Differential glucuronidation of bile acids, androgens and estrogens by human UGT1A3 and 2B7

J Steroid Biochem Mol Biol. 1999 Jul-Aug;70(1-3):101-8. doi: 10.1016/s0960-0760(99)00088-6.

Abstract

In this work, UDP-glucuronosyltransferases (UGTs), UGT1A3, 2B7(H268) and 2B7(Y268), stably expressed in human embryonic kidney cells (HK293) were used to assess glucuronidation activities with a variety of steroid hormone and bile acid substrates. The rate of synthesis of carboxyl- and hydroxyl-linked glucuronides was determined under optimal reaction conditions. Expressed UGT1A3 catalyzed bile acid glucuronidation at high rates exclusively at the carboxyl moiety for all compounds tested. In contrast, UGT1A4 catalyzed bile acid glucuronidation at very low rates exclusively at the 3alpha-hydroxyl function. Both UGT2B7 allelic variants glucuronidated the bile acid substrates at both carboxyl and hydroxyl moieties, however, the 3alpha-hydroxyl position was preferentially conjugated compared to the carboxyl function. Similarly, androsterone, a 3alpha-hydroxylated androgenic steroid, was glucuronidated at very high rates by expressed UGT2B7. Of the estrogenic compounds tested, UGT2B7 catalyzed the glucuronidation of estriol at rates comparable to those determined for androsterone. Other structural discrimination was found with UGT2B7 which had activity toward estriol and estradiol exclusively at the 17beta-OH position, yielding the cholestatic steroid D-ring glucuronides.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Androgens / metabolism*
  • Bile Acids and Salts / metabolism*
  • Catalysis
  • Cells, Cultured
  • Electrophoresis, Polyacrylamide Gel
  • Estrogens / metabolism*
  • Glucuronides / metabolism*
  • Glucuronosyltransferase / metabolism*
  • Humans
  • Microsomes, Liver / enzymology
  • Models, Chemical

Substances

  • Androgens
  • Bile Acids and Salts
  • Estrogens
  • Glucuronides
  • UDP-glucuronosyltransferase, UGT1A3
  • UGT2B7 protein, human
  • Glucuronosyltransferase