Gallic and glycyrrhetinic acids prevent azithromycin-induced liver damage in rats by mitigating oxidative stress and inflammation

Natural products like gallic acid (GA), a phenolic compound, and glycyrrhetinic acid (GLA), a pentacyclic triterpene, have been shown to exhibit antioxidant, ant-inflammatory, and hepatoprotective properties. This study aims to investigate the protective effects of GA, GLA and their combination and to explore their underlying mechanisms against acute liver damage induced by azithromycin (AZM) in rats. Seven groups of male Wistar rats were used namely control, GA, GLA, AZM, AZM + GA, AZM + GLA, and AZM + GA + GLA groups. We treated the rats for 21 days, administering GA and GLA at 50 mg/kg one week prior to AZM (30 mg/kg). Serum levels of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase in rats AZM-induced and pre-treated with of GA, GLA, and combination therapy were much lower than those in the AZM group Elevated levels of glutathione, catalase, and superoxide dismutase in preventive rats demonstrated that GA, GLA, and their combinations notably reduced AZM-induced malondialdehyde levels, an oxidative stress marker, improving the antioxidant system in those groups. Furthermore, GA, GLA, and their combinations reduced pro-inflammatory cytokines, such as tumor necrosis factor-α and nuclear factor kappa beta (NF-kB), thus reversing hepatic inflammation. We also discovered that AZM down-regulated nuclear factor erythroid 2-related factor 2 (Nrf2), and that its normal levels were restored post treatments with GA, GLA, and their combination suggesting a Nrf2 signaling pathway-mediated prevention of AZM-induced liver damage. In conclusion, GA, GLA, and their combination protected rats against AZM-induced liver injury through their demonstrated ability to lower oxidative stress and inflammation by preventing downregulation of Nrf2 and upregulation of NF-kB. After determining their efficacy and safety in clinical settings in future studies, GA and GLA could potentially make useful therapeutic drugs to mitigate AZM-induced hepatotoxicity.