Stereoselective Conjugation of Oxazepam by Human UDP-Glucuronosyltransferases (UGTs): S-Oxazepam Is Glucuronidated by UGT2B15, While R-Oxazepam Is Glucuronidated by UGT2B7 and UGT1A9

• DOI: 10.1124/dmd.30.11.1257
• Publication Date: 2003-01-15T23:17:35Z
• Authors: Michael H. Court; Su X. Duan; Chantal Guillemette; Kim Journault; Soundararajan Kri...; Lisa L. von Moltke; David J. Greenblatt
• Keywords: Oxazepam; UGT2B7; Glucuronide

(<i>R</i>,<i>S</i>)-Oxazepam is a 1,4-benzodiazepine anxiolytic drug that metabolized primarily by hepatic glucuronidation. In previous studies, <i>S</i>-oxazepam (but not <i>R</i>-oxazepam) was shown to be polymorphically glucuronidated in humans. The aim of the present study identify UDP-glucuronosyltransferase (UGT) isoforms mediating <i>R</i>- and glucuronidation human liver, with long term objective elucidating molecular genetic basis for this metabolism polymorphism. All available recombinant UGT were screened activities. Enzyme kinetic parameters then determined representative liver microsomes (HLMs) UGTs showed significant activity. Of 12 different evaluated, only UGT2B15 Furthermore, apparent <i>K</i>_m (29–35 μM) similar values HLMs (43–60 μM). contrast, <i>R</i>-oxazepam UGT1A9 UGT2B7. Although (256–303 most UGT2B7 (333 rather than (12 μM), intrinsic clearance 10 times higher A common variation results aspartate (UGT2B15*1) or tyrosine (UGT2B15*2) at position 85 protein. Microsomes from embryonic kidney (HEK)-293 cells overexpressing UGT2B15*1 5 higher<i>S</i>-oxazepam activity did UGT2B15*2 microsomes. Similar obtained other substrates, including eugenol, naringenin, 4-methylumbelliferone, androstane-3α-diol. conclusion, stereoselectively UGT2B15, whereas<i>R</i>-oxazepam multiple isoforms. Allelic associated gene may explain polymorphic