were divided equally into six groups and treated intraperitoneally with normal saline (control), DEN (200 mg/kg) alone, CeO2NPs 1 (100 μg/kg) + DEN (200 mg/kg), CeO2NPs 2 (200 μg/kg) + DEN (200 mg/kg), CeO2NPs 1 alone, and CeO2NPs 2 alone. Animals were pretreated with CeO2NPs daily for eight consecutive days, while DEN was administered 48 h before the animals were sacrificed. Administration of DEN caused a significant increase in serum alanine aminotransferase (ALT) and urea by 51% and 96%, respectively. Markers of oxidative stress (malondialdehyde) and inflammation (nitric oxide and myeloperoxidase) in hepatic tissues of DEN-treated mice were increased by 60%, 16%, and 38%, respectively. The activities of hepatic superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, and level of reduced glutathione were significantly decreased in DEN-treated mice by 50%, 123%, 23%, 419%, and 78%, respectively. In addition, DEN increased the expression of hepatic Bcl2 and COX-2, while p53, Bax, and iNOS were mildly expressed. Pretreatment with CeO2NPs attenuated the activities of antioxidant enzymes and expression of Bcl2 and COX-2. Overall, CeO2NPs confers protection from DEN-induced liver damage via antioxidative activity.


Cerium oxide Nanoparticles Hepatotoxicity Oxidative stress Inflammation 



The authors gratefully acknowledge with thanks the free gift of cerium oxide nanoparticles from Greg Goss Research Group, Department of Biological Sciences, Faculty of Science, University of Alberta, Edmonton, Canada. This research was done without specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Akhtar MJ, Ahamed M, Alhadlaq HA, Alrokayan SA, Kumar S (2014) Targeted anticancer therapy: overexpressed receptors and nanotechnology. Clin Chim Acta 436:78–92CrossRefGoogle Scholar
  2. 2.
    Tarnuzzer TW, Colon J, Patil S, Seal S (2005) Vacancy engineered ceria nanostructures for protection from radiation induced cellular damage. Nano Lett 5(12):2573–2577CrossRefGoogle Scholar
  3. 3.
    Chen J, Patil S, Seal S, McGinnis JF (2006) Rare earth nanoparticles prevent retinal degeneration induced by intracellular peroxides. Nat Nanotechnol 1(2):142–150CrossRefGoogle Scholar
  4. 4.
    Niu JA, Azfer LM, Rogers XW, Kolattukudy PE (2007) Cardio-protective effects of cerium oxide nanoparticles in a transgenic murine model of cardiomyopathy. Cardiovasc Res 73(3):549–559CrossRefGoogle Scholar
  5. 5.
    Singh S (2016) Cerium oxide based nanozymes: redox phenomenon at biointerfaces. Biointerphases 11:04B202CrossRefGoogle Scholar
  6. 6.
    Karakoti AS, Monteiro-Riviere NA, Aggarwal R, Davis JP, Narayan RJ, Self WT, McGinnis J, Sea S (2008) CeO2NPs as antioxidant: synthesis and biomedical applications. JOM 60(3):33–37CrossRefGoogle Scholar
  7. 7.
    Rubio L, Annangi B, Vila L, Hernandez A, Marcos R (2016) Antioxidant and anti-genotoxic properties of cerium oxide nanoparticles in a pulmonary-like cell system. Arch Toxicol 90:269–278CrossRefGoogle Scholar
  8. 8.
    Pal P, Kansara K, Singh R, Singh S, Dhawan A, Kumar A (2018) Cellular internalization and antioxidant activity of cerium oxide nanoparticles in human monocytic leukemia cells. Int J Nanomedicine 13:39–41CrossRefGoogle Scholar
  9. 9.
    Singh R, Singh S (2019) Redox-dependent catalase mimetic cerium oxide-based nanozyme protect human hepatic cells from 3-AT induced acatalasemia. Colloids Surf B: Biointerfaces 175:625–635CrossRefGoogle Scholar
  10. 10.
    Singh R, Karakoti AS, Self WT, Seal S, Singh S (2016) Redox-sensitive cerium oxide nanoparticles protect human keratinocytes from oxidative stress induced by glutathione depletion. Langmuir 32:12202–12211. CrossRefGoogle Scholar
  11. 11.
    Adebayo OA, Akinloye O, Adaramoye OA (2017) Cerium oxide nanoparticle elicits oxidative stress, endocrine imbalance and lowers sperm characteristics in testes of BALB/c mice. Andrologia 50(3).
  12. 12.
