Substrate specificities of two stably expressed human liver UDP-glucuronosyltransferases of the UGT1 gene family.

Two cloned human hepatic UDP-glucuronosyltransferase (UGT) cDNAs were stably expressed in chinese hamster V79 cells. More than 100 drugs and xenobiotics were used as substrates for glucuronidation catalyzed by the cloned human transferases to determine the chemical structures accepted as substrates. UGT HP1 exhibited a limited substrate specificity for planar phenolic compounds, whereas UGT HP4 was more promiscuous in acceptance of non-planar phenols, anthraquinones, flavones, aliphatic alcohols, aromatic carboxylic acids, steroids, and many drugs of varied structure. Levels of HP4 UGT activity toward some substrates were sufficient to allow determination of kinetic parameters for the enzyme reaction. Metabolism of drugs could be studied by addition to the recombinant cell lines in culture, and extraction of the media allowed analysis of glucuronide formation. Data presented herein demonstrate the potential of using these recombinant cell lines for investigation of phase II metabolism by human UGTs.