Role of the UGT2B17 deletion in exemestane pharmacogenetics

S. Luo, G. Chen, C. Truica, C. C. Baird, K. Leitzel, P. Lazarus

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)295-300
Number of pages6
JournalPharmacogenomics Journal
Volume18
Issue number2
DOIs
StatePublished - Apr 1 2018

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exemestane
Pharmacogenetics
Genotype
Breast Neoplasms
Aromatase Inhibitors
Glucuronides
Metabolic Networks and Pathways

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Genetics
  • Pharmacology

Cite this

Luo, S., Chen, G., Truica, C., Baird, C. C., Leitzel, K., & Lazarus, P. (2018). Role of the UGT2B17 deletion in exemestane pharmacogenetics. Pharmacogenomics Journal, 18(2), 295-300. https://doi.org/10.1038/tpj.2017.18
Luo, S. ; Chen, G. ; Truica, C. ; Baird, C. C. ; Leitzel, K. ; Lazarus, P. / Role of the UGT2B17 deletion in exemestane pharmacogenetics. In: Pharmacogenomics Journal. 2018 ; Vol. 18, No. 2. pp. 295-300.
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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.",
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Luo, S, Chen, G, Truica, C, Baird, CC, Leitzel, K & Lazarus, P 2018, 'Role of the UGT2B17 deletion in exemestane pharmacogenetics', Pharmacogenomics Journal, vol. 18, no. 2, pp. 295-300. https://doi.org/10.1038/tpj.2017.18

Role of the UGT2B17 deletion in exemestane pharmacogenetics. / Luo, S.; Chen, G.; Truica, C.; Baird, C. C.; Leitzel, K.; Lazarus, P.

In: Pharmacogenomics Journal, Vol. 18, No. 2, 01.04.2018, p. 295-300.

Research output: Contribution to journalArticle

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T1 - Role of the UGT2B17 deletion in exemestane pharmacogenetics

AU - Luo, S.

AU - Chen, G.

AU - Truica, C.

AU - Baird, C. C.

AU - Leitzel, K.

AU - Lazarus, P.

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