Shuguang Hospital Affiliated with Shanghai University of Traditional Chinese Medicine, No. 528 Zhangheng Road, Shanghai 201203, People's Republic of China; Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated with Shanghai University of Traditional Chinese Medicine, No. 528 Zhangheng Road, Shanghai 201203, People's Republic of China.
Shuguang Hospital Affiliated with Shanghai University of Traditional Chinese Medicine, No. 528 Zhangheng Road, Shanghai 201203, People's Republic of China; Laboratory of Clinical Pharmacokinetics, Shuguang Hospital Affiliated with Shanghai University of Traditional Chinese Medicine, No. 528 Zhangheng Road, Shanghai 201203, People's Republic of China.
Toxicol Appl Pharmacol. 2018 Mar 1;342:69-78. doi: 10.1016/j.taap.2018.01.019. Epub 2018 Feb 1.
The aim of this study was to determine the effect of ursodeoxycholic acid (UDCA) on the alpha-naphthylisothiocyanate (ANIT)-induced acute and recovery stage of cholestasis model mice. In the acute stage of model mice, pretreatment with UDCA (25, 50, and 100 mg·kg, ig) for 12 days prior to ANIT administration (50 mg·kg, ig) resulted in the dramatic increase in serum biochemistry, with aggrevation of bile infarcts and hepatocyte necrosis. The elevation of beta-muricholic acid (β-MCA), cholic acid (CA), and taurocholic acid (TCA) in serum and liver, and reduction of these bile acids (BAs) in bile was observed. In contrast, in the recovery stage of model mice, treatment with UDCA (25, 50, and 100 mg·kg, ig) for 7 days after ANIT administration (50 mg·kg, ig) resulted in the significant decrease in levels of serum alanine aminotransferase (ALT) and total bile acid (TBA). Liver injury was attenuated, and the levels of TBA, CA, TCA, and β-MCA in the liver were significantly decreased. Additionally, UDCA can upregulate expression of BSEP, but it cannot upregulate expression of AE2. UDCA, which induced BSEP to increase bile acid-dependent bile flow, aggravated cholestasis and liver injury when the bile duct was obstructed in the acute stage of injury in model mice. In contrast, UDCA alleviated cholestasis and liver injury induced by ANIT when the obstruction was improved in the recovery stage.
本研究旨在探讨熊去氧胆酸（UDCA）对α-萘异硫氰酸酯（ANIT）诱导的急性和恢复期胆汁淤积模型小鼠的影响。在模型小鼠的急性阶段，在给予 ANIT（50mg·kg，ig）前用 UDCA（25、50 和 100mg·kg，ig）预处理 12 天，导致血清生化指标显著升高，胆汁淤积和肝细胞坏死加重。观察到血清和肝脏中β-鼠胆酸（β-MCA）、胆酸（CA）和牛磺胆酸（TCA）的升高，以及胆汁中这些胆汁酸（BAs）的减少。相比之下，在模型小鼠的恢复期，在给予 ANIT（50mg·kg，ig）后用 UDCA（25、50 和 100mg·kg，ig）治疗 7 天，导致血清丙氨酸氨基转移酶（ALT）和总胆汁酸（TBA）水平显著降低。肝损伤减轻，肝内 TBA、CA、TCA 和 β-MCA 的水平明显降低。此外，UDCA 可以上调 BSEP 的表达，但不能上调 AE2 的表达。UDCA 诱导 BSEP 增加依赖胆汁酸的胆汁流量，在模型小鼠损伤的急性阶段胆管阻塞时加重胆汁淤积和肝损伤。相反，在恢复期阻塞改善时，UDCA 缓解了 ANIT 诱导的胆汁淤积和肝损伤。
