Hypophyllanthin Protects Against Alcohol-Induced Hepatotoxicity in Rats: Involvement of Oxidative Stress, Inflammatory Cytokines, Apoptosis, and Autophagy
Abstract
Introduction Ethanol consumption is a primary global health concern, frequently leading to severe hepatic injury. The present study assessed the hepatoprotective effects of hypophyllanthin against ethanol-induced hepatotoxicity in rats. Methods A Wistar rats were randomly assigned into five groups (n=6/group): Group I (normal control), Group II (ethanol control), Group III-IV (ethanol + low-high-doses hypophyllanthin [5 and 10 mg/kg]), and Group V (high-dose hypophyllanthin per se [10 mg/kg]). At the end of the study, the biochemical assessment, including serum biomarkers (ALT, AST, ALP, TG, TBA, TC), serum alcohol, oxidative stress, inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-α), interleukins (IL-1β and IL-6), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), caspase-3, Beclin-1, and LC3B, complex II, and complex IV, were determined. Additionally, a histological evaluation was also performed. Results Hypophyllanthin significantly attenuated ethanol-induced oxidative stress, as evidenced by decreased mitochondrial enzymes such as complex II and complex IV, as well as increased activity of antioxidant enzymes (SOD, CAT, GSH) and decreased lipid peroxidation (MDA). Hypophyllanthin mitigated inflammation by reducing cytokines (IL-1β, IL-6, TNF-α, NF-κB, iNOS, and COX-2) and serum biomarkers (ALT, AST, ALP, TG, TBA, and TC), as well as serum alcohol levels. Hypophyllanthin promoted apoptosis by modulating caspase-3 activity, facilitating the elimination of damaged cells. It also inhibited autophagy by suppressing the levels of Beclin-1 and LC3B, potentially limiting excessive cellular degradation. Histopathological analysis confirmed the protective effects of hypophyllanthin, demonstrating reduced hepatic necrosis, steatosis, and inflammatory cell infiltration. A dose-dependent effect was observed between the treated groups. Discussion These findings suggested a strong physiological basis for ethanol-induced hepatotoxicity and the hepatoprotective effects of hypophyllanthin.