Azer S A, Stacey N H
National Institute of Occupational Health and Safety, University of Sydney, Australia.
Biochem Pharmacol. 1993 Sep 1;46(5):813-9. doi: 10.1016/0006-2952(93)90489-j.
Cyclosporin A (CsA) treatment has been reported to cause rises in serum bile acids both in humans and rats. It has also been shown to suppress bile flow in situ in rats and inhibit the transport of bile salts by rat hepatocytes. The purpose of this study was to examine the influence of CsA on uptake of radiolabelled cholate (CA), glycocholate (GC) and taurocholate (TC) by isolated human hepatocytes. CsA did not significantly change Vmax for CA uptake [0.23 +/- 0.01 vs 0.25 +/- 0.02 nmol/mg protein/min for control and CsA (10 microM), respectively], but significantly increased Km (37 +/- 2 vs 86 +/- 8 microM). Similarly, Vmax for TC uptake was not affected (0.51 +/- 0.02 vs 0.67 +/- 0.05 nmol/mg protein/min) while Km was significantly increased [46 +/- 3 vs 109 +/- 11 microM for control and CsA (10 microM), respectively]. On the other hand, neither Vmax nor Km for GC uptake was affected by CsA. The data indicate a competitive pattern of inhibition induced by CsA on CA and TC uptake. Furthermore, CsA was found to cause a dose-related inhibition of accumulation of both cholate and taurocholate, but not GC accumulation. None of the concentrations of CsA showed a significant effect on the integrity of the human hepatocytes as assessed by ALT (alanine aminotransferase), AST (aspartate aminotransferase) and LDH (lactate dehydrogenase) release. The findings, in human hepatocytes, are generally consistent with the observations reported from rodent studies. They strongly support the contention that serum bile acid increases in CsA-treated patients are due to interference with the hepatocellular transport and accumulation of particular bile acids.
据报道，环孢素A（CsA）治疗可导致人类和大鼠血清胆汁酸升高。研究还表明，它可抑制大鼠原位胆汁流动，并抑制大鼠肝细胞对胆盐的转运。本研究的目的是检测CsA对分离的人肝细胞摄取放射性标记胆酸盐（CA）、甘氨胆酸盐（GC）和牛磺胆酸盐（TC）的影响。CsA对CA摄取的最大速率（Vmax）没有显著影响[对照组和CsA（10μM）分别为0.23±0.01与0.25±0.02 nmol/mg蛋白/分钟]，但显著增加了米氏常数（Km）（37±2与86±8μM）。同样，TC摄取的Vmax未受影响（0.51±0.02与0.67±0.05 nmol/mg蛋白/分钟），而Km显著增加[对照组和CsA（10μM）分别为46±3与109±11μM]。另一方面，CsA对GC摄取的Vmax和Km均无影响。数据表明CsA对CA和TC摄取诱导的是竞争性抑制模式。此外，发现CsA对胆酸盐和牛磺胆酸盐的积累均有剂量相关的抑制作用，但对GC积累无影响。通过丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）和乳酸脱氢酶（LDH）释放评估，CsA的任何浓度对人肝细胞的完整性均无显著影响。在人肝细胞中的这些发现总体上与啮齿动物研究报告的观察结果一致。它们有力地支持了以下观点：CsA治疗患者血清胆汁酸升高是由于对特定胆汁酸的肝细胞转运和积累的干扰。
