Methotrexate hepatotoxicity is associated with oxidative stress, and down-regulation of PPARγ and Nrf2: Protective effect of 18β-Glycyrrhetinic acid

Chem Biol Interact. 2017 May 25:270:59-72. doi: 10.1016/j.cbi.2017.04.009. Epub 2017 Apr 13.


18β-glycyrrhetinic acid (18β-GA) is a bioactive component of licorice with promising hepatoprotective activity. However, its protective mechanism on methotrexate (MTX) hepatotoxicity in not well defined. We investigated the hepatoprotective effect of 18β-GA, pointing to the role of peroxisome proliferator activated receptor gamma (PPARγ) and the redox-sensitive nuclear factor erythroid 2-related factor 2 (Nrf2). Wistar rats were orally administered 18β-GA (50 and 100 mg/kg) 7 days either before or after MTX injection. MTX induced significant increase in circulating liver function marker enzymes and bilirubin with concomitant declined albumin levels. Serum pro-inflammatory cytokines, and liver malondialdehyde and nitric oxide were significantly increased in MTX-induced rats. Treatment with 18β-GA significantly reduced serum enzymes of liver function, bilirubin and pro-inflammatory cytokines. 18β-GA attenuated MTX-induced oxidative stress and restored the antioxidant defenses. In addition, 18β-GA improved liver histological structure and decreased the expression of Bax whereas increased Bcl-2 expression. MTX-induced rats showed significant down-regulation of Nrf2, hemoxygenase-1 and PPARγ, an effect that was markedly reversed by 18β-GA supplemented either before or after MTX. In conclusion, 18β-GA protected against MTX-induced liver injury, possibly by activating Nrf2 and PPARγ, and subsequent attenuation of inflammation, oxidative stress and apoptosis. Therefore, 18β-GA can provide protection against MTX-induced hepatotoxicity.

Keywords: Glycyrrhetinic acid; Inflammation; Methotrexate; Nrf2; Oxidative stress; PPAR.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Body Weight / drug effects
  • Down-Regulation / drug effects*
  • Glycyrrhetinic Acid / analogs & derivatives*
  • Glycyrrhetinic Acid / pharmacology
  • Glycyrrhetinic Acid / therapeutic use
  • Inflammation
  • Liver / drug effects*
  • Liver / pathology*
  • Male
  • Methotrexate / toxicity
  • NF-E2-Related Factor 2 / genetics*
  • NF-E2-Related Factor 2 / metabolism
  • Oxidative Stress / drug effects
  • PPAR gamma / genetics*
  • PPAR gamma / metabolism
  • Rats
  • Rats, Wistar


  • NF-E2-Related Factor 2
  • PPAR gamma
  • 18alpha-glycyrrhetinic acid
  • Glycyrrhetinic Acid
  • Methotrexate