The effects of colchicine on secretion into bile of bile salts, phospholipids, cholesterol and plasma membrane enzymes: bile salts are secreted unaccompanied by phospholipids and cholesterol

Abstract

Colchicine, a drug which interferes with microtubular function, has no effect on the secretion of taurodehydrocholate into bile; it is therefore suggested that bile salts are unlikely to be packaged in vesicles during cellular transit from sinusoidal to canalicular membranes. Colchicine greatly reduces the secretion of phospholipid and cholesterol into bile; it is suggested that this is due to an interruption in the supply of vesicles bringing lipids to repair the canalicular membrane during bile salt output. In the absence of the protective effect of a continuous supply of repair vesicles, micelleforming bile salts damage the canalicular membrane; the increased concentration of plasma membrane enzymes in bile and the increased aspartate aminotransferase activity in plasma and bile are evidence of this damage. Damage to the canalicular membrane may also be an explanation for the reduction in taurocholate transport and the taurocholate-induced cholestasis which are seen with colchicine-treated livers. Such membrane damage is not observed in colchicine-treated livers during the secretion of the non-micelle forming bile salt, taurodehydrocholate.

Modulation of intrahepatic cholesterol trafficking: evidence by in vivo antisense treatment for the involvement of sterol carrier protein-2 in newly synthesized cholesterol transport into rat bile

“…This incorporation is not mediated by SCP-2 [37] and is not affected by microtubule-disrupting drugs [35,36]. In contrast, biliary cholesterol and phospholipids are markedly decreased by inhibitors of the cytoskeleton (present results and [17,38]) and the contribution of lysosomal lipid constituents to bile seems to be low [39]. The role of the Golgi apparatus in the packing and sorting of intracellular lipids, including cholesterol, to the plasma membrane has been clearly characterized in peripheral cells [40][41][42].…”

“…This transport was not affected by colchicine or monensin. Colchicine is a well known microtubule-disrupting agent [45] and its effects on the vesicle-mediated transport of proteins and lipids have been extensively studied in cultured cells and in the whole animal [15][16][17]46]. Monensin is an ionophore that disrupts the trans-Golgi elements and inhibits the intracellular transport of membrane and secretory proteins, and some lipids [15,16,18,43].…”

“…Some animals received colchicine (0.4 mg\100 g body weight) or monensin (3.5 mg\100 g body weight) intraperitoneally 90 min before the pulse-chase experiments [17,18].…”

Biliary lipid secretion in man

“…Direct evidence for a vesicular mechanism for bile acid transport involving the Golgi apparatus has been obtained using autoradiography [73,74] and antibodies directed against cholic and ursodeoxycholic acid conjugates on rat liver sections [75]. Such a transport system is probably too slow to account for the very rapid transcellular transport of bile acid [67,76]. Furthermore, the inhibitory effect ofcolchicine and vinblastine on bile acid secretion is less marked than for cholesterol and phospholipid secretion [65,77], and it is only observed at high bile acid secretion rates [77-791.…”

Nutritional Regulation of Pancreatic and Biliary Secretions

“…The biliary phospholipids are essentially derived from a rapidly turning-over pool synthesized in the liver (Kawamoto et al 1980;Barnwell et al 1983), whereas biliary cholesterol is both newly synthesized in the liver and taken up by the hepatocyte from various circulating lipoproteins (Koelz et al 1982;Brown & Goldstein, 1983). This intracellular lipid material could migrate to and fuse with the canalicular membrane which would be continuously damaged by bile salts and then repaired again by new intracellular lipid material (Barnwell et al 1984). Accordingly, complete understanding of the adaptation of biliary lipid to dietary fat content should integrate : (1) the regulation of ' biliary-type' lipid supply in the hepatocyte (phospholipid synthesis and cholesterol synthesis and uptake), (2) the eventual dietary regulation of transport of this intracellular lipid to the canalicular membrane, (3) the extent of lipid material solubilization from the canalicular membrane.…”