Microfilament dysfunction as a possible cause of intrahepatic cholestasis

The effects of cytochalasin B on bile canalicular structure and function were examined. Three experimental models were used, cultured hepatocytes, isolated perfused liver, and in vivo infused liver. The techniques used were light and electron microscopy and, in selected instances, scanning electron microscopy, electron "stains" for microfilaments, and measurements of bile flow. Microfilament disruption and dilation of bile canaliculi were consistently found and closely paralleled a reduction in bile flow in both in vitro and in vivo infused animals. It is proposed that under normal circumstances, the microfilaments maintain the canaliculi in a contracted or partly contracted state. Hence, the microfilamentous network would provide tone to the canalicular system which would tend to reduce stagnation and facilitate the flow of bile. Removal of normal microfilament contractile function would be expected to produce canalicular ectasia and reduction of bile flow, as was observed. Microfilament dysfunction may therefore be a possible cause of intrahepatic cholestasis. Crucial to this hypothesis are the presence of actin-containing microfilaments in the pericanalicular web, and an action of cytochalasin B on their contractility. Evidence pertaining to these requirements is presented and discused.