Deters M, Strubelt O, Younes M
Institut für Toxikologie der Medizinischen Universität zu Lübeck, Germany.
Toxicology. 1997 Dec 5;123(3):197-206. doi: 10.1016/s0300-483x(97)00123-6.
Livers of male rats were perfused for 120 min in a recirculating hemoglobin-free system with different concentrations of cyclosporine (CS 2, 10, 50, 150 and 200 mg/l). CS produced damage to the livers in a dose dependent manner. The first sign of hepatotoxicity was a reduction of bile flow amounting to 50% already at 50 mg/l CS. At concentrations of 150 mg/l and 200 mg/l, CS lead to a nearly complete suppression of bile flow, furthermore to a release of cytosolic (GPT, glutamate-pyruvate transaminase, LDH, lactate dehydrogenase) and mitochondrial (GLDH, glutamate dehydrogenase) enzymes into the perfusate and to a decrease in hepatic oxygen consumption (30% at 200 mg/l CS). As a consequence of the reduced aerobic energy supply, hepatic ATP concentration declined (70% at 200 mg/l CS). The hepatic concentrations of reduced glutathione (GSH) were not changed but those of oxidized glutathione (GSSG) increased up to 5-fold by CS. Malondialdehyde (MDA) concentrations in the liver and in the perfusate were not affected consistently by CS. The toxic actions of CS in the isolated rat liver were not influenced (a) by the feeding status of the rats (fed or fasted before surgery) or (b) by addition of superoxide dismutase (SOD, 20 mg/l) and catalase (20 mg/l) to the perfusate 30 min before CS. On the other hand, CS-induced hepatic injury could be attenuated or inhibited completely by addition to the perfusate of (1) 2 mmol/l GSH; (2) 12 mmol/l serine; (3) 12 mmol/l glycine; (4) 0.09 mmol/l deferoxamine (DFO).
CS induces cholestasis at lower concentrations, probably by another mechanism(s) than the other signs of hepatotoxicity (enzyme release, ATP depletion). Several lines of evidence indicate a probable participation of reactive oxygen species in CS-induced hepatotoxicity. GSH, DFO, glycine and serine could provide therapeutic opportunities to prevent CS-induced hepatotoxicity in patients treated with high doses of CS.
在无血红蛋白的循环系统中，用不同浓度（2、10、50、150和200毫克/升）的环孢素对雄性大鼠肝脏进行120分钟的灌注。环孢素以剂量依赖性方式对肝脏造成损伤。肝毒性的第一个迹象是胆汁流量减少，在环孢素浓度为50毫克/升时，胆汁流量已减少50%。在150毫克/升和200毫克/升的浓度下，环孢素导致胆汁流量几乎完全抑制，此外还导致细胞溶质酶（谷丙转氨酶、乳酸脱氢酶）和线粒体酶（谷氨酸脱氢酶）释放到灌注液中，并导致肝脏耗氧量降低（在环孢素浓度为200毫克/升时降低30%）。由于有氧能量供应减少，肝脏ATP浓度下降（在环孢素浓度为200毫克/升时下降70%）。肝脏中还原型谷胱甘肽（GSH）的浓度没有变化，但氧化型谷胱甘肽（GSSG）的浓度因环孢素增加了5倍。环孢素对肝脏和灌注液中丙二醛（MDA）浓度的影响并不一致。环孢素在离体大鼠肝脏中的毒性作用不受以下因素影响：（a）大鼠的喂养状态（手术前喂食或禁食），或（b）在加入环孢素前30分钟向灌注液中添加超氧化物歧化酶（20毫克/升）和过氧化氢酶（20毫克/升）。另一方面，通过向灌注液中添加以下物质，环孢素诱导的肝损伤可以减轻或完全抑制：（1）2毫摩尔/升谷胱甘肽；（2）12毫摩尔/升丝氨酸；（3）12毫摩尔/升甘氨酸；（4）0.09毫摩尔/升去铁胺（DFO）。
环孢素在较低浓度下诱导胆汁淤积，其机制可能与肝毒性的其他迹象（酶释放、ATP耗竭）不同。多项证据表明活性氧可能参与环孢素诱导的肝毒性。谷胱甘肽、去铁胺、甘氨酸和丝氨酸可为高剂量环孢素治疗的患者预防环孢素诱导的肝毒性提供治疗机会。
