Quercetin attenuates vancomycin-induced acute hepatotoxicity in rats through modulation of Nrf2 and NF-κB related oxidative stress and inflammatory signaling pathways.

Abstract

Vancomycin (VM) therapy is one of the cornerstone options in the treatment of resistant Gram-positive bacterial infections. However, its drawback is associated with the side effect hepatotoxicity during optimal high doses. It is unknown whether quercetin (Que), a natural bioactive flavonoid, could protect the liver against VM-induced hepatotoxicity. The study thus aimed to explore the potential protective effects of Que on VM-induced hepatotoxicity in male Wistar rats. Rats were randomized into groups and administered VM (200 mg/kg body weight, twice a day) and/or Que (100 mg/kg body weight) for 7 consecutive days. The VM injection induced liver dysfunction revealed via significantly elevated serum activities of ALT, AST, and GGT compared to the control group (p < 0.001). VM markedly decreased hepatic activities of SOD, CAT and GPx, while MDA level increased compared to the control group (p < 0.001). Additionally, VM increased TNF-α levels while decreasing IL-10 levels. There were considerable increases in the hepatic expression of caspase-3, NF-κB, Keap1, NOX4, 4-HNE and NLRP3, whereas the expression of HO1, Nrf2, PI3K, p-Akt decreased significantly as revealed by qRT-PCR and immunohistochemical analyses (p < 0.001). Interestingly, the Que administration attenuated the VM-induced alterations on the liver enzymes and antioxidant enzymes, including the MDA and 4-HNE. Que exerted prominent modulatory effects on the mechanistic proteins and mRNA expression in a manner comparable to the control. Overall, the present findings suggest that quercetin may mitigate vancomycin-induced hepatotoxicity in rats by modulating oxidative stress, inflammatory signaling, and apoptosis-related pathways.