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

18 beta-glycyrrhetinic acid (18 beta-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 18 beta-GA, pointing to the role of peroxisome proliferator activated receptor gamma (PPAR gamma) and the redox-sensitive nuclear factor erythroid 2-related factor 2 (Nrf2). Wistar rats were orally administered 18 beta-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 18 beta-GA significantly reduced serum enzymes of liver function, bilirubin and pro-inflammatory cytokines. 18 beta-GA attenuated MTX-induced oxidative stress and restored the antioxidant defenses. In addition, 18 beta-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 PPAR gamma, an effect that was markedly reversed by 18 beta-GA supplemented either before or after MTX. In conclusion, 18 beta-GA protected against MTX-induced liver injury, possibly by activating Nrf2 and PPAR gamma, and subsequent attenuation of inflammation, oxidative stress and apoptosis. Therefore, 18 beta-GA can provide protection against MIX-induced hepatotoxicity. (C) 2017 Elsevier B.V. All rights reserved.