Cyclosporin A-induced cholestasis. The mechanism in a rat model.
Cyclosporin A-induced cholestasis. The mechanism in a rat model.
复制标题
环孢素A诱导的胆汁淤积。
作者：
Bradford G. Stone;Bradford G. Stone;Mahendra Udani;Mahendra Udani;Ajit Sanghvi;Ajit Sanghvi;Vijay Warty;Vijay Warty;Keith Plocki;Keith Plocki;Carlos D. Bedetti;Carlos D. Bedetti;David H. Van Thiel;David H. Van Thiel
环孢菌素A（CyA）在相当大比例的移植患者中引起胆汁淤积。将5、10和15 mg CyA/kg体重剂量或Miglyol 812溶媒腹膜内给药1、2和3周，以研究这种胆汁淤积的机制。在第1周，血清CyA水平和增加CyA剂量之间的剂量反应关系。10和15 mg/kg剂量组在2周时达到最大CyA血液水平。随后的研究使用较小剂量（10 mg/kg）给药3周。与溶剂处理对照组相比，该剂量导致血清胆汁酸水平显著升高（24.6 +/-4.0 vs. 4.3 +/-1.2 mumol/L，p <0.001），而未诱导血清谷草转氨酶、血清谷草转氨酶、胆红素、碱性磷酸酶和白蛋白水平的显著变化或肝结构改变。与溶剂处理的动物相比，CyA处理的基线胆汁流量减少35%，胆盐分泌减少25%。环孢菌素A和溶剂处理的大鼠静脉输注牛磺胆酸盐（4 μ mol/min X kg）2 h，然后在接下来的24 h内耗尽胆汁盐。将在此期间收集的胆汁样品绘制为胆盐分泌与胆汁流量。CyA处理大鼠的线性回归的平均斜率为对照的62%，表明胆盐依赖性流量降低。线性回归外推到纵坐标显示CyA治疗的胆汁非依赖性流量减少22%。因此，在我们的CyA诱导胆汁淤积的实验模型中，观察到的流量减少是胆盐依赖性和胆盐非依赖性流量减少的结果，并且发生在没有显著的生化或组织学明显肝毒性的情况下。
Cyclosporin A (CyA) causes cholestasis in a significant proportion of transplant patients. Doses of 5, 10, and 15 mg CyA/kg body wt or the Miglyol 812 vehicle were administered intraperitoneally for 1, 2, and 3 wk to separate groups of rats to investigate the mechanism of this cholestasis. At 1 wk a dose-response relationship between serum CyA levels and increasing CyA doses was noted. A maximum CyA blood level was achieved by 2 wk with the 10- and 15-mg/kg doses. Subsequent studies were performed using the smaller (10 mg/kg) dose administered for 3 wk. This dose resulted in a marked increase in serum bile acid levels compared with vehicle-treated controls (24.6 +/- 4.0 vs. 4.3 +/- 1.2 mumol/L, p less than 0.001) without inducing significant changes in serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, bilirubin, alkaline phosphatase, and albumin levels or hepatic architectural alterations. With CyA treatment, baseline bile flow decreased by 35% and bile salt secretion decreased by 25% compared with vehicle-treated animals. Cyclosporin A and vehicle-treated rats were infused intravenously with taurocholate (4 mumol/min X kg) for 2 h and then depleted of bile salts over the next 24 h. Bile samples collected over this period were graphed as bile salt secretion versus bile flow. The mean slope of the linear regression for the CyA-treated rats was 62% of the control, demonstrating a decrease in bile salt-dependent flow. Extrapolation of the linear regression to the ordinate demonstrated a 22% decrease in bile-independent flow with CyA treatment. Therefore, in our experimental model of CyA-induced cholestasis, the decrease in flow observed was the result of a decrease in both bile salt-dependent and bile salt-independent flows and occurred in the absence of significant biochemical or histologically evident hepatotoxicity.
影响因子：
6.5
作者：
Gurantz,D;Laker,MF;Hofmann,AF
通讯作者：
Hofmann,AF