3 '-azido-3 '-deoxythimidine (AZT) is glucuronidated by human UDP-glucuronosyltransferase 2B7 (UGT2B7)

3'-Azido-3'-deoxythymidine (AZT) is frequently prescribed to patients infec ted with the human immunodeficiency virus. After absorption, AZT is rapidly metabolized into 3'-azido-3'-deoxy-5'-glucuronylthymidine by UDP-glucurono syltransferase (UGT) enzymes. Using labeled [C-14]UDP-glucuronic acid and m icrosomal preparations from human kidney 293 cells stably expressing the di fferent human UGT2B isoenzymes, it was demonstrated that AZT glucuronidatio n is catalyzed specifically by human UGT2B7. The identity of the metabolite formed was confirmed as AZT-G by liquid chromatography coupled with mass s pectrometry. UGT2B7 is encoded by a polymorphic gene and kinetic analysis o f AZT glucuronidation by the two allelic variants UGT2B7(H-268) and UGT2B7( Y-268), yielded apparent K-m values of 91.0 and 80.1 mu M, respectively. No rmalization to protein levels yielded glucuronidation efficiency ratios (V- max/K-m) of 21.3 and 11.0 mu l . min(-1) . mg protein(-1) for UGT2B7(H-268) and UGT2B7(Y-268), respectively. It remains possible that other UGT enzyme s are also involved in AZT conjugation; however, the glucuronidation of AZT by UGT2B7, which is a UGT2B protein expressed in the liver, is consistent with previous findings and supports the physiological relevance of this enz yme in AZT conjugation.