hepatocytes showed prominent subcellular damage with CA We evaluated cytotoxic effects of different unconjugated and CDCA, and profound alterations of the canalicular memand glycine-and taurine-conjugated bile salts (BS) against bile brane with LCA and tauro-LCA. We have shown that, in vitro, duct epithelial cells in isolated bile ductule fragments and BDE cells are not damaged by taurine-or glycine-conjugated isolated perfused rat liver. Ultrastructural morphometric stud-BS, but they are very sensitive to cytotoxicity of hydrophobic ies were performed in polarized rat bile ductule fragments unconjugated BS. Such sensitivity is not present in the whole exposed in vitro to increasing concentrations (10-100 mmol/ The cytotoxicity of bile salts (BS) against different cell types, were isolated from rats with impaired taurine-conjugation caincluding hepatocytes, 1-4 HepG2 cell, 5 erythrocytes, 2 mast pacity (b-alanine treatment) and perfused for 70 minutes with cells, 6 and gastric and intestinal cells, 7 has been extensively 2 mmol/min LCA (n Å 6), CDCA (n Å 6), CA (n Å 6), or investigated in vitro. In general, the cytotoxicity increases with 0.5 mmol/min tauro-LCA (n Å 4). In isolated bile ductule increasing BS hydrophobicity (unconjugated ú glycoconjufragments, hydrophobic unconjugated bile salts (LCA, CDCA, gated ú taurine-conjugated; monohydroxy-ú dihydroxy-ú DCA) induced a marked damage of intracellular organelles, trihydroxy-BS). The position of hydroxy groups is also very mainly mitochondria. The damage started at a concentration important, because the 7b-dihydroxy BS, ursodeoxycholate of 10 mmol/L and became prominent at concentrations higher (UDCA), shows no cytotoxicity, and is instead protective. hepatocellular damage correlates with the hydrophobicity of UDCA, taurine and glycoconjugated bile salts failed to induce administered BS. [9][10][11][12][13] In light of these findings, current opinion any evident ultrastructural alteration. In taurine-depleted isoconcurs that in the course of cholestatic disorders, retention lated livers, perfused with LCA, CDCA, or CA, bile duct of hydrophobic BS could have a role in the development of epithelial cells showed no evidence of intracellular damage, hepatocellular damage. Although speculative, a direct, pathodespite the increased biliary excretion of unconjugated BS.genetic role of hydrophobic BS in human chronic cholestatic Marked alterations of the apical cell membrane were seen liver diseases has been proposed. 2,[9][10][11][12]
