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

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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.