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

• Published in: Clinical pharmacokinetics 2016-10, Vol.55 (10), p.1239-1250
• Main Authors: Sutiman, Natalia, Lim, Joanne Siok Liu, Muerdter, Thomas E., Singh, Onkar, Cheung, Yin Bun, Ng, Raymond Chee Hui, Yap, Yoon Sim, Wong, Nan Soon, Ang, Peter Cher Siang, Dent, Rebecca, Schroth, Werner, Schwab, Matthias, Khor, Chiea Chuen, Chowbay, Balram
• Format: Article
• Language: English
• Subjects: Adult; Aged; Asian Continental Ancestry Group - ethnology; Asian Continental Ancestry Group - genetics; Breast Neoplasms - drug therapy; Breast Neoplasms - ethnology; Cytochrome P-450 CYP2D6 - genetics; Ethnic Groups; Female; Genotype; Glucuronosyltransferase - genetics; Humans; Internal Medicine; Medicine; Medicine & Public Health; Middle Aged; Original Research Article; Pharmacogenetics; Pharmacology/Toxicology; Pharmacotherapy; Polymorphism, Single Nucleotide; Tamoxifen - analogs & derivatives; Tamoxifen - blood; Tamoxifen - metabolism; Tamoxifen - pharmacokinetics; Tamoxifen - therapeutic use
• ISSN: 0312-5963; 1179-1926
• DOI: 10.1007/s40262-016-0402-7

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