The pathogenesis of
lithocholic acid (LCA-Na)-induced
cholestasis involves a rapid accumulation of
cholesterol in the bile canalicular membrane. Since microtubules play an important role in the intracellular transport of many materials, including
cholesterol, the present study was undertaken to assess the extent to which they participate in the development of LCA-Na-induced
cholestasis. Rats were pretreated with either
colchicine (0.2 mumol/100 g body wt.) or
saline solution 90 min before injection with LCA-Na (12 mumol/100 g body wt.).
Colchicine, although not increasing bile flow by itself, significantly reduced the
cholestasis caused by LCA-Na (57-32% reduction in bile flow) without affecting its metabolism into less toxic
bile acids or its distribution in blood, liver or bile. Bile canalicular membranes isolated from animals treated with a combination of
colchicine and LCA-Na contained less
cholesterol than those treated with LCA-Na alone. However, membranes obtained from rats treated with
colchicine alone contained much less
cholesterol than did controls. It was found that the total amount of
cholesterol accumulated within the bile canalicular membrane following LCA-Na treatment (LCA-Na +
colchicine versus
colchicine alone compared with LCA-Na versus controls) was unchanged by
colchicine treatment. In view of these findings it is suggested that the total amount of
cholesterol present within the bile canalicular membrane determines the extent of LCA-Na-induced
cholestasis, LCA-Na probably moves
cholesterol to the bile canalicular membrane via a microtubule independent pathway, and microtubules are unlikely to function in the transcellular transport of LCA-Na.