Acetaminophen (APAP) overdose-induced hepatotoxicity is tightly associated with oxidative stress. Tetrahydrocurcumin (THC) and octahydrocurcumin (OHC), the primary and final hydrogenated metabolites of curcumin (CUR), possess stronger antioxidant activity in vitro. The present study was performed to investigate the potential and mechanism of OHC and THC against APAP-induced hepatotoxicity in parallel to CUR. Our results showed that OHC and THC dose-dependently enhanced liver function (ALT and AST levels) and alleviated histopathological deterioration. Besides, OHC and THC significantly restored the hepatic antioxidant status by miring level of MDA and ROS, and elevated levels of GSH, SOD, CAT and T-AOC. In addition, OHC and THC markedly suppressed the activity and expressions of CYP2E1, and bound to the active sites of CYP2E1. Moreover, OHC and THC activated the Keap1-Nrf2 pathway and enormously enhanced the translational activation of Nrf2-targeted gene (GCLC, GCLM, NQO1 and HO-1) against oxidative stress, via inhibiting the expression of Keap1 and blocking the interaction between Keap1 and Nrf2. Particularly, OHC and THC exerted superior hepato-protective and antioxidant activities to CUR. In conclusion, OHC and THC possess favorable hepato-protective effect through restoring antioxidant status, inhibiting CYP2E1 and activating Keap1-Nrf2 pathway, which might represent promising antioxidants for the treatment of APAP-induced hepatotoxicity.

对乙酰氨基酚（APAP）过量引起的肝毒性与氧化应激密切相关。四氢姜黄素（THC）和八氢姜黄素（OHC）是姜黄素（CUR）的主要和最终氢化产物，在体外具有更强的抗氧化活性。进行本研究以调查OHC和THC与CUR平行对抗APAP诱导的肝毒性的潜力和机制。我们的结果表明，OHC和THC剂量依赖性地增强了肝功能（ALT和AST水平）并减轻了组织病理学恶化。此外，通过观察MDA和ROS的水平以及升高的GSH，SOD，CAT和T-AOC的水平，OHC和THC可以显着恢复肝脏的抗氧化状态。此外，OHC和THC显着抑制CYP2E1的活性和表达，并与CYP2E1的活性位点结合。此外，OHC和THC激活了Keap1-Nrf2途径，并通过抑制Keap1的表达并阻断了Keap1和Nap的相互作用，极大地增强了Nrf2靶向基因（GCLC，GCLM，NQO1和HO-1）针对氧化应激的翻译激活。 Nrf2。特别是，OHC和THC对CUR具有优异的肝保护和抗氧化活性。总之，OHC和THC通过恢复抗氧化剂状态，抑制CYP2E1和激活Keap1-Nrf2途径具有良好的肝保护作用，这可能是治疗APAP所致肝毒性的有希望的抗氧化剂。