Pharmacogenetics of UGT1A4, UGT2B7 and UGT2B15 and Their Influence on Tamoxifen Disposition in Asian Breast Cancer Patients.
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.
Clinical Pharmacology, SingHealth, Singapore, Singapore.
Natalia
N
Sutiman
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
JSL
Lim
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.|University of Tubingen, Tubingen, Germany.
Thomas E
TE
Muerdter
Clinical Pharmacology Laboratory, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore.
Onkar
O
Singh
Center for Quantitative Medicine, Duke-NUS Graduate Medical School, Singapore, Singapore.|Department for International Health, University of Tampere, Tampere, Finland.
Yin Bun
YB
Cheung
Division of Medical Oncology, National Cancer Centre, Singapore, Singapore.
Raymond Chee Hui
RCH
Ng
Division of Medical Oncology, National Cancer Centre, Singapore, Singapore.
Yoon Sim
YS
Yap
OncoCare Cancer Centre, Mount Elizabeth Novena Medical Centre, Singapore, Singapore.
Nan Soon
NS
Wong
OncoCare Cancer Centre, Mount Elizabeth Novena Medical Centre, Singapore, Singapore.
Peter Cher Siang
PCS
Ang
Division of Medical Oncology, National Cancer Centre, Singapore, Singapore.
Rebecca
R
Dent
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.|University of Tubingen, Tubingen, Germany.
Werner
W
Schroth
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.|Department of Clinical Pharmacology, University Hospital, Tubingen, Germany.
Matthias
M
Schwab
Singapore Eye Research Institute, Singapore, Singapore.|Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.|Division of Human Genetics, Genome Institute of Singapore, Singapore, Singapore.
Chiea Chuen
CC
Khor
Clinical Pharmacology, SingHealth, Singapore, Singapore. ctebal@nccs.com.sg.|Clinical Pharmacology Laboratory, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore. ctebal@nccs.com.sg.|Office of Clinical Sciences, Duke-NUS Graduate Medical School, Singapore, Singapore. ctebal@nccs.com.sg.
Balram
B
Chowbay
D000328:Adult; D000368:Aged; D044466:Asian People / Q000208:ethnology / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000208:ethnology; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D005006:Ethnicity; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use*
D013629:Tamoxifen; C016601:afimoxifene; C055492:4-hydroxy-N-desmethyltamoxifen; D019389:Cytochrome P-450 CYP2D6; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; C472000:UDP-glucuronosyltransferase 2B15, human