Department of Internal Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan.
Antioxid Redox Signal. 2010 Aug 1;13(3):259-68. doi: 10.1089/ars.2009.2903.
The cytoprotective mechanisms of ursodeoxycholic acid (UDCA) in primary biliary cirrhosis (PBC) have not been fully clarified. UDCA has some antioxidant properties. Nuclear factor-E2-related factor-2 (Nrf2) plays a critical role in protecting a variety of tissues against oxidative stress. Therefore, to investigate the potential antioxidant effects of UDCA in PBC, we determined the intracellular status of both oxidant stress and antioxidant defenses in paired pre- and posttreatment liver biopsies from 13 PBC patients by immunodetection of 8-hydroxydeoxyguanosine (8-OHdG), Nrf2-, and Nrf2-mediated antioxidant proteins. After UDCA treatment, the number of 8-OHdG-positive hepatocytes or bile duct cells decreased with improvement of hepatic injury. The hepatic levels of both total and phosphorylated Nrf2 protein were increased, along with upregulation of nuclear phosphorylated Nrf2 expression in bile duct cells. In addition, the levels of both thioredoxin (TRX) and thioredoxin reductase 1 (TrxR1) protein were increased in the liver after UDCA. The upregulation of hepatic TRX or TrxR1 protein expression positively correlated with that of total Nrf2 protein expression. In conclusion, UDCA treatment can enhance hepatic Nrf2 activation and upregulate hepatic TRX and TrxR1 protein expression. Hepatic Nrf2 activation may play a role in the therapeutic response to UDCA in PBC.
熊去氧胆酸（UDCA）在原发性胆汁性肝硬化（PBC）中的细胞保护机制尚未完全阐明。UDCA 具有一些抗氧化特性。核因子-E2 相关因子-2（Nrf2）在保护各种组织免受氧化应激方面起着关键作用。因此，为了研究 UDCA 在 PBC 中的潜在抗氧化作用，我们通过免疫检测 8-羟基脱氧鸟苷（8-OHdG）、Nrf2-和 Nrf2 介导的抗氧化蛋白，在 13 例 PBC 患者的配对治疗前后肝活检中确定了氧化应激和抗氧化防御的细胞内状态。在 UDCA 治疗后，随着肝损伤的改善，8-OHdG 阳性肝细胞或胆管细胞的数量减少。总 Nrf2 蛋白和磷酸化 Nrf2 蛋白的肝水平增加，胆管细胞中核磷酸化 Nrf2 表达上调。此外，在 UDCA 治疗后，肝脏中硫氧还蛋白（TRX）和硫氧还蛋白还原酶 1（TrxR1）蛋白的水平也增加。肝 TRX 或 TrxR1 蛋白表达的上调与总 Nrf2 蛋白表达的上调呈正相关。总之，UDCA 治疗可增强肝 Nrf2 激活并上调肝 TRX 和 TrxR1 蛋白表达。肝 Nrf2 激活可能在 PBC 对 UDCA 的治疗反应中起作用。
