Hepatoprotective effects of the xanthine oxidase inhibitor Febuxostat against thioacetamide-induced liver injury in rats: The role of the Nrf2/ HO-1 and TLR4/ NF-κB pathways.

Experimental models of liver injury have been established utilizing thioacetamide (TAA), a classic liver toxic chemical that causes organ damage via oxidative stress and inflammatory induction. This study examined the impact of Febuxostat (a xanthine oxidase inhibitor; Febu, 10-15 mg/kg, orally) against TAA (500 mg/kg, i.p.) -induced liver injury in rats. Febu significantly attenuated TAA-induced alterations in liver function parameters, in addition to promoting hepatic antioxidant effects through a significant elevation of Heme-oxygenase-1(HO-1), nuclear factor erythroid 2-related factor2 (Nrf2), reduced glutathione (GSH) and superoxide dismutase (SOD) levels and reduction in hepatic malondialdehyde (MDA) content. Moreover, Febu improved the hepatic anti-inflammatory status by increasing the anti-inflammatory cytokine Interleukin (IL-10) level and reducing the levels of the pro-inflammatory cytokines (Nuclear factor kappa B (NF-κB), IL-1β, high-mobility group box1 (HMGB1), receptor for advanced glycation end products (RAGE), and toll-like receptor4 (TLR4) levels, in addition to suppressing the increased protein and mRNA expression levels of tumor necrosis factor alpha (TNF-α) and IL-6, hepatic expression of TNF-α and activated mitogen-activated protein kinases (p-JNK/p-p38 MAPK). Histopathologically, Febu markedly normalized TAA-induced alteration in liver sections. In conclusion, Febu, in a dose-dependent fashion, refines TAA-induced hepatotoxicity by enhancing antioxidant capabilities and decreasing inflammatory signals.