    Gagnon J, Fromm KM (2015) Toxicity and protective effects of cerium oxide nanoparticles (nanoceria) depending on their preparation method, particle size, cell type, and exposure route. Eur J Inorg Chem 27:4510–4517CrossRefGoogle Scholar
  13. 13.
    Hirst SM, Karakoti A, Singh S, Self W, Tyler R, Seal S, Reilly CM (2013) Bio-distribution and in vivo antioxidant effects of cerium oxide nanoparticles in mice. Environ Toxicol 28(2):107–118CrossRefGoogle Scholar
  14. 14.
    El-Serag HB, Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132(7):2557–2576CrossRefGoogle Scholar
  15. 15.
    Ferrin G, Aguilar-Melero P, Rodriguez-Peralvarez M, Montero-Alvarez JL, de la Mata M (2015) Biomarkers for hepatocellular carcinoma: diagnostic and therapeutic utility. Hepat Med 7:1–10. Google Scholar
  16. 16.
    Hsu SH, Wang B, Kutay H, Bid H, Shreve J, Zhang X, Costinean S, Bratasz A, Houghton P, Ghoshal K (2013) Hepatic loss of miR-122 predisposes mice to hepatobiliary cyst and hepatocellular carcinoma upon diethylnitrosamine exposure. Am J Pathol 183(6):1719–1730CrossRefGoogle Scholar
  17. 17.
    Chen X, Chan CY, Li D, Yuan C, Yu F, Lin MC, Yew DT, Kung HF, Lai L (2008) Two-dimensional differential gel electrophoresis/analysis of diethylnitrosamine induced rat hepatocellular carcinoma. Int J Cancer 122:2682–2688CrossRefGoogle Scholar
  18. 18.
    Al-Rejaie SS, Aleisa AM, Al-Yahya AA, Bakheet SA, Alsheikh A, Fatani AG, Al-Shabanah OA, Sayed-Ahmed MM (2009) Progression of diethylnitrosamine-induced hepatic carcinogenesis in carnitine-depleted rats. World J Gastroenterol 15(11):1373–1380CrossRefGoogle Scholar
  19. 19.
    Santos NP, Colaço A, da Costa RM, Oliveira MM, Peixoto F, Oliveira PA (2014) N-diethylnitrosamine mouse hepatotoxicity: time related effects on histology and oxidative stress. Exp Toxicol Pathol 66:429–436CrossRefGoogle Scholar
  20. 20.
    Felix LC, Ortega VA, Ede JD, Goss GG (2013) Physicochemical characteristics of polymer-coated metal-oxide nanoparticles and their toxicological effects on zebrafish (Danio rerio) development. Environ Sci Technol 47(12):6589–6596CrossRefGoogle Scholar
  21. 21.
    Rahman KM, Sugie S, Okamoto K, Watanabe T, Tanaka T, Mori H (1999) Modulating effects of diets high in omega-3 and omega-6 fatty acids in initiation and post-initiation stages of diethylnitrosamine-induced hepatocarcinogenesis in rats. Jpn J Cancer Res 90(1):31–39CrossRefGoogle Scholar
  22. 22.
    Mohun AF, Cook LJ (1957) Simple method for measuring serum level of glutamate-oxaloacetate and glutamate-pyruvate transaminases in laboratories. J Clin Pathol 10(4):394–399CrossRefGoogle Scholar
  23. 23.
    Reitman S, Frankel S (1957) A colorimetric method for the determination of serum level of glutamate-oxaloacetate and pyruvate transaminases. Am J Clin Pathol 28(1):56–63CrossRefGoogle Scholar
  24. 24.
    Jendrassik L, Grof P (1938) Simplified photometric methods for the determination of bilirubin. Biochem J 297:81–89Google Scholar
  25. 25.
    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275Google Scholar
  26. 26.
    Aebi H (1974) Catalase. In: Bergmeyer HU (ed) Methods of enzymatic analysis. Verlag Chemie/Academic Press Inc., Weinheim, pp 673–680. CrossRefGoogle Scholar
  27. 27.
    McCord JM, Fridovich I (1969) Superoxide dismutase, an enzymatic function for erythrocuprein. J Biol Chem 244:6049–6055Google Scholar
  28. 28.
    Habig WH, Pabst MJ, Jakoby WB (1974) Glutathione-S-transferases. The first enzymatic step in mercapturic acid formation. J Biol Chem 249:7130–7139Google Scholar
  29. 29.
    Rotruck JT, Pope AL, Ganther HE, Swanson AB, Hafeman DG, Hoekstra WG (1973) Selenium: biochemical role as a component of glutathione peroxidase. Science 179:588–590CrossRefGoogle Scholar
  30. 30.
