Role of the UGT2B17 deletion in exemestane pharmacogenetics. Other Scholarly Work

Luo, S, Chen, G, Truica, C et al. (2018). Role of the UGT2B17 deletion in exemestane pharmacogenetics. . 18(2), 295-300. 10.1038/tpj.2017.18

cited authors

  • Luo, S; Chen, G; Truica, C; Baird, CC; Leitzel, K; Lazarus, P

fiu authors

abstract

  • Exemestane (EXE) is an aromatase inhibitor used for the prevention and treatment of breast cancer. The major metabolic pathway for EXE is reduction to form the active 17β-dihydro-EXE (17β-DHE) and subsequent glucuronidation to 17β-hydroxy-EXE-17-O-β-D-glucuronide (17β-DHE-Gluc) by UGT2B17. The aim of the present study was to determine the effects of UGT2B17 copy number variation on the levels of urinary and plasma 17β-DHE-Gluc and 17β-DHE in patients taking EXE. Ninety-six post-menopausal Caucasian breast cancer patients with ER+ breast tumors taking 25 mg EXE daily were recruited into this study. UGT2B17 copy number was determined by a real-time PCR copy number variant assay and the levels of EXE, 17β-DHE and 17β-DHE-Gluc were quantified by UPLC/MS in patients' urine and plasma. A 39-fold decrease (P<0.0001) in the levels of creatinine-adjusted urinary 17β-DHE-Gluc was observed among UGT2B17 (*2/*2) subjects vs subjects with the UGT2B17 (*1/*1) genotype. The plasma levels of 17β-DHE-Gluc was decreased 29-fold (P<0.0001) in subjects with the UGT2B17 (*2/*2) genotype vs subjects with UGT2B17 (*1/*1) genotype. The levels of plasma EXE-adjusted 17β-DHE was 28% higher (P=0.04) in subjects with the UGT2B17 (*2/*2) genotype vs subjects with the UGT2B17 (*1/*1) genotype. These data indicate that UGT2B17 is the major enzyme responsible for 17β-DHE-Gluc formation in vivo and that the UGT2B17 copy number variant may play a role in inter-individual variability in 17β-DHE levels in vivo.

publication date

  • April 1, 2018

keywords

  • Adult
  • Aged
  • Aged, 80 and over
  • Androstadienes
  • Antineoplastic Agents
  • Breast Neoplasms
  • Female
  • Gene Deletion
  • Glucuronosyltransferase
  • Humans
  • Middle Aged
  • Minor Histocompatibility Antigens
  • Pharmacogenetics

Digital Object Identifier (DOI)

Medium

  • Print-Electronic

start page

  • 295

end page

  • 300

volume

  • 18

issue

  • 2