TRIMETHYLCOLCHICINIC ACID DECREASES LIVER FIBROSIS AND CHOLESTASIS INDUCED BY PROLONGED BILIARY OBSTRUCTION IN THE RAT

Colchicine is effective in decreasing hepatic fibrosis. However, sever al toxic reactions have been reported after colchicine treatment which are attributed to its ability to bind tubulin. The aim of this work i s to determine if trimethylcolchicinic acid, which does not bind tubul in, is able to decrease experimental liver fibrosis and cholestasis. I n male Wistar rats, the common bile duct was ligated, Administration o f trimethylcolchicinic acid (TMCA, 100 mu g rat(-1) day(-1), p.o.) beg an 4 weeks after biliary obstruction and continued for a further 4 wee ks, The liver was used for histological and ultrastructural analysis a nd for collagen quantification (hydroxyproline content). The degradati on of Matrigel(R) and collagen (types I and III), as well as plasminog en activator activity, was determined in liver homogenates. Bilirubins and enzyme activities were measured in serum. Trimethylcolchicinic ac id was able to improve normal liver histology, ultrastructure, collage n content and biochemical markers of liver damage. It also increased m atrigel degradation and plasminogen activator activity. The mechanism of TMCA is probably associated with its ability to increase Matrigel(R ) degradation; however, other actions cannot be discarded. (C) 1997 by John Wiley & Sons, Ltd.