UDP-Glucuronosyltransferase(UGT)2B15 Pharmacogenetics:UGT2B15 D85Y Genotype and Gender Are Major Determinants of Oxazepam Glucuronidation by Human Liver

摘要

Oxazepam is a commonly used 1,4-benzodiazepine anxiolytic drug that is polymorphically metabolized in humans.However,the molecular basis for this phenomenon is currently unknown.We have previously shown that S-oxazepam glucuronide,the major oxazepam metabolite,is selectively formed by UDP-glucuronosyltransferase(UGT)2B15,whereas the minor R-oxazepam glucuronide is produced by multiple UGTs other than UGT2B15.Phenotype-genotype studies were conducted using microsomes and DNA prepared from the same set of 54 human livers.Sequencing of the UGT2B15 gene revealed three nonsynonymous polymorphisms,D85Y,T352I,and K523T,with variant allele frequencies of 0.56,0.02,and 0.40,respectively.D85Y genotype showed a significant effect(p = 0.012)on S-oxazepam glucuronidation with lower median activities in 85Y/Y livers(49 pmol/min/mg protein)compared with 85D/D livers(131 pmol/min/mg),whereas 85D/Y livers were intermediate in activity(65 pmol/min/mg).There was also a significant trend(p = 0.049)for higher S-oxazepam activities in the two 352T/I livers(135 and 210 pmol/min/mg)compared with the remaining 352T/T livers(median,64 pmol/min/mg).Conversely,K523T genotype had no apparent effect on oxazepam glucuronidation(p > 0.05).Donor gender also significantly influenced S-oxazepam glucuronidation with higher median activities in male(65 pmol/min/mg)compared with female(39 pmol/min/ mg)livers(p = 0.042).R-Oxazepam glucuronidation was not affected by either genotype or gender(p > 0.05).In conclusion,gender and D85Y genotype are identified as major determinants of S-oxazepam glucuronidation by human liver and may explain in part polymorphic oxazepam glucuronidation by human subjects.