Hepatoprotective efficacy of L-arginine in mitigating amiodarone-induced hepatotoxicity: Mechanistic insights and therapeutic implications.

Amiodarone, a vital class III antiarrhythmic drug, carries a significant risk of dose-dependent hepatotoxicity, driven by oxidative stress and inflammation. There is a critical lack of approved prophylactic agents to mitigate this liver injury. This study investigated the therapeutic potential of L-arginine, a semi-essential amino acid with antioxidative and anti-inflammatory properties, to protect against amiodarone-induced hepatotoxicity in a rat model. Forty male Wistar rats were allocated into five groups: a negative control; L-arginine control (100 mg/100 g/day); an amiodarone-only group (50 mg/kg/day i.p.); and groups receiving amiodarone co-administered with low- or high-dose L-arginine for six days. We assessed liver function, oxidative stress markers, inflammatory cytokines, histopathology, and fibrogenic gene expression. Amiodarone intoxication significantly induced liver damage, evidenced by elevated liver enzymes (ALT, AST, GGT & ALP), oxidative stress (increased MDA, depleted SOD, CAT, GSH), and pro-inflammatory cytokines (TNF-α, IL-6, IL-17). It also promoted fibrosis, upregulating Acta2 and Col1a1 gene expression and causing severe histological alterations. Co-treatment with high-dose L-arginine effectively normalized liver enzymes, restored antioxidant defenses, suppressed inflammatory and fibrogenic mediators, and preserved hepatic architecture, as confirmed by histology and immunohistochemistry. L-arginine confers protection, which is associated with the amelioration of oxidative stress, inflammation, and fibrotic markers. Its role as a NO precursor suggests a plausible contributing pathway meriting further investigation.