RT Journal Article
SR Electronic
T1 3′-azido-3′-deoxythimidine (AZT) is glucuronidated by human UDP-glucuronosyltransferase 2B7 (UGT2B7)
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 497
OP 502
VO 28
IS 5
A1 Olivier Barbier
A1 David Turgeon
A1 Caroline Girard
A1 Mitchell D. Green
A1 Thomas R. Tephly
A1 Dean W. Hum
A1 Alain Bélanger
YR 2000
UL http://dmd.aspetjournals.org/content/28/5/497.abstract
AB 3′-Azido-3′-deoxythymidine (AZT) is frequently prescribed to patients infected with the human immunodeficiency virus. After absorption, AZT is rapidly metabolized into 3′-azido-3′-deoxy-5′-glucuronylthymidine by UDP-glucuronosyltransferase (UGT) enzymes. Using labeled [14C]UDP-glucuronic acid and microsomal preparations from human kidney 293 cells stably expressing the different human UGT2B isoenzymes, it was demonstrated that AZT glucuronidation is catalyzed specifically by human UGT2B7. The identity of the metabolite formed was confirmed as AZT-G by liquid chromatography coupled with mass spectrometry. UGT2B7 is encoded by a polymorphic gene and kinetic analysis of AZT glucuronidation by the two allelic variants UGT2B7(H268) and UGT2B7(Y268), yielded apparent Km values of 91.0 and 80.1 μM, respectively. Normalization to protein levels yielded glucuronidation efficiency ratios (Vmax/Km) of 21.3 and 11.0 μl · min−1 · mg protein−1for UGT2B7(H268) and UGT2B7(Y268), respectively. It remains possible that other UGT enzymes 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 enzyme in AZT conjugation. The American Society for Pharmacology and Experimental Therapeutics