Effects of bile salts on cholestan-3 beta,5 alpha,6 beta-triol-induced apoptosis in dog gallbladder epithelial cells

Oxysterols are cytotoxic agents. The gallbladder epithelium is exposed to h igh concentrations of oxysterols, and so elucidating the mechanisms of cyto toxicity in this organ may enhance our understanding of the pathogenesis of biliary tract disorders. We investigated the cytotoxic effects of the oxys terol cholestan-3 beta ,5 alpha ,6 beta -triol (TriolC) on dog gallbladder epithelial cells. Apoptosis was the major form of cytotoxicity, as determin ed by analysis of nuclear morphologic changes and by multiparameter flow cy tometry. Hydrophobic bile salts are known to have cytotoxic effects, wherea s hydrophilic bile salts have cytoprotective effects. We therefore examined whether the hydrophobic bile acid taurodeoxycholic acid (TDC) and the hydr ophilic bile acid tauroursodeoxycholic acid (TUDC) had modifying effects on oxysterol-induced cytotoxicity. TriolC caused an increase in the number of apoptotic cells from 14 +/- 11% (control) to 48 +/- 12% of total cells (P < 0.01). After combining TriolC with TDC, cell apoptosis increased to 63 +/ - 16% (P < 0.05), whereas after addition of TUDC, the number of apoptotic c ells decreased to 31 +/- 12% (P < 0.05) of total cells. In summary, oxyster ols such as TriolC induce apoptosis. Hydrophobic bile salts enhance TriolC- induced apoptosis, whereas hydrophilic bile salts diminish TriolC-induced a poptosis. These results suggest that interactions between oxysterols and bi le salts play a role in the pathophysiology of biliary tract disorders. (C) 2001 Elsevier Science B.V. All rights reserved.