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
Clinical Pharmacology, SingHealth, Singapore, Singapore.
Clinical Pharmacology Laboratory, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore.
Clin Pharmacokinet. 2016 Oct;55(10):1239-1250. 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 < 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.
他莫昔芬（TAM）是一种已确立的用于各阶段雌激素受体（ER）阳性乳腺癌的内分泌治疗药物。其复杂的代谢过程会导致多种活性和非活性代谢产物的形成。他莫昔芬及其活性代谢产物4-羟基他莫昔芬（4-OHT）和内昔芬的主要解毒和消除途径之一是通过尿苷5'-二磷酸葡萄糖醛酸基转移酶（UGT）催化的葡萄糖醛酸化作用。然而，很少有研究全面考察编码主要肝脏UGT的基因变异对他莫昔芬及其代谢产物处置的影响。在本研究中，我们对240名不同亚洲种族（中国人、马来人和印度人）的健康受试者的UGT1A4、UGT2B7和UGT2B15的外显子、外显子/内含子边界及侧翼区域进行了系统测序，以鉴定单倍型标签单核苷酸多态性。随后，对202名接受他莫昔芬治疗的亚洲乳腺癌患者进行了这三个UGT基因中50个选定变异的基因分型，以全面研究它们与他莫昔芬及其活性代谢产物以及它们的结合物的稳态血浆水平之间的关联。UGT1A4单倍型（包含变异142T>G，L48V定义*3等位基因）与较高的TAM-N-葡萄糖醛酸血浆水平密切相关，在校正协变量后，该单倍型携带者中观察到的TAM-N-葡萄糖醛酸/TAM代谢率高出两倍（P<0.0001）。UGT2B7中的变异与4-OHT和内昔芬的O-葡萄糖醛酸化改变无关，而在调整CYP2D6基因型后，UGT2B15单倍型对（E）-内昔芬血浆水平有适度影响。我们的研究结果突出了UGT1A4单倍型对亚洲乳腺癌患者他莫昔芬处置的影响，而UGT2B7和UGT2B15中的基因变异似乎不太重要。
