School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China.
Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300121, China.
Toxicol Sci. 2021 May 27;181(2):295-305. doi: 10.1093/toxsci/kfab034.
Cholestasis is one of the most severe manifestations of liver injury and has limited therapeutic options. Allopurinol (AP), an inhibitor of uric acid (UA) synthesis, was reported to prevent liver damage in several liver diseases. However, whether AP protects against intrahepatic cholestatic liver injury and what is the role of UA in the pathogenesis of cholestasis remain unknown. In this study, we reported that AP attenuated liver injury in a mouse model of intrahepatic cholestasis induced by alpha-naphthylisothiocyanate (ANIT). AP showed no significant effect on glutathione depletion, inflammation, or bile acid metabolism in livers of ANIT-treated mice. Instead, AP significantly improved fatty acid β-oxidation in livers of ANIT-treated mice, which was associated with activation of PPARα. The protective effect of AP on cholestatic liver injury was not attributable to the depletion of UA, because both exogenous and endogenous UA prevented liver injury in ANIT-treated mice via inhibition of NF-kB-mediated inflammation. In conclusion, the present study provides a new perspective for the therapeutic use of AP and the role of UA in cholestatic liver injury.
胆汁淤积是肝脏损伤的最严重表现之一，其治疗选择有限。别嘌醇 (AP)，一种尿酸 (UA) 合成抑制剂，据报道可预防几种肝脏疾病中的肝损伤。然而，AP 是否能预防肝内胆汁淤积性肝损伤以及 UA 在胆汁淤积发病机制中的作用尚不清楚。在这项研究中，我们报道了 AP 可减轻 α-萘基异硫氰酸酯 (ANIT) 诱导的肝内胆汁淤积小鼠模型中的肝损伤。AP 对 ANIT 处理小鼠肝脏中的谷胱甘肽耗竭、炎症或胆汁酸代谢没有明显影响。相反，AP 可显著改善 ANIT 处理小鼠肝脏中的脂肪酸 β-氧化，这与 PPARα 的激活有关。AP 对胆汁淤积性肝损伤的保护作用并非归因于 UA 的耗竭，因为外源性和内源性 UA 通过抑制 NF-κB 介导的炎症来预防 ANIT 处理小鼠的肝损伤。总之，本研究为 AP 的治疗用途和 UA 在胆汁淤积性肝损伤中的作用提供了新的视角。
