Studies on the mechanism of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU)-induced hepatotoxicity. III. Ultrastructural characterization of bile duct injury.

The antineoplastic nitrosourea CCNU is a known hepatotoxin which has been shown to cause hyperbilirubinemia and reduction in bile flow. We studied morphological alterations in the common bile duct and interlobular bile ducts at 6, 12, and 24 h in male rats given a single oral dose (50 mg/kg) of CCNU. The portal vein was perfused with 1.0% glutaraldehyde fixative. Portal areas and the common bile duct were selectively dissected and processed using standard methods for light and transmission electron microscopy. The epithelial cells of larger common bile duct and interlobular bile ducts showed increased rough endoplasmic reticulum, markedly increased free ribosomes, and mitochondrial degeneration at 6 and 12 h after CCNU. There was also bile imbibition and loss of microvilli, which increased in severity at 12 and 24 h. The interstitium showed infiltration by acute inflammatory cells and dilated capillaries at 6 h. By 24 h, degeneration of epithelial cells was extensive; cells became necrotic and sloughed into the duct lumen. The smaller bile ductules showed no significant degenerative changes; adjacent hepatocytes were unremarkable. Early CCNU injury appears localized in the large bile ducts and reflects inflammatory edema, bile stasis, and degeneration of epithelial cells. Our studies suggest that this ductal injury may reflect metabolism of CCNU to reactive species within the bile ducts.