Effects of chlorpromazine on bilirubin metabolism and biliary secretion in the rat.

Chlorpromazine (CPZ) is a long recognized cause of jaundice, but the mechanism by which this agent produces icteric liver disease is not well defined. This study examined some effects of CPZ administration on bilirubin metabolism and biliary secretion in the rat. Acute CPZ treatment (25 mg per kg intravenously) produced hemolysis and resulted in increased bilirubin output and stimulation of hepatic heme synthesis. Both unconjugated bilirubin and a gamma-azopigment found primarily in obstructed rat bile were seen. Acute infusion of hemoglobin solutions to simulate the hemolysis produced by acute CPZ treatment resulted in increased bilirubin output and increased hepatic heme synthesis, but no alterations in the normal conjugation pattern of bilirubin in bile were seen. Chronic CPZ treatment for 4 and 8 days (25 mg per kg intraperitoneally) increased bilirubin output without elevating plasma hemoglobin levels and increased the fraction of monoconjugated bilirubin in bile; the 8-day chronic treatment regimen also caused unconjugated bilirubin to appear in bile. No change in liver weight, bile salt, phospholipid, or cholesterol output was seen with chronic CPZ therapy. Changes in bilirubin production and conjugation caused by CPZ may be a contributing factor in this agent's hepatotoxicity.