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Pharmacogenetics of UGT1A4, UGT2B7 and UGT2B15 and Their Influence on Tamoxifen Disposition in Asian Breast Cancer Patients

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Abstract

Tamoxifen (TAM) is an established endocrine treatment for all stages of oestrogen receptor (ER)-positive breast cancer. Its complex metabolism leads to the formation of multiple active and inactive metabolites. One of the main detoxification and elimination pathways of tamoxifen and its active metabolites, 4-hydroxytamoxifen (4-OHT) and endoxifen, is via glucuronidation catalysed by uridine 5′-diphospho-glucuronosyltransferases (UGTs). However, few studies have comprehensively examined the impact of variations in the genes encoding the major hepatic UGTs on the disposition of tamoxifen and its metabolites. In the present study, we systematically sequenced exons, exon/intron boundaries, and flanking regions of UGT1A4, UGT2B7 and UGT2B15 in 240 healthy subjects of different Asian ethnicities (Chinese, Malays and Indians) to identify haplotype tagging single nucleotide polymorphisms. Subsequently, 202 Asian breast cancer patients receiving tamoxifen were genotyped for 50 selected variants in the three UGT genes to comprehensively investigate their associations with steady-state plasma levels of tamoxifen, its active metabolites and their conjugated counterparts. The UGT1A4 haplotype (containing variant 142T>G, L48 V defining the *3 allele) was strongly associated with higher plasma levels of TAM-N-glucuronide, with a twofold higher metabolic ratio of TAM-N-glucuronide/TAM observed in carriers of this haplotype upon covariate adjustment (P < 0.0001). Variants in UGT2B7 were not associated with altered O-glucuronidation of both 4-OHT and endoxifen, while UGT2B15 haplotypes had a modest effect on (E)-endoxifen plasma levels after adjustment for CYP2D6 genotypes. Our findings highlight the influence of UGT1A4 haplotypes on tamoxifen disposition in Asian breast cancer patients, while genetic variants in UGT2B7 and UGT2B15 appear to be of minor importance.

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Author information

Author notes

    Authors and Affiliations

    1. Clinical Pharmacology, SingHealth, Singapore, Singapore

      Natalia Sutiman & Balram Chowbay

    2. Clinical Pharmacology Laboratory, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore

      Joanne Siok Liu Lim, Onkar Singh & Balram Chowbay

    3. Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany

      Thomas E. Muerdter, Werner Schroth & Matthias Schwab

    4. University of Tubingen, Tubingen, Germany

      Thomas E. Muerdter & Werner Schroth

    5. Center for Quantitative Medicine, Duke-NUS Graduate Medical School, Singapore, Singapore

      Yin Bun Cheung

    6. Department for International Health, University of Tampere, Tampere, Finland

      Yin Bun Cheung

    7. Division of Medical Oncology, National Cancer Centre, Singapore, Singapore

      Raymond Chee Hui Ng, Yoon Sim Yap & Rebecca Dent

    8. OncoCare Cancer Centre, Mount Elizabeth Novena Medical Centre, Singapore, Singapore

      Nan Soon Wong & Peter Cher Siang Ang

    9. Department of Clinical Pharmacology, University Hospital, Tubingen, Germany

      Matthias Schwab

    10. Office of Clinical Sciences, Duke-NUS Graduate Medical School, Singapore, Singapore

      Balram Chowbay

    11. Singapore Eye Research Institute, Singapore, Singapore

      Chiea Chuen Khor

    12. Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

      Chiea Chuen Khor

    13. Division of Human Genetics, Genome Institute of Singapore, Singapore, Singapore

      Chiea Chuen Khor

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    1. Natalia Sutiman
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    Correspondence to Balram Chowbay.

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    Funding

    This study was supported by the National Medical Research Council Singapore (Grant numbers NMRC/1159/2008, NMRCB1011, NRFCG1516, NMRCG13163 and NMRC/CIRG/1423/2015); by the Robert Bosch Foundation, Stuttgart, Germany; by the German Federal Ministry of Education and Research (Grant number 03 IS 2061C); and in part by the Deutsche Foschungsgemeinschaft (Grant numbers SCHR 1323/2-1 and MU 1727/2-1) and the FP7 EU Initial Training Network Programme “Fighting Drug Failure” (Grant number PITN-GA-2009-238132).

    Conflict of interest

    Natalia Sutiman, Joanne Siok Liu Lim, Thomas E. Muerdter, Onkar Singh, Yin Bun Cheung, Raymond Chee Hui Ng, Yoon Sim Yap, Nan Soon Wong, Peter Cher Siang Ang, Rebecca Dent, Werner Schroth, Matthias Schwab, Chiea Chuen Khor and Balram Chowbay declare that they have no conflicts of interest.

    Ethical approval

    All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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    Written informed consent was obtained from all individual participants included in the study.

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    N. Sutiman and J. S. L. Lim contributed equally to this work.

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    Sutiman, N., Lim, J.S.L., Muerdter, T.E. et al. Pharmacogenetics of UGT1A4, UGT2B7 and UGT2B15 and Their Influence on Tamoxifen Disposition in Asian Breast Cancer Patients. Clin Pharmacokinet 55, 1239–1250 (2016). https://doi.org/10.1007/s40262-016-0402-7

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