    Moron MS, Depierre JW, Mannervick B (1979) Levels of glutathione, glutathione reductase and glutathione-S-transferase activities in rat lung and liver. Biochim Biophys Acta 582:67–78CrossRefGoogle Scholar
  31. 31.
    Buege JA, Aust SD (1978) Microsomal lipid peroxidation. Methods Enzymol 52:302–310CrossRefGoogle Scholar
  32. 32.
    Palmer RM, Ferrige AG, Moncada S (1987) Nitric oxide release accounts for the biological activity of endothelium derived relaxing factor. Nature 327:524–526CrossRefGoogle Scholar
  33. 33.
    Trush MA, Egner PA, Kensler TW (1994) Myeloperoxidase as a biomarker of skin irritation and inflammation. Food Chem Toxicol 32:143–147CrossRefGoogle Scholar
  34. 34.
    Snow SJ, Mcgee J, Miller DB (2014) Inhaled diesel emissions generated with cerium oxide nanoparticle fuel additive induce adverse pulmonary and systemic effects. Toxicol Sci 142:403–417CrossRefGoogle Scholar
  35. 35.
    Anoopraj R, Hemalatha S, Balachandra C (2014) A preliminary study on serum liver function indices of diethylnitrosamine induced hepatotocarcinogenesis and chemoprotective potential of Eclipta alba in male Wistar rats. Vet World 7(6):439–442CrossRefGoogle Scholar
  36. 36.
    Sallie R, Tredger JM, Williams R (1991) Drugs and the liver part 1: testing liver function. Biopharm Drug Dispos 12:251–259CrossRefGoogle Scholar
  37. 37.
    Scandalios JG (2005) Oxidative stress: molecular perception and transduction of signals triggering antioxidant gene defenses. Braz J Med Biol Res 38(7):995–1014CrossRefGoogle Scholar
  38. 38.
    Li S, Tan HY, Wang N, Zhang ZJ, Lao L, Wong CW, Feng Y (2015) The role of oxidative stress and antioxidants in liver diseases. Int J Mol Sci 16:26087–26124CrossRefGoogle Scholar
  39. 39.
    Sanchez-Valle V, Chavez-Tapia NC, Uribe M, Mendez-Sanchez N (2012) Role of oxidative stress and molecular changes in liver fibrosis: a review. Curr Med Chem 19:4850–4860CrossRefGoogle Scholar
  40. 40.
    Allen RG, Tresini M (2000) Oxidative stress and gene regulation. Free Radic Biol Med 28(3):463–499CrossRefGoogle Scholar
  41. 41.
    Wang J, Chen Y, Gao N (2013) Inhibitory effect of glutathione on oxidative liver injury induced by dengue virus serotype 2 infections in mice. PLoS One 8(1):55407–55407CrossRefGoogle Scholar
  42. 42.
    Dowding JM, Dosani T, Kumar A, Seal S, Self WT (2012) Cerium oxide nanoparticles scavenge nitric oxide radical (˙NO). Chem Commun (Camb) 48(40):4896–4898CrossRefGoogle Scholar
  43. 43.
    Ighodaro OM, Akinloye OA (2017) First line defence antioxidants-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX): their fundamental role in the entire antioxidant defence grid. Alexandra J Med 54:287–293. CrossRefGoogle Scholar
  44. 44.
    Edwards R, Dixon DP, Walbot V (2000) Plant glutathione-S-transferase: enzymes with multiple functions in sickness and in health. Trends Plant Sci 5(5):193–198CrossRefGoogle Scholar
  45. 45.
    Khan AA, Alsahli MA, Rahmani AH (2018) Myeloperoxidase as an active disease biomarker: recent biochemical and pathological perspectives. Med Sci (Basel) 6(2):33.439–33.442Google Scholar
  46. 46.
    Guan L, Rui W, Bai R, Zhang W, Zhang F, Ding W (2017) Effects of size-fractionated particulate matter on cellular oxidant radical generation in human bronchial epithelial BEAS-2B cells. Int J Environ Res Public Health 13(5):483CrossRefGoogle Scholar
  47. 47.
    Joldersma E, Burger C, Semeins J, Klein N (2000) Mechanical stress induces COX-2 mRNA expression in bone cells from elderly women. J Biomech 33(1):53–61CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Biochemistry, Faculty of Basic Medical Sciences, College of MedicineUniversity of IbadanIbadanNigeria
  2. 2.Clinical Chemistry and Molecular Diagnostic Laboratory, Department of Medical Laboratory Science, Faculty of Basic Medical SciencesUniversity of LagosLagosNigeria

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