Colchicine inhibits lithocholate-3-O-glucuronide-induced cholestasis in rats

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Background/Aims: It has been suggested that vesicular transport of bile acids in hepatocytes occurs, especially at high-dose loads. Methods: The effect was studied of colchicine, a vesticular transport inhibitor, on lithocholate-3-O-glucuronide-induced cholestasis in rats. Cholestasis was induced by an intravenous infusion of lithocholate-3-O-glucoronide at the rate of 0.1 μmol·min −1·100 g −1 for 40 min. Results: Colchicine treatment almost completely inhibited cholestasis and increased biliary excretion of lithocholate-3-O-glucoronide, whereas lumicolchicine had no effect. Treatment with vinblastine, another vesicular transport inhibitor, also reduced the cholestasis. Colchicine did not affect biliary excretion of taurocholate infused at the rate of 0.3 μmol·min −1. 100 g −1 for 40 min, but markedly inhibited its biliary excretion when infused at the rate of 1.5 μmol·min −1·100 g −1 for 40 min. Colchicine had no effect on biliary excretion of tauroursodeoxycholate (1.5 μmol·min −1·100 g −1 for 40 min), lithocholate-3-sulfate (0.3 μmol·min −1·100 g −1 for 40 min), or a trace amount of lithocholate-3-O-glucuronide. Conclusions: These findings indicate that lithocholate-3-O-glucoronide-induced cholestasis is caused by its increased access to the vesicular transport pathway, possibly beyond the capacity of the transport by the cytosolic binders, and that the transport of lithocholate-3-O-glucoronide via the vesicular pathway induces cholestasis. Furthermore, the contribution of the vesicular pathway to hepatic transport may be different among bile acids, and lithocholate-3-O-glucuronide seems to have higher accessibility to this transport system.