Biliary excretion in Sprague-Dawley and Gunn rats during manganese-bilirubin-induced cholestasis

Abstract

We previously showed that alterations of the bile canalicular membrane are likely to occur following a cholestatic regimen composed sequentially of manganese and bilirubin. The present study was designed primarily to investigate the biliary excretion of organic bile constituents following administration of the manganese-bilirubin combination. Experiments in hyperbilirubinemic Gunn rats were also performed to determine whether the unconjugated or the conjugated form of bilirubin is involved in this cholestatic interaction. Male Sprague-Dawley rats and male homozygous Gunn rats were given the following (i.v.): (a) manganese (4.5 mg per kg); (b) unconjugated bilirubin (25 mg per kg); (c) bilirubin ditaurate (38 mg per kg); (d) manganese-unconjugated bilirubin, or (e) manganese-bilirubin ditaurate. Bile flow was measured and bile was analyzed for manganese, total bilirubin, bile salts, cholesterol and phospholipid content. The results show that: (i) manganese-unconjugated bilirubin treatment caused about a 50% reduction in bile flow in Sprague-Dawley rats, whereas in Gunn rats the manganese-bilirubin ditaurate treatment resulted in about a 75% reduction, and (ii) in both strains, bile salt excretion was not appreciably modified during the cholestatic phase, as biliary bile salt concentration increased. The results suggest that although important differences regarding the form of bilirubin apparently exist, unconjugated bilirubin could be implicated in the cholestatic interaction in both strains of rats. Manganese-bilirubin-induced cholestasis is not related to a defect in bile salt excretion. The latter supports our contention that diminished canalicular membrane permeability to water is likely to be a key factor in this form of experimental cholestasis.