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

Area of Science:

• Pharmacology and Toxicology
• Natural Product Chemistry
• Hepatology

Background:

• Methotrexate (MTX) is a vital chemotherapeutic and immunosuppressive drug, but its clinical utility is hampered by dose-limiting hepatotoxicity.
• Oxidative stress and inflammation are key mechanisms contributing to MTX-induced liver injury.
• Paeonol, a natural phenolic compound, possesses known antioxidant and anti-inflammatory properties.

Purpose of the Study:

• To evaluate the protective effects of paeonol against methotrexate-induced hepatotoxicity in a rat model.
• To elucidate the underlying mechanisms of paeonol's hepatoprotective action.

Main Methods:

• Rats were administered paeonol (100 mg/kg) orally for 10 days, with or without a single intraperitoneal dose of MTX (20 mg/kg) on day 5.
• Hepatic function, oxidative stress markers (MDA, NO, SOD), inflammatory cytokines (iNOS, TNF-α), cell proliferation (PCNA), apoptosis, collagen deposition, and drug efflux transporters (P-gp, Mrp-2) were assessed.

Main Results:

• Paeonol administration significantly ameliorated MTX-induced liver damage, improving liver function and histological integrity.
• Paeonol treatment restored oxidative stress balance, reduced inflammation, suppressed apoptosis and fibrosis, and upregulated P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (Mrp-2).
• Cell proliferation marker PCNA was upregulated by paeonol in MTX-treated livers.

Conclusions:

• Paeonol demonstrates significant hepatoprotective effects against MTX-induced liver injury in rats.
• The protective mechanisms involve the suppression of oxidative stress, inflammation, apoptosis, and fibrosis.
• Upregulation of drug efflux transporters P-gp and Mrp-2 by paeonol may also contribute to its therapeutic efficacy.