Crocenzi F A, Sisti A, Pellegrino J M, Roma M G
Instituto de Fisiología Experimental, Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET-U.N.R., Rosario, Argentina.
Toxicology. 1997 Aug 15;121(2):127-42. doi: 10.1016/s0300-483x(97)00064-4.
Colchicine, a microtubule-disrupting agent, induces hepatotoxicity in experimental animals at the doses commonly employed to explore vesicular transport in the liver. The effect of manipulations of the bile salt pool on colchicine-induced hepatotoxicity was studied in rats to determine the role of bile salts in this phenomenon. Leakage of enzyme markers of liver-cell damage into plasma and bile induced by colchicine pre-treatment displayed a sigmoidal log dose-effect curve, the half-maximal effect being reached at 0.12 micromol per 100 g body wt. Lumicolchicine, instead, showed no harmful effect. Maximal increment of biliary LDH discharge induced by colchicine was reduced from 950 +/- 124% to 216 +/- 29% by bile diversion leading to a marked reduction in bile salt output, and this parameter was further decreased to 100 +/- 13% and 157 +/- 39% by subsequent repletion of the bile salt pool with the hydrophilic bile salts taurodehydrocholate and tauroursodeoxycholate, respectively. Conversely, infusion of taurocholate into non-bile salt depleted, colchicine-treated rats led to cholestasis and massive discharge of enzymes into both blood and bile. Our data show conclusively that colchicine-induced hepatotoxicity depends on the magnitude and composition of the bile salt flux traversing the liver. They also support the view that functional integrity of vesicular mechanisms presumably involved in membrane repair are indispensable to protect the hepatocytes from the damaging effect of bile salts during normal bile formation.
秋水仙碱是一种破坏微管的药物，在用于研究肝脏中囊泡运输的常用剂量下，可在实验动物中诱发肝毒性。在大鼠中研究了胆盐池的操作对秋水仙碱诱导的肝毒性的影响，以确定胆盐在这一现象中的作用。秋水仙碱预处理诱导的肝细胞损伤酶标志物向血浆和胆汁中的渗漏呈现出S形对数剂量效应曲线，在每100克体重0.12微摩尔时达到半数最大效应。相反，光秋水仙碱没有显示出有害作用。通过胆汁引流导致胆盐输出显著减少，秋水仙碱诱导的胆汁LDH释放的最大增量从950±124%降至216±29%，随后分别用亲水性胆盐牛磺去氢胆酸盐和牛磺熊去氧胆酸盐补充胆盐池后，该参数进一步降至100±13%和157±39%。相反，向未耗尽胆盐的秋水仙碱处理大鼠输注牛磺胆酸盐会导致胆汁淤积，并使酶大量释放到血液和胆汁中。我们的数据确凿地表明，秋水仙碱诱导的肝毒性取决于穿过肝脏的胆盐通量的大小和组成。它们还支持这样一种观点，即在正常胆汁形成过程中，推测参与膜修复的囊泡机制的功能完整性对于保护肝细胞免受胆盐的损伤作用是不可或缺的。
