Primary culture of rat hepatocytes as a model system of canalicular development, biliary secretion, and intrahepatic cholestasis. V. Disturbance of the cellular membrane and bile canalicular ultrastructure induced by chlorpromazine.

Abstract

In the present paper rat hepatocytes in primary monolayer culture were used to investigate the adverse effects of chlorpromazine (CPZ) at the cellular level. As revealed by thin sectioning many of the ultrastructural alterations were comparable to those described for the isolated perfused rat liver under the influence of CPZ. Alterations comprised short-term effects, such as dilation of the rough endoplasmic reticulum and the nuclear envelope, and long-term effects including huge accumulations of myeloid bodies within the cytoplasm as well as dilation and diverticulation of bile canaliculi. Freeze-fracturing revealed the dislocation of intramembrane particles in the sinusoidal plasma membrane which could be detected as early as 30 min after exposure to CPZ. As judged from filipin cytochemistry, alterations in the cholesterol content seems to play a minor role in the process of membrane damage except at the sinusoidal surface where a reduction of cholesterol content may contribute to the impairment of membrane functions. It is concluded that CPZ exerts its cholestatic effect primarily by a rapid disturbance of the membrane architecture of the sinusoidal surface and secondarily by other interactions with the bile secretory apparatus.