Ethyl gallate attenuates 5-fluorouracil induced hepatic injury via MAPK/NF-κB downregulation in rats

5-Fluorouracil (5-FU) is known to cause liver injury in cancer patients. Experimental studies have reported that administration of 5-FU induces oxidative stress and inflammation in liver tissue. Ethyl gallate (EG), a plant-derived phytocompound, has been shown to possess antioxidant and anti-inflammatory properties. Therefore, in this study, we evaluated the protective effect of EG against 5-FU-induced acute liver injury in rats.

Rats were intraperitoneally injected with a single dose of 5-FU (150 mg/kg) to induce acute liver injury. In separate groups, rats were concurrently treated with EG (10 and 20 mg/kg) or silymarin (SIL) daily once for 7 days. At the end of an experimental period, serum transaminase activities, oxidative stress markers, inflammatory markers, and histopathological changes were assessed in liver tissue.

A single dose of 5-FU caused a significant increase of transaminases in serum and oxidative stress, and DNA fragmentation in liver tissue. 5-FU administration also decreased the mRNA expression of its catabolizing enzyme, dihydropyrimidine dehydrogenase. At the molecular level, 5-FU upregulated apoptosis signal-regulating kinase 1, c-Jun N-terminal kinase 1, and extracellular signal-regulated kinase 1 mRNA expressions in liver tissue. It also downregulated nuclear factor erythroid 2-related factor 2 and upregulated its inhibitor Kelch-like ECH-associated protein 1, indicating oxidative stress. Similarly, 5-FU administration increased tumor necrosis factor-α and nuclear factor kappa B (NF-κB) expression while reducing its inhibitor, inhibitor of κB, confirming the activation of inflammation cascade. These abnormalities were significantly prevented in rats treated concurrently with EG or SIL. Histopathological analysis revealed reduced necrosis and better preservation of liver architecture in the 5-FU + EG and 5-FU + SIL groups.

Our study demonstrates that EG and SIL treatments effectively alleviate 5-FU-induced acute liver injury by modulating 5-FU catabolism and suppressing the mitogen-activated protein kinase and NF-κB signaling pathways in rats.