D‐Glucaro‐1,4‐lactone: Its excretion in the bile and urine and effect on the biliary secretion of β‐glucuronidase after oral administration in rats

Andrew Macfadyen, Kang‐Jey ‐J Ho

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

This experiment was designed to test the hypothesis that orally administered D‐glucaro‐1,4‐lactone might be excreted in the bile and thus suppress the activity of biliary β‐glucuronidase, which is believed to play a key role in the development of pigment gallstones. D‐Glucaro‐1,4‐lactone, 50 to 2,600 μmoles, was fed to adult Sprague‐Dawley rats which had a bile fistula and were kept in metabolic cages for bile and urine collection. A total of 21 feeding experiments were carried out. Quantitation of D‐glucaro‐1,4‐lactone and total D‐glucaric acid as the sum of D‐glucaric acid and its lactones in the bile and urine involved extraction of bile with tetrahexylammonium chloride, adjustment of pH, boiling and determination of percentage inhibition of β‐glucuronidase activity. The maximal velocity of β‐glucuronidase in the bile was also determined by the enzyme kinetic method. The results showed that 11% of administered D‐glucaro‐1,4‐lactone was excreted in the urine and only 0.2% in the bile, with D‐glucaro‐1,4‐lactone accounting for 20% of the total excreted D‐glucaric acid. The concentration and excretory rate of total D‐glucaric acid and D‐glucaro‐1,4‐lactone in the urine, but not in the bile, were proportional to the amount of D‐glucaro‐1,4‐lactone fed. The mean concentration of D‐glucaro‐1,4‐lactone in the bile after feeding was 0.06 mM, which was capable of suppression of 75% of β‐glucuronidase activity. Oral administration of D‐glucaro‐1,4‐lactone decreased biliary β‐glucuronidase concentration, slowed bile flow rate and hence decreased biliary β‐glucuronidase secretion. The effect reached a maximum of 80% suppression at an oral dose of 1,000 μmoles or more of D‐glucaro‐1,4‐lactone. The combined effect of the presence of D‐glucaro‐1,4‐lactone in the bile and the suppression of β‐glucuronidase secretion was the reduction of the endogenous β‐glucuronidase to 5% of its original activity. We therefore concluded that oral administration of D‐glucaro‐1,4‐lactone markedly lowers biliary endogenous β‐glucuronidase activity due to both the presence of D‐glucaro‐1,4‐lactone in the bile and the decrease in hepatic β‐glucuronidase secretion.

Original languageEnglish (US)
Pages (from-to)552-556
Number of pages5
JournalHepatology
Volume9
Issue number4
DOIs
StatePublished - Apr 1989

ASJC Scopus subject areas

  • Hepatology

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