Intrahepatic cholestasis and hyperbilirubinemia in ethynyl estradiol and chlorpromazine-treated rats

Abstract

Intrahepatic cholestasis associated with hyperbilirubinemia was induced by the simultaneous administration of ethynyl estradiol (EE) and chlorpromazine hydrochloride (CPZ) for 7 days to female Sprague-Dawley rats. Increases in direct serum bilirubin levels and alkaline phosphatase activities were observed concomitantly with diminished bile flow and bile acid excretion. However, the bilirubin output in the bile remained unchanged. [14C]Erythritol clearance decreased in parallel with the diminished bile flow, while [14C]sucrose biliary clearance increased, suggesting that the decrease in bile flow was of canalicular origin and also due to increased permeability in the biliary tract. There was a prominent decrease in the bile acid-independent flow, and the bile acid-dependent flow also decreased concomitantly with the diminished bile acid excretion. Slight increases in cytochrome P-450 and anilin hydroxylase activities in liver microsomes were observed, and bilirubin UDP-glucuronyl transferase activity increased significantly. Indirect bilirubin clearances determined by a bilirubin load test were markedly reduced in the icteric rats. The bilirubin load test also suggested that bilirubin flowed back into the circulating blood and that gluculonidation of bilirubin mono-gluculonide (BMG) to bilirubin diglucuronide (BDG) was impaired. Light microscopic examinations of the liver revealed marked proliferation of the bile ductules and numerous vacuoles in the hepatocytes. Dilatation of the bile canaliculi with diminished microvilli was also detected by scanning electron microscopy.