Hepatic metabolism of 3 alpha-hydroxy-5 beta-etianic acid (3 alpha-hydroxy-5 beta-androstan-17 beta-carboxylic acid) in the adult rat

Little, J.M.; St Pyrek, J.; Lester, R.

Journal of Clinical Investigation 71(1): 73-80


ISSN/ISBN: 0021-9738
PMID: 6848561
Accession: 005560773

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Normal human meconium has been shown to contain short-chain (C20-C22) bile acids and, recently, these compounds have been identified in sera of patients with cholestasis. Short-chain bile acids may be secreted in bile. This point was examined by studying the hepatic metabolism and biliary secretion of one naturally occurring C20 bile acid, 3.alpha.-hydroxy-5.beta.-etianic acid (3.alpha.-hydroxy-5.beta.-androstan-17.beta.-carboxylic acid). [3-3H]-3.alpha.-hydroxy-5.beta.-etianic acid was prepared and administered i.v. to rats prepared with an external biliary fistula. Of the administered dose, 85.5 .+-. 1.2% was recovered in bile over 20 h with 71.5 .+-. 1.3% appearing in the first hour. Of the dose estimated to be distributed in body water, 11.9 .+-. 1.6% was measured and 0.6 .+-. 0.2% was recovered as organic matter in urine. Total recovrey of label was 98.0 .+-. 2.6%. Administration of milligram quantitites of 3.alpha.-hydroxy-5.beta.-etianic acid produced an increase in bile flow (58.9 .+-. 7.1% over basal levels) within 20 min after injection of the steroid. The radiolabeled material in bile was shown by TLC to be a polar conjugate which, after .beta.-glucuronidase hydrolysis, cochromatographed with authentic free 3.alpha.-hydroxy-5.beta.-etianic acid. After purification and derivatization, the steroid moiety was proven by gas chromatography-mass spectrometry to be identical to 3.alpha.-hydroxy-5.beta.-etianic acid. Characterization of the conjugate by TLC and by 3.alpha.-hydroxysteroid dehydrogenase assay, before and after .beta.-glucuronidase hydrolysis, indicated that the steroid was secreted in bile as the 3-O-.beta.-glucuronide. 3.alpha.-Hydroxy-5.beta.-etianic acid is cleared from the plasma, conjugated with glucuronic acid and secreted into bile rapidly and in high concentration. The choleretic properties of this short-chain bile acid contrast with the cholestatic effects of lithocholic acid, its C24 analog. Both the form of conjugation of etianic acid and its effect on bile flow suggest that the shortened side chain of this steroid markedly alters the hepatic metabolism and physiology.