Paeonol Protects against Methotrexate Hepatotoxicity by Repressing Oxidative Stress, Inflammation, and Apoptosis—The Role of Drug Efflux Transporters

Methotrexate (MTX) is an effective chemotherapeutic agent against a wide range of tumors and autoimmune diseases; however, hepatotoxicity limits its clinical use. Oxidative stress and inflammation have been implicated in the pathogenesis of MTX-induced hepatotoxicity. Paeonol is a natural phenolic compound reported for its antioxidant and anti-inflammatory properties. The current study aimed to investigate the protective effect of paeonol against MTX-induced hepatotoxicity in rats and various mechanisms that underlie this postulated effect. Paeonol was administered orally in a dose of 100 mg/kg, alone or along with MTX, for 10 days. Hepatotoxicity was induced via a single intraperitoneal dose of MTX (20 mg/kg) on day 5 of the experiment. Concomitant administration of paeonol with MTX significantly ameliorated distorted hepatic function and histological structure, restored hepatic oxidative stress parameters (MDA, NO, and SOD), and combated inflammatory response (iNOS and TNF-α). Additionally, paeonol enhanced cell proliferation and survival, evidenced by upregulating the proliferating cell nuclear antigen (PCNA) and suppressing apoptosis and the disposition of collagen fibers in rat livers treated with MTX. Importantly, paeonol upregulated the drug efflux transporters, namely P-glycoprotein (P-gp) and the multidrug resistance-associated protein 2 (Mrp-2) in MTX-treated rats. In conclusion, paeonol offered a potent protective effect against MTX-induced hepatotoxicity through suppressing oxidative stress, inflammation, fibrosis, and apoptosis pathways, along with P-gp and Mrp-2 upregulation.