Naringin prevents cyclophosphamide-induced hepatotoxicity in rats by attenuating oxidative stress, fibrosis, and inflammation

Food Chem Toxicol. 2021 Jul:153:112266. doi: 10.1016/j.fct.2021.112266. Epub 2021 May 14.


Cyclophosphamide (CYCP), a synthetic alkylating antineoplastic, disrupts both cancerous and non-cancerous cells to cause cancer regression and multi organotoxicity respectively. CYCP-induced hepatotoxicity is rare but possible. Evidence has shown that naringin has several beneficial potentials against oxidative stress, inflammation, and fibrosis. This study examined the chemoprotective potentials of naringin on exited radical scavenging, hepatic integrity, oxidative stress, fibrosis, and inflammation in CYCP-mediated hepatotoxicity. Rats were pre-treated orally by gavage for fourteen consecutive days with three doses (50, 100, and 200 mg/kg) of naringin before single CYCP (200 mg/kg, i.p.) administration. Subsequently, the rats were euthanized; blood and liver were removed, and assessed for serum and hepatic enzymes, oxidative stress, inflammation, and gene expression dynamics. Naringin concentrations required for 50% scavenging hydroxyl radical and 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulphonic acid) radical cation were 0.32 mg/mL and 0.39 mg/mL, respectively. Pretreatment with naringin significantly (p < 0.05) abolish CYCP-induced changes in the activities of serum and hepatic ALT, AST, GGT, ALP, and LDH. Pretreatment with naringin remarkably (p < 0.05) reversed CYCP-mediated increases in hepatic levels of malondialdehyde, hydroperoxide, and nitric oxide; reverse CYCP-induced decreases in the hepatic glutathione levels, activities of catalase, glutathione peroxidase, and glutathione reductase; and also attenuated CYCP-induced upregulation of expression of hepatic chemokine (C-C motif) ligand 2 (CCL2), interferon alpha1 (IFN-α1), interleukine-1β, interleukine-1 receptor, and transforming growth factor beta 1 (TGF-β1). Taken together, different doses of naringin can prevent CYCP-induced oxidants generation, hepatocytes dysfunctions, oxidative stress as well as inflammatory perturbations in rats when pre-administered for as few as 14 days.

Keywords: Anti-inflammation; Cyclophosphamide; Fibrosis; Hepatotoxicity; Interleukin; Naringin; Oxidative stress.

MeSH terms

  • Animals
  • Chemical and Drug Induced Liver Injury / metabolism
  • Chemical and Drug Induced Liver Injury / prevention & control*
  • Cyclophosphamide
  • Cytokines / metabolism
  • Female
  • Fibrosis / chemically induced
  • Fibrosis / metabolism
  • Fibrosis / prevention & control*
  • Flavanones / therapeutic use*
  • Free Radical Scavengers / therapeutic use*
  • Inflammation / chemically induced
  • Inflammation / metabolism
  • Inflammation / prevention & control*
  • Liver / drug effects
  • Nitric Oxide / metabolism
  • Oxidative Stress / drug effects*
  • Rats
  • Rats, Wistar


  • Cytokines
  • Flavanones
  • Free Radical Scavengers
  • Nitric Oxide
  • Cyclophosphamide
  • naringin