Effects of Aramchol on in vitro bile cholesterol crystallization and bile acid detergency

The hydrophilic bile acid ursodeoxycholic acid may dissolve cholesterol gallstones and is beneficial in cholestatic liver diseases. The C20 fatty acid-bile acid conjugate arachidyl amido cholanoic acid (Aramchol) could be a more effective option. We therefore studied its effects on cholesterol crystallization and on bile salt-induced cytotoxicity. Effects of Aramchol at therapeutically relevant concentrations on crystallization in supersaturated model biles (by microscopy and chemical measurement), on the ternary cholesterol-taurocholate-phosphatidylcholine phase diagram, and on micelle ↔ vesicle transitions (by serial dilution or by incubation of cholesterol-phosphatidylcholine vesicles with taurocholate) were evaluated. Effects on bile salt-induced cytotoxicity were determined in erythrocytes and CaCo2 cells. Incorporation of Aramchol in model biles did not change micellar cholesterol solubilization, induced a small rightward shift of crystal-containing zones of the ternary phase diagram, exerted no appreciable effects on vesicle ↔ micelle transitions and had only minor effects on cholesterol crystallization. Bile salt-induced cytotoxicity was increased by Aramchol in all models. Since Aramchol does not affect cholesterol crystallization, its previously reported beneficial effects in animal gallstone models should relate to other mechanisms. Since Aramchol increases bile salt detergency, it is not likely to be beneficial in cholestatic liver disease.