The Mutant Eisai Hyperbilirubinemic Rat Is Resistant to Bile Acid-Induced Cholestasis and Cytotoxicity

We investigated bile flow and biliary excretion of bile acids in the Eisai hyperbilirubinemic rat, a Sprague–Dawley mutant rat with conjugated hyperbilirubinemia, using both in vivo and in vitro models. In vivo bile flow was lower in Eisai hyperbilirubinemic rats than in the control rats before and after taurocholate was infused. After taurocholate was infused, bile acid output was similar in the Eisai hyperbilirubinemic rats and control rats. In the isolated perfused rat liver, biliary excretion of bile acids was higher in the Eisai hyperbilirubinemic rats than in the control rats after a high–dose infusion of taurocholate (0.33 μmol/min/gm liver). Infusion of taurochenodeoxycholate (0.22 μmol/min/gm liver) did not produce cholestasis and did not reduce the biliary excretion of bile acids in the Eisai hyperbilirubinemic rats. Taurochenodeoxycholate significantly increased the phospholipid/bile acid molar ratio and slightly reduced bile acid-induced alkaline phosphatase output into bile. The release of lactate dehydrogenase from the perfused liver 30 min after the start of the taurochenodeoxycholate infusion was 10 times lower in the Eisai hyperbilirubinemic rats than in the control rats (2.0 ± O.8 vs. 28.7 ± 6.8 mU/min/gm liver). When the isolated perfused rat liver was infused with a 1–min pulse of horseradish peroxidase (25 mg), we observed an early and late peak of biliary excretion of horseradish peroxidase. The Eisai hyperbilirubinemic rats showed a significant increase in the late peak. Although taurochenodeoxycholate produced dose–dependent increases in lactate dehydrogenase levels in the medium at 3 hr in primary cultured hepatocytes from both strains, the increase was significantly smaller in the Eisai hyperbilirubinemic rat. The intracellular content of taurochenodeoxycholate in the Eisai hyperbilirubinemic rat was 11.7 ± 1.5 nmol/mg protein, half that seen in the control rats. These findings indicate that the Eisai hyperbilirubinemic rat is resistant to bile acid-induced cholestasis and liver injury and that this resistance may be related, in part, to a reduction in the intracellular accumulation of bile acids. This phenomenon might be explained by an increased intrahepatic microtubule–dependent vesicle transport of bile acids in the mutant rats. (Hepatology 1994;20:932-939).