Role of bile salts in colchicine-induced hepatotoxicity. Implications for hepatocellular integrity and function.
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.
Crocenzi
F A
FA
Instituto de Fisiología Experimental, Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET-U.N.R., Rosario, Argentina.
Sisti
A
A
Pellegrino
J M
JM
Roma
M G
MG
D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism* / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D003078:Colchicine / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006074:Gout Suppressants / Q000633:toxicity*; D007536:Isomerism; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008162:Lumicolchicines / Q000633:toxicity; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013655:Taurochenodeoxycholic Acid / Q000378:metabolism; D013656:Taurocholic Acid / Q000031:analogs & derivatives / Q000378:metabolism
D001647:Bile Acids and Salts; D006074:Gout Suppressants; D008162:Lumicolchicines; C042109:lumicolchicine; D013655:Taurochenodeoxycholic Acid; C019560:taurodehydrocholate; D013656:Taurocholic Acid; C031655:ursodoxicoltaurine; D007770:L-Lactate Dehydrogenase; D000469:Alkaline Phosphatase; D003078:Colchicine