Department of Pharmacy, Wuhan Fourth Hospital.
Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
J Tradit Chin Med. 2019 Jun;39(3):402-409.
To investigate the pathway through which Calculus Bovis Sativus (CBS) up-regulates hepatic multidrug resistance-associated protein 2 (Mrp2) and Mrp4 in 17α-ethynylestradiol (EE)-induced cholestasis.
Five groups of rats were designed: control group, EE+ICI182780 group, EE group, EE+CBS 50 mg/kg group and EE + CBS 150 mg/kg group. CBS (50 and 150 mg·kg－1·d－1 ) was orally given to rats by gavage for five consecutive days in coadministration with EE. The levels of cholestasis biomarkers, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bilirubin (TBIL) were determined by biochemical methods. The bile flow was measured. The histopathology of the liver tissue was evaluated. The expression of Mrp2, Mrp3, Mrp4, estrogen receptor α (ERα) and ERß was determined by Western blotting.
CBS markedly improved EE-induced cholestasis. EE exposure significantly reduced hepatic Mrp2 and Mrp4 expression compared with the control group. EE also dramatically up-regulated the expression of Mrp3. Compared to the EE group, CBS notably up-regulated hepatic Mrp2 and Mrp4 but failed to influence the Mrp3 level significantly. ICI182780, an ER antagonist, showed similar beneficial effects as CBS. Decreased expression of Mrp2 and Mrp4 caused by EE was also restored by ICI182780. Additionally, EE significantly induced he- patic ERα expression, which was reversed by ICI182780 or CBS (150 mg/kg) treatment, suggesting that CBS exerted a moderate regulatory effect on ER signaling.
CBS up-regulated hepatic Mrp2 and Mrp4 expression in EE-induced cholestasis, which might be associated with its regulation of ER signaling.
研究磁石（CBS）上调 17α-乙炔基雌二醇（EE）诱导的胆汁淤积中肝多药耐药相关蛋白 2（Mrp2）和 Mrp4 的途径。
设计了五组大鼠：对照组、EE+ICI182780 组、EE 组、EE+CBS 50mg/kg 组和 EE+CBS 150mg/kg 组。连续 5 天，EE 合用 CBS（50 和 150mg·kg－1·d－1）灌胃给药。采用生化方法测定胆汁淤积生物标志物丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、碱性磷酸酶（ALP）和总胆红素（TBIL）水平。测量胆汁流量。评估肝组织的组织病理学。通过 Western 印迹法测定 Mrp2、Mrp3、Mrp4、雌激素受体 α（ERα）和 ERß 的表达。
CBS 显著改善 EE 诱导的胆汁淤积。与对照组相比，EE 暴露显著降低了肝 Mrp2 和 Mrp4 的表达。EE 还显著上调了 Mrp3 的表达。与 EE 组相比，CBS 显著上调了肝 Mrp2 和 Mrp4，但对 Mrp3 水平无明显影响。ER 拮抗剂 ICI182780 表现出与 CBS 相似的有益作用。EE 引起的 Mrp2 和 Mrp4 表达减少也被 ICI182780 恢复。此外，EE 显著诱导肝 ERα 表达，这被 ICI182780 或 CBS（150mg/kg）处理逆转，表明 CBS 对 ER 信号发挥了适度的调节作用。
CBS 上调 EE 诱导的胆汁淤积中肝 Mrp2 和 Mrp4 的表达，这可能与其对 ER 信号的调节有关。
