Pyrazinamide Induced Rat Cholestatic Liver Injury through Inhibition of FXR Regulatory Effect on Bile Acid Synthesis and Transport
Pyrazinamide Induced Rat Cholestatic Liver Injury through Inhibition of FXR Regulatory Effect on Bile Acid Synthesis and Transport
复制标题
吡嗪酰胺通过抑制 FXR 对胆汁酸合成和运输的调节作用诱导大鼠胆汁淤积性肝损伤
DOI：
10.1093/toxsci/kfw098
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发表时间：
2016-08-01
影响因子：
3.8
通讯作者：
Jiang, Zhen-Zhou
中科院分区：
文献类型：
--
作者：
Guo, Hong-Li;Hassan, Hozeifa M.;Jiang, Zhen-Zhou
吡嗪酰胺（PZA）是治疗结核病不可缺少的一线药物，可引起严重的肝毒性；然而，人们对这些毒性的机制知之甚少。胆汁淤积在药物性肝损伤中起重要作用。由于之前没有发表的文献报道胆汁淤积与PZA肝毒性的关系，本研究旨在确定PZA是否可以诱导具有胆汁淤积特征的肝损伤，并阐明PZA诱导的肝损伤中胆汁酸合成和转运相关蛋白的表达变化。通过口服管饲法连续7天施用PZA（2g/kg）。结果显示，PZA 治疗大鼠的 ALT 和 AST 血清水平均升高 2 倍。此外，服用 PZA 后观察到血清总胆汁酸增加了 10 倍。胆汁酸合成和转运参数的 mRNA 和蛋白表达显着改变，其中 FXR、Bsep、Mrp2、Mdr2、Ost α/β、Oatp1a1、Oatp1b2 和 Cyp8b1 降低（P
Pyrazinamide (PZA) is an indispensable first-line drug used for the treatment of tuberculosis which may cause serious hepatotoxicity; however, the mechanisms underlying these toxicities are poorly understood. Cholestasis plays an important role in drug-induced liver injury. Since there were no previous published works reported cholestasis and PZA hepatotoxicity relationship, this study aimed to identify whether PZA can induce liver injury with characterized evidences of cholestasis and to clarify expression changes of proteins related to both bile acid synthesis and transport in PZA-induced liver injury. PZA (2 g/kg) was administered for 7 consecutive days by oral gavage. Results showed there were 2-fold elevation in both ALT and AST serum levels in PZA-treated rats. In addition, a 10-fold increment in serum total bile acid was observed after PZA administration. The mRNA and protein expressions of bile acid synthesis and transport parameters were markedly altered, in which FXR, Bsep, Mrp2, Mdr2, Ost alpha/beta, Oatp1a1, Oatp1b2, and Cyp8b1 were decreased (P