Biliary secretion and hepatic metabolism of taurine-conjugated 7α-hydroxy and 7β-hydroxy bile acids in the dog: Defective hepatic transport and bile hyposecretion

Abstract

Experiments were carried out using chronic bile fistula dogs to define the physiologic properties and metabolism of two unnatural epimeric monohydroxy conjugated bile acids, 7α-hydroxy cholanoyltaurine and 7β-hydroxy cholanoyltaurine. The compounds, labeled with 14C, were infused intravenously at a rate of 1 μmol/kg · min; effects on bile flow and biliary lipid secretion as well as hepatic biotransformation were defined. The 7-monohydroxy bile acids were secreted quite slowly in bile: recovery during the 90-min infusion interval averaged 16% for the 7α compound and 23% for the 7β compound and after 6 h was only about 60% for the 7α compound and 80% for the 7β compound. Uptake by tissues, presumably the liver, appeared to be efficient, as the level of radioactivity in peripheral blood remained quite low. Both bile acids failed to induce the anticipated increase in bile flow; canalicular bile flow, which was assessed using erythritol clearance, was about half the value observed when cholyltaurine was infused at a similar rate. The “hyposecretion” of bile, which was thought likely to be caused by impaired canalicular transport of the monohydroxy conjugates, was fully reversible, as a subsequent cholyltaurine infusion at a rate of 1 μmol/min · kg immediately restored bile flow and the infused cholyltaurine was secreted normally Each compound was partly 3-hydroxylated during hepatic passage: the 7α compound, about 36% (to form chenodeoxycholyltaurine); the 7β compound, about 23% (to form ursodeoxycholyltaurine). No other biotransformation occurred. Each compound induced phospholipid and cholesterol secretion, but compared to the effects of cholyltaurine, the amount of phospholipid secretion induced (per micromole of secreted bile acid) was less, and that of cholesterol, greater. Thus, the two 7-monohydroxy taurine-conjugated bile acids caused a striking dissociation of induced phospholipid and cholesterol secretion. The results indicate that taurine-conjugated 7-monohydroxy bile acids are poorly secreted by the liver and that their impaired transport is associated with bile hyposecretion, possibly reflecting decreased bile acid-dependent flow; the configuration of their 7-hydroxy group influences their rate of secretion into bile. The results also establish a novel type of bile acid biotransformation (3-hydroxylation) in the dog.