Effect of CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes on tamoxifen metabolism
Open Access
- 28 August 2017
- journal article
- pharmacogenetics
- Published by Springer Science and Business Media LLC in European Journal of Clinical Pharmacology
- Vol. 73 (12), 1589-1598
- https://doi.org/10.1007/s00228-017-2323-2
Abstract
Background Tamoxifen is one of the cornerstones of endocrine therapy for breast cancer. Recently, the decreased activity CYP3A4*22 allele and the loss of function CYP3A5*3 allele have been described as potential factors that could help to explain the inter-patient variability in tamoxifen metabolism. The aim of this study is to investigate the effect of CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes on tamoxifen metabolism. Methods DNA from 667 women enrolled in the CYPTAM study (NTR1509) was genotyped (CYP2D6, CYP3A4*22, and CYP3A5*3). Tamoxifen and metabolite concentrations were measured in serum, and metabolic ratios were calculated. The effect of the CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes in addition to the CYP2D6 genotypes was examined by multiple linear regression analysis. Results CYP3A4*22 carriers reached significant higher concentrations of tamoxifen, N-desmethyl-tamoxifen, and 4-hydroxy-tamoxifen compared to non-carriers, whereas a tendency toward increased endoxifen levels was observed (p = 0.088). The metabolic ratio tamoxifen/N-desmethyl-tamoxifen was significantly higher in CYP3A4*22 individuals (0.59 vs. 0.52, p < 0.001). At the same time, CYP3A4*22 genotype contributed to improving the inter-variability [R 2 of the (log-transformed) metabolic ratio tamoxifen/N-desmethyl-tamoxifen improved from 21.8 to 23.9%, p < 0.001]. CYP3A5*3 marginally improved the explained variability of the (log transformed) metabolic ratio 4-hydroxy-tamoxifen/endoxifen (from 44.9 to 46.2%, p < 0.038). Conclusion Our data demonstrate that CYP3A genotype has a minor effect to explaining the variability between patients in tamoxifen metabolism and has no added value in addition to CYP2D6 genotype.Keywords
Funding Information
- Leiden University Medical Center (LUMC)
This publication has 31 references indexed in Scilit:
- Global Cancer Incidence and Mortality Rates and Trends—An UpdateCancer Epidemiology, Biomarkers & Prevention, 2016
- Estrogen receptors in breast carcinogenesis and endocrine therapyMolecular and Cellular Endocrinology, 2015
- Functional Gene Variants of CYP3A4Clinical Pharmacology & Therapeutics, 2014
- PharmGKB summaryPharmacogenetics and Genomics, 2013
- Activity Levels of Tamoxifen Metabolites at the Estrogen Receptor and the Impact of Genetic Polymorphisms of Phase I and II Enzymes on Their Concentration Levels in PlasmaClinical Pharmacology & Therapeutics, 2011
- Tamoxifen: Catalyst for the change to targeted therapyEuropean Journal of Cancer, 2008
- Tamoxifen Pharmacogenomics: The Role of CYP2D6 as a Predictor of Drug ResponseClinical Pharmacology & Therapeutics, 2007
- Endoxifen (4-hydroxy-N-desmethyl-tamoxifen) has anti-estrogenic effects in breast cancer cells with potency similar to 4-hydroxy-tamoxifenCancer Chemotherapy and Pharmacology, 2005
- Comprehensive Evaluation of Tamoxifen Sequential Biotransformation by the Human Cytochrome P450 System in Vitro: Prominent Roles for CYP3A and CYP2D6The Journal of pharmacology and experimental therapeutics, 2004
- Tamoxifen (‘Nolvadex’): a reviewCancer Treatment Reviews, 2002