Phalloidin-induced cholestasis: a microfilament-mediated change in junctional complex permeability

Area of Science:

• Hepatology
• Cell Biology
• Toxicology

Background:

• The role of hepatic microfilaments in regulating bile canalicular permeability is not fully understood.
• Phalloidin is a toxin known to interact with actin filaments in hepatocytes.

Purpose of the Study:

• To investigate the effect of phalloidin on hepatocyte tight junctions and bile flow.
• To explore the influence of microfilaments on junctional permeability in the liver.

Main Methods:

• Male rats were administered phalloidin (500 µg/kg/day) for 7 days.
• Measurements included hepatic filamentous actin content, bile flow, bile acid excretion, and paracellular transport using [3H]inulin and [14C]sucrose.
• Freeze-fracture electron microscopy was used to examine tight junction structure.

Main Results:

• Phalloidin increased hepatic filamentous actin content, decreased bile flow and bile acid excretion.
• Bile-to-plasma ratios of inulin and sucrose significantly increased, indicating enhanced paracellular permeability.
• Lanthanum tracer penetrated the zonula occludens, and freeze-fracture revealed altered tight junctional structures.

Conclusions:

• Hepatic microfilaments, influenced by phalloidin, play a critical role in maintaining tight junction integrity between hepatocytes.
• Disruption of these microfilaments leads to increased junctional permeability and may cause bile reflux, contributing to cholestasis.