Azer S A, Stacey N H
Toxicology Unit, National Institute of Occupational Health and Safety, University of Sydney, New South Wales, Australia.
Toxicol Appl Pharmacol. 1994 Feb;124(2):302-9. doi: 10.1006/taap.1994.1036.
Cyclosporin A treatment has been reported to induce hepatotoxicity marked by a rise in total serum bile acid and total bilirubin. The mechanism of cyclosporin A-induced hepatotoxicity seems to be related to interference with hepatocellular transport of these substrates although this remains to be fully substantiated. The purpose of this study was to investigate whether the hepatocellular uptake of the different bile acids, in the presence of cyclosporin A, is consistent with the changes in their respective individual serum bile acid concentrations. High-performance liquid chromatography has been used to assay individual serum bile acids in cyclosporin A-treated rats at doses of 0.1, 1, and 10 mg/kg/day for 4 days. Control rats were treated with Cremophor (1 ml/kg/day). At the higher doses, cyclosporin A produced a significant increase in levels of cholic acid, taurocholic acid, chenodeoxycholic acid, and deoxycholic acid compared with controls. Serum glycocholate was unaffected even at the highest dose. Inhibition of initial rate of uptake and accumulation of [14C]cholic acid, [14C]chenodeoxycholic acid, and [14C]deoxycholic acid by isolated rat hepatocytes was consistent with the changes in their respective serum bile acids. Coincubation of rat hepatocytes with unlabeled cholic acid (100 microM), the major serum bile acid in cyclosporin A-treated rats, showed a further inhibitory effect on [14C]cholic acid and [14C]deoxycholic acid accumulation. The initial rate of uptake of [14C]glycocholate was also inhibited. However, accumulation of glycocholic acid did not show significant changes at the longer incubation times (2-30 min). In addition, coincubation of rat hepatocytes with unlabeled cholic acid (100 microM) plus cyclosporin A did not induce any inhibition of glycocholate accumulation. Together, these differences provide an explanation for the unchanged serum levels of glycocholate. In conclusion, the changes in individual serum bile acids in cyclosporin A-treated rats are consistent with the effect of this drug on their hepatocellular accumulation.
据报道，环孢素A治疗可引发肝毒性，其特征为血清总胆汁酸和总胆红素升高。环孢素A诱导肝毒性的机制似乎与干扰这些底物的肝细胞转运有关，尽管这一点仍有待充分证实。本研究的目的是调查在环孢素A存在的情况下，不同胆汁酸的肝细胞摄取是否与它们各自血清胆汁酸浓度的变化一致。采用高效液相色谱法测定了环孢素A以0.1、1和10 mg/kg/天的剂量处理4天的大鼠的血清中各胆汁酸。对照大鼠用聚氧乙烯蓖麻油（1 ml/kg/天）处理。与对照组相比，在较高剂量下，环孢素A使胆酸、牛磺胆酸、鹅去氧胆酸和脱氧胆酸水平显著升高。即使在最高剂量下，血清甘氨胆酸盐也未受影响。分离的大鼠肝细胞对[14C]胆酸、[14C]鹅去氧胆酸和[14C]脱氧胆酸摄取和积累初始速率的抑制与它们各自血清胆汁酸的变化一致。大鼠肝细胞与未标记的胆酸（100 microM）共同孵育，胆酸是环孢素A处理大鼠血清中的主要胆汁酸，对[14C]胆酸和[14C]脱氧胆酸的积累有进一步的抑制作用。[14C]甘氨胆酸的摄取初始速率也受到抑制。然而，在较长孵育时间（2 - 30分钟），甘氨胆酸的积累未显示出显著变化。此外，大鼠肝细胞与未标记的胆酸（100 microM）加环孢素A共同孵育未诱导甘氨胆酸盐积累的任何抑制。总之，环孢素A处理大鼠血清中各胆汁酸的变化与该药物对其肝细胞积累的影响一致。
