Next Article in Journal
MiR-126-3p and MiR-223-3p as Biomarkers for Prediction of Thrombotic Risk in Patients with Acute Myocardial Infarction and Primary Angioplasty
Next Article in Special Issue
Targeted Sequencing of Taiwanese Breast Cancer with Risk Stratification by the Concurrent Genes Signature: A Feasibility Study
Previous Article in Journal
What Can We Change in Diet and Behaviour in Order to Decrease Carotid Intima-Media Thickness in Patients with Obesity?
Article

Effect of Genetic Variability in 20 Pharmacogenes on Concentrations of Tamoxifen and Its Metabolites

1
Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI 48109-1065, USA
2
Department of Pharmacotherapy, Washington State University College of Pharmacy & Pharmaceutical Sciences, Spokane, WA 99202, USA
3
Department of Breast and Endocrine Surgery, Stavanger University Hospital, P.O. Box 8100, 4068 Stavanger, Norway
4
Department of Clinical Science, University of Bergen, 5021 Bergen, Norway
5
Hormone Laboratory, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, 5021 Bergen, Norway
*
Author to whom correspondence should be addressed.
Academic Editors: Werner Schroth and Matthias Schwab
J. Pers. Med. 2021, 11(6), 507; https://doi.org/10.3390/jpm11060507
Received: 4 May 2021 / Revised: 28 May 2021 / Accepted: 31 May 2021 / Published: 4 June 2021
(This article belongs to the Special Issue Genome Research and Personalized Medicine in Breast Cancer)
Background: Tamoxifen, as a treatment of estrogen receptor positive (ER+) breast cancer, is a weak anti-estrogen that requires metabolic activation to form metabolites with higher anti-estrogenic activity. Endoxifen is the most-studied active tamoxifen metabolite, and endoxifen concentrations are highly associated with CYP2D6 activity. Associations of tamoxifen efficacy with measured or CYP2D6-predicted endoxifen concentrations have been inconclusive. Another active metabolite, 4-OHtam, and other, less active metabolites, Z-4′-endoxifen and Z-4′-OHtam, have also been reported to be associated with tamoxifen efficacy. Method: Genotype for 20 pharmacogenes was determined by VeriDose® Core Panel and VeriDose®CYP2D6 CNV Panel, followed by translation to metabolic activity phenotype following standard activity scoring. Concentrations of tamoxifen and seven metabolites were measured by UPLC-MS/MS in serum samples collected from patients receiving 20 mg tamoxifen per day. Metabolic activity was tested for association with tamoxifen and its metabolites using linear regression with adjustment for upstream metabolites to identify genes associated with each step in the tamoxifen metabolism pathway. Results: A total of 187 patients with genetic and tamoxifen concentration data were included in the analysis. CYP2D6 was the primary gene associated with the tamoxifen metabolism pathway, especially the conversion of tamoxifen to endoxifen. CYP3A4 and CYP2C9 were also responsible for the metabolism of tamoxifen. CYP2C9 especially impacted the hydroxylation to 4-OHtam, and this involved the OATP1B1 (SLCO1B1) transporter. Conclusion: Multiple genes are involved in tamoxifen metabolism and multi-gene panels could be useful to predict active metabolite concentrations and guide tamoxifen dosing. View Full-Text
Keywords: pharmacogenetics; tamoxifen; endoxifen; active metabolites; CYP2D6; CYP3A4; CYP2C9; SLCO1B1; breast cancer pharmacogenetics; tamoxifen; endoxifen; active metabolites; CYP2D6; CYP3A4; CYP2C9; SLCO1B1; breast cancer
Show Figures

Figure 1

MDPI and ACS Style

Chen, Y.; Marcath, L.A.; Eliassen, F.M.; Lende, T.H.; Soiland, H.; Mellgren, G.; Helland, T.; Hertz, D.L. Effect of Genetic Variability in 20 Pharmacogenes on Concentrations of Tamoxifen and Its Metabolites. J. Pers. Med. 2021, 11, 507. https://doi.org/10.3390/jpm11060507

AMA Style

Chen Y, Marcath LA, Eliassen FM, Lende TH, Soiland H, Mellgren G, Helland T, Hertz DL. Effect of Genetic Variability in 20 Pharmacogenes on Concentrations of Tamoxifen and Its Metabolites. Journal of Personalized Medicine. 2021; 11(6):507. https://doi.org/10.3390/jpm11060507

Chicago/Turabian Style

Chen, Yuanhuang, Lauren A. Marcath, Finn M. Eliassen, Tone H. Lende, Havard Soiland, Gunnar Mellgren, Thomas Helland, and Daniel L. Hertz 2021. "Effect of Genetic Variability in 20 Pharmacogenes on Concentrations of Tamoxifen and Its Metabolites" Journal of Personalized Medicine 11, no. 6: 507. https://doi.org/10.3390/jpm11060507

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop