Investigation of the hepatoprotective effect of rapamycin in experimental hepatotoxicity caused by acetaminophen administration

Objective: This thesis aimed to establish a detailed rat model of hepatotoxicity induced by high-dose acetaminophen and to investigate the potential effects of rapamycin on intestinal microbiota and liver injury. Materials and Methods: Thirty Sprague Dawley rats (200–260 g) were used. An experimental hepatotoxicity model was induced by oral administration of a single dose of 835 mg/kg acetaminophen. The rats were given 1.5 mg/kg/day of rapamycin for 3 days, and blood, small intestine, and liver tissue samples were collected. Serum levels of alkaline phosphatase, alanine transaminase, and aspartate aminotransferase were measured from the blood samples. Some of the liver and small intestine tissue samples were used for histological evaluations, while others were used to determine tissue antioxidant and mTOR levels. 16S rRNA-based metagenomic analyses were also performed. Results: While acetaminophen-administered rats exhibited elevated liver enzymes, deterioration in oxidative stress markers, and significant histopathological damage, these effects were alleviated by rapamycin administration in acetaminophen-induced hepatotoxicity. Improvements were observed in biochemical parameters. Histopathological evaluations revealed that rapamycin had partially protective effects. Microbiota analysis revealed that acetaminophen administration had negative effects on bacterial diversity, while rapamycin provided stabilizing effects in some species, but was not fully curative. Conclusion: Rapamycin demonstrated partial hepatoprotective and microbiota-stabilizing effects in acetaminophen -induced hepatotoxicity. These beneficial outcomes were parameter-dependent and not completely restorative. The findings suggest that rapamycin's efficacy may depend on dose, treatment duration, and experimental protocol. Further long-term and dose-optimization studies are warranted to confirm its potential in mitigating hepatotoxicity and bacterial translocation.