Colchicine-induced hepatotoxicity: role of bile salts

ROMA, MARCELO G; CROCENZI, FERNANDO A.; SISTI, ALFONSO

Congreso; Biennial Scientific Meeting of the International Association for the Study of the Liver (IASL); 1996

Colchicine, a microtubule-disrupting agent, is widely used as a tool to explore vesicular (microtubule-dependent) transport mechanisms in the liver. However, at the doses usually employed to produce virtual microtubule disappearance, colchicine induces conspicuous hepatotoxicity. Although the mechanisms implicated have not been elucidated as yet, involvement of endogenous bile salts is likely, since these animals display a large susceptibility to the hepatotoxic effect of exogenously administered bile salts. Therefore, we have studied in detail the role of bile salts in colchicine-induced hepatotoxicity, as assessed by the release into both bile and blood of enzyme markers of hepatic damage (LDH and aminotransferases). Colchicine-induced hepatotoxicity showed a typical sigmoidal curve when plotted against the log of the dose administered, with an apparent maximal effect (950±124 % increment of biliary LDH output) at 0.5 µmol/100 g b.w. and a half-maximal effective dose (EC50) of 0.12 µmol/100 g b.w. The inactive analogue lumicolchicine, instead, did not exerted any harmful effect. Administration of taurocholate at stepwise-increasing rates (0.10-0.30 µmol/min per 100 g b.w.) induced a progressive decrease in both bile flow and bile salt output in colchicine-, but not in lumicolchicine-treated rats. Cholestasis was accompanied by massive discharge of the enzyme markers into both blood and bile. Increment of biliary LDH release following colchicine administration (0.5 µmol/100 g b.w.) was reduced from 950±124% to 216±29% by chronic biliary drainage leading to depletion of the endogenous bile salt pool, and this release was further decreased to 100±13% and 157±39% following depletion and subsequent repletion with the hydrophilic (non-hepatotoxic) bile salts taurodehydrocholate and tauroursodeoxycholate, respectively. Our data indicate that colchicine-induced hepatotoxicity is dependent on the magnitude and composition of the bile salt flux traversing the liver, thus pointing to a role of bile salts in this alteration. They also support the view that functional integrity of vesicular mechanism involved in membrane repair is indispensable to protect hepatocyte from damage during normal bile formation.