Abstract
[3-3H]Cholic acid glucuronide [7 alpha,12 alpha-dihydroxy-3 alpha-O-(beta-D-glucopyranosyluronate)-5 beta- cholan-24-oate] was synthesized and administered to rats prepared with either an external biliary fistula or a ligated bile duct. When bile fistula animals were given either microgram or milligram amounts of the glucuronide, biliary secretion of label was rapid and efficient: greater than 90% of the administered label was secreted within 60 min and total recovery of label in bile was 98.6 +/- 1.2%. Studies in which [14C]taurocholate was included in the dose indicated that this bile acid was secreted into bile significantly more rapidly than was the glucuronide. In animals with ligated bile ducts, urinary excretion was the major route of elimination: after 20 hr, 83.4 +/- 9.3% of the administered dose had been excreted in urine. Urinary excretion of cholate glucuronide was significantly more rapid than that of taurocholate. Gas-liquid chromatographic analysis of the methyl ester acetate derivatives of labeled compounds isolated from bile and urine by chromatography established that the bulk (greater than 70%) of the administered material was secreted in bile or excreted in urine as the intact cholate glucuronide. From these results, we conclude that the glucuronidation of cholic acid produces a derivative which is rapidly and effectively cleared from the circulation and excreted.
Highlights
3a-0-(~-D-glucopyranosyluronate)-5~-cholan-24-oawteas] synthesizedandadministered to ratsprepared with eitheran external biliary fistula or a ligated bile duct
Urinaryexcretion of cholate glucuronidewas significantly morerapidthanthat of taurocholate.Gas-liquidchromatographic analysisof the methylester acetate derivativesof labeled compoundsisolatedfrombileandurine by chromatography established that the bulk (> 70%) of the administered material wassecretedinbile or excretedinurine as theintactcholate glucuronide.IFromtheseresults, we conclude that the glucuronidation ofcholicacidproduces a derivativewhich is rapidlaynedffectivelcylearefdromthceirculatioannd excreted. -Little, J
The kinetics of bile acid glucuronyl transferase have been studiedinvitro [6, 7] and stimulation of bile acid glucuronidation by pheno-. barbital has been demonstrated in vivo [6, 8], little else is known aboutthemetabolism of bile acid glucuronides
Summary
The objective of the studies was to examine the hepatic metabolism and biliary secretion of the 3-O-@-D-glucuronide of cholic acid (hereafter referred to as cholate glucuronide). 10% ammonium hydroxide and the residues in each tube bile was collected at 30-min intervals for an additional 2 were lyophilized to remove all traces of ammonium hr and as a single sample until the animals were killed at acetate. The protected cholate sp act 40 mCi/mmol; New England Nuclear, Boston, glucuronide was eluted as thefirst crystalline fraction and MA) was administered to fistula animals simultaneously on recrystallization from 90% ethanol formed colorless with the[3H]cholate glucuronide. In these studies, bile was collected dropwise in individual scintillation vials for a period of 30 min, at 30-min intervals until 3 hr and as a single sample from to 20 hr.
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