The stereospecificity of mechanisms for hepatic transport of short-chain
bile acids has been examined by following the hepatic metabolism and biliary secretion of 3 beta-hydroxy-5 beta-androstane-17 beta-
carboxylic acid (
isoetianic acid) administered in two different labeled forms to rats prepared with an external
biliary fistula. While 93% of the administered [2,2,4,4-3H]
isoetianic acid was recovered in bile after 20 h, only 18% of a similar dose of [3 alpha-3H]
isoetianic acid was secreted in bile over the same time period. The recovered radioactivity of the latter compound was mainly associated with bile water. With the [2,2,4,4-3H]
isoetianic acid, the bulk of the biliary
isotope was determined to be in the form of two
glucuronide conjugates. Spectral analysis identified these metabolites as the
hydroxyl-linked (major) and carboxyl-linked (minor) beta-
glucuronides, not of the 3 beta-hydroxy compound administered, but of 3 alpha-hydroxy-5 beta-androstane-17 beta-
carboxylic acid (
etianic acid), i.e., the products of
hydroxyl group inversion. It is concluded that
isoetianic acid is efficiently cleared from plasma and conjugated with
glucuronic acid after its epimerization to
etianic acid. The prevalent, but not complete, loss of the 3-tritium atom and the retention of the 2- and 4-tritium atoms probably indicates a 3-oxo-5 beta-androstane-17 beta-
carboxylic acid intermediate with partial return of the label via a limited labeled pool of reduced
nicotinamide cofactor.