Bile salts may initiate or aggravate
cholestasis in man. Infusion of
Taurochenodeoxycholate (TCDCA) represents a model of
bile salt-induced
cholestasis in rat. The events leading to
cholestasis are incompletely understood. The canalicular conjugate export pump Mrp2 is the major driving force for the
bile salt-independent bile flow. Redistribution of Mrp2 has been suggested to cause reduction in bile flow in others models of acute
cholestasis (i.e.
endotoxin,
phalloidin, GSH-depletion). We have studied the effects of TCDCA on the distribution of Mrp2 and
P-glycoproteins with respect to changes in the actin cytoskeleton and actin associated
proteins radixin and ZO-1. Bile duct cannulated rats were infused with TCDCA (0.1 and 0.4 micromol/min/100g
body weight) and bile flow was measured. After 30 min livers were removed and distribution of Mrp2,
P-glycoproteins, actin, actin-associated
radixin and ZO1 were studied by immunofluorescence analysis. TCDCA at subcholestatic amounts (0.1 micromol/min/100 g
body weight) led to distortion and dilation of the canaliculi which was apparent in actin, ZO-1, and Mrp2 fluorescence. Administration of higher amounts of TCDCA (0.4 micromol/min/100g
body weight) led to a reduction of bile flow to 31 % of control bile flow.
Radixin, which localized strictly to the plasmamembrane in controls, was detected in intracellular structures partially colocalizing with actin aggregates especially at the sinusoidal membranes as visualized by double-immunofluorescence staining. Mrp2 appeared in pericanalicular membrane structures in cholestatic animals whereas
P-glycoproteins remained unchanged under these conditions.
CONCLUSIONS: