Bile acid structure and bile formation in the guinea pig

Abstract

The effects of intravenous infusions (1–4 μmol/min/kg) of 14 bile acids, cholic, deoxycholic, ursodeoxycholic, chenodeoxycholic, dehydrocholic, and their glycine and taurine conjugates, on bile flow and composition and on the biliary permeation of inert carbohydrates have been studied in the guinea pig bile fistula. Hydroxy bile acids were eliminated in bile without major transformation, except for conjugation (over 90%) when unconjugated bile acids were infused. During infusion of dehydrocholate and taurodehydrocholate, 77–100% of the administered dose was recovered in bile as 3-hydroxy bile acids, thus indicating that reduction of the keto group in position 3 was virtually complete. All bile acids produced choleresis at the doses employed: the strongest choleretic was deoxycholate (81.78 μ/μmol), the weakest was taurodehydrocholate (10.2 μ/μmol). Choleretic activity was directly and linearly related to bile acid hydrophobicity, as inferred by HPLC., both for similarly conjugated bile acids, and for bile acids having the same number, position, or configuration of the hydroxyl groups. In all instances, the rank ordering was: deoxycholate ⪢ chenodeoxycholate ⪢ cholate ⪢ ursodeoxycholate. During choleresis produced by any of the bile acids tested, bicarbonate concentration in bile slightly declined, but the calculated concentration in bile-acid-stimulated bile (45–57 mmol/1) was always higher than that measured in plasma (23–26 mmol/l). Biliary concentrations of cholesterol (20–68 μmol/1) and phospholipid (14–63 μmol/1) were very low during spontaneous secretion, and declined even further following bile acid choleresis. None of the infused bile acids consistently modified biliary excretion of cholesterol and phospholipid. Consistent with a previous observation from this laboratory, all hydroxy bile acids reversibly diminished [ 14C]erythritol and [ 14C]mannitol biliary entry during choleresis, while they increased or failed to modify that of [ 3H]sucrose and [ 3H]inulin. The rank ordering for the inhibitory effect on [ 14C]erythritol and [ 14C]mannitol permeation was: 3α,7α,12α-trihydroxy ⪢ 3α,7α-dihydroxy ⪢ 3α,7β-dihydroxy ⪢ 3α,12α-dihydroxy bile acids. These results are interpreted to suggest that, in the guinea pig, (i) the differing choleretic effects of bile acids reflect differences in their cholehepatic cycling and/or in their stimulation of a bicarbonate pump; (ii) bile acids do not regulate cholesterol and phospholipid biliary excretion; and (iii) hydroxy bile acids diminish the canalicular membrane permeability to [ 14C]erythritol and [ 14C]mannitol by rearranging the architecture of the membrane ‘aqueous pores’ through which these solutes enter the canalicular lumen.