Functional significance of UDP-glucuronosyltransferase variants in the metabolism of active tamoxifen metabolites.
Functional significance of UDP-glucuronosyltransferase variants in the metabolism of active tamoxifen metabolites.
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DOI：
10.1158/0008-5472.can-08-3708
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发表时间：
2009-03-01
期刊：
影响因子：
11.2
通讯作者：
Lazarus P
中科院分区：
文献类型：
--
作者：
Blevins-Primeau AS;Sun D;Chen G;Sharma AK;Gallagher CJ;Amin S;Lazarus P
三苯氧胺（TAM）是一种选择性雌激素受体调节剂，广泛用于乳腺癌的预防和治疗。TAM、4-OH-TAM和内昔芬的主要活性代谢物的主要代谢模式是通过UDP-葡糖醛酸基转移酶（UGT）家族酶进行葡糖醛酸化。为了检查负责活性TAM代谢物的葡萄糖醛酸化的UGT酶的多态性是否在TAM代谢的个体间差异中起重要作用，检查过表达野生型或变体UGT的细胞系在体外对TAM代谢物的活性。对于活性肝外UGT的变体，UGT 1A 8173 Ala/277 Tyr变体对4-OH-TAM或内昔芬的反式异构体未表现出可检测的葡萄糖醛酸化活性。与其野生型对应物相比，未观察到UGT 1A 8173 Gly/277 Cys或UGT 1A 10139 Lys变体的TAM葡萄糖醛酸化活性存在差异。对于活性肝UGT，与野生型UGT 2B 7268 His相比，UGT 2B 7268 Tyr变体对4-OH-TAM和内昔芬反式异构体的活性分别显著降低2倍和5倍（p<0.01）。在对111份人肝微粒体标本的研究中，反式-4-OH-TAM和反式-内昔芬的O-葡萄糖醛酸化率为28%（p<0.001）和27%与具有UGT 2B 7 His 268 His基因型的受试者相比，UGT 2B 7 Tyr 268 Tyr基因型纯合子个体中的（p=0.002）分别较低，随着UGT 2B 7268 His等位基因数量的增加，对两种底物的活性有显著（p<0.01）降低的趋势。这些结果表明，TAM代谢UGT（包括UGT 2B 7和潜在的UGT 1A 8）的功能多态性可能在TAM代谢和TAM治疗反应的个体间变异性中很重要。
Tamoxifen (TAM) is a selective estrogen receptor modulator widely used in the prevention and treatment of breast cancer. A major mode of metabolism of the major active metabolites of TAM, 4-OH-TAM and endoxifen, is by glucuronidation via the UDP-glucuronosyltransferase (UGT) family of enzymes. To examine whether polymorphisms in the UGT enzymes responsible for the glucuronidation of active TAM metabolites play an important role in inter-individual differences in TAM metabolism, cell lines over-expressing wild-type or variant UGTs were examined for their activities against TAM metabolites in vitro. For variants of active extra-hepatic UGTs, the UGT1A8173Ala/277Tyr variant exhibited no detectable glucuronidation activity against the trans isomers of either 4-OH-TAM or endoxifen. No difference in TAM glucuronidating activity was observed for the UGT1A8173Gly/277Cys or UGT1A10139Lys variants as compared to their wild-type counterparts. For active hepatic UGTs, the UGT2B7268Tyr variant exhibited significant (p<0.01) 2- and 5-fold decreases in activity against the trans isomers of 4-OH-TAM and endoxifen, respectively, as compared to wild-type UGT2B7268His. In studies of 111 human liver microsomal specimens, the rate of O-glucuronidation against trans-4-OH-TAM and trans-endoxifen was 28% (p<0.001) and 27% (p=0.002) lower, respectively, in individuals homozygous for the UGT2B7 Tyr268Tyr genotype as compared to subjects with the UGT2B7 His268His genotype, with a significant (p<0.01) trend of decreasing activity against both substrates with increasing numbers of the UGT2B7268His allele. These results suggest that functional polymorphisms in TAM-metabolizing UGTs, including UGT2B7 and potentially UGT1A8, may be important in inter-individual variability in TAM metabolism and response to TAM therapy.