Effective glucuronidation of 6α‐hydroxylated bile acids by human hepatic and renal microsomes

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Abstract
The glucuronidation of bile acids is an established metabolic pathway in different human organs. The hepatic and renal UDP‐glucuronyltransferase activities vary according to the bile acids concerned. Thus, hyodeoxycholic acid is clearly differentiated from other bile acids by its high rate of glucuronidation and elevated urinary excretion in man. To determine whether such in vivo observations are related to variations in bile acid structure, human hepatic and renal microsomes were prepared and time courses of bile acid glucuronidation measured with the bile acids possessing hydroxyl groups in different positions. Eleven [24‐14C]bile acids were chosen or synthesized in respect of their specific combination of hydroxyl and oxo groups at the 3, 6, 7 and 12 positions and of their α or β hydroxyl configurations. The results clearly demonstrate that bile acids with an hydroxyl group in the 6a position underwent a high degree of glucuronidation. Apparent kinetic Km and Vmax values for UDP‐glucuronyltransferase activities ranged over 78–66 μM and 1.8–3.3 nmol · min−1· mg−1 protein in the liver and over 190–19 μM and 0.5–9.2 nmol · min−1· mg−1 protein in the kidney. All the other bile acids tested, each of which possessed a 3α‐hydroxyl group and whose second or third hydroxyl was bound at the 6β, 7 or 12 positions, were glucuronidated to a degree far below that of the 6α‐hydroxylated bile acids. We conclude that an active and highly specific UDP‐glucuronyltransferase activity for 6α‐hydroxylated bile acids exists in human liver and kidneys. Moreover, this activity results in the linkage of glucuronic acid to the 6α‐hydroxyl group and not to the usual 3α‐hydroxyl group of bile acids.