(Z)-4-Hydroxytamoxifen

(Z)-4-Hydroxytamoxifen is a selective estrogen receptor modulator (SERM) that influences the binding of [3H]oestradiol to the estrogen receptor with an IC50 value of 3.3 nM[1]. (Z)-4-Hydroxytamoxifen can reduce off-target effects in CRISPR-mediated gene editing[2]. It is a metabolite of tamoxifen, targeting estrogen receptors, especially in breast cancer cells, acting as an antagonist in breast tissues and as an agonist in other tissues such as the endometrium. This dual action makes it a key drug in the treatment and chemoprevention of estrogen receptor-positive breast cancer[3].

In vitro, (Z)-4-Hydroxytamoxifen (1-100nM) treatment of immature rat pituitary cells for 6 days inhibits estradiol-stimulated PRL synthesis more effectively than tamoxifen[4]. At low concentrations (0.01-1.00 nM) in the absence of estradiol, (Z)-4-Hydroxytamoxifen significantly stimulates the formation of MCF-7 cell colonies[5].

In vivo, (Z)-4-Hydroxytamoxifen (0.2, 1, 5 µg/d, p.o.) causes a dose-dependent decrease in wet weight of the uterus in immature rats[1]. (Z)-4-Hydroxytamoxifen (6 µg/0.1 mL/day, s.c.) effectively reduces methamphetamine-induced depletion of striatal dopamine in both intact and adrenalectomized male and female C57BL/6J mice without altering dopamine levels in the striatum[6].

References:
[1] Jordan VC, et al. A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J Endocrinol. 1977 Nov;75(2):305-16.
[2] Davis KM, et al. Small molecule-triggered Cas9 protein with improved genome-editing specificity. Nat Chem Biol. 2015 May;11(5):316-8.
[3]Shagufta,Irshad,Ahmad.Tamoxifen a pioneering drug: An update on the therapeutic potential of tamoxifen derivatives[J].European Journal of Medicinal Chemistry: Chimie Therapeutique, 2018, 143:515-531.
[4] JORDAN V C, KOCH R, LANGAN S, et al. Ligand interaction at the estrogen receptor to program antiestrogen action: a study with nonsteroidal compounds in vitro[J]. Endocrinology, 1988, 122(4): 1449-1454.
[5] Defriend D , Anderson E , Bell J ,et al.Effects of 4-hydroxytamoxifen and a novel pure antioestrogen (ICI 182780) on the clonogenic growth of human breast cancer cells in vitro[J].Br J Cancer, 1994, 70(2):204-211.
[6] Kuo YM, et al. 4-Hydroxytamoxifen attenuates methamphetamine-induced nigrostriatal dopaminergic toxicity in intact and gonadetomized mice. J Neurochem. 2003 Dec;87(6):1436-43.

4-羟基他莫昔芬((Z)-4-Hydroxytamoxifen)是雌激素受体的选择性调节剂(SERM),其影响[3H]oestradiol与雌激素受体结合的IC50值为3.3 nM[1]。(Z)-4-Hydroxytamoxifen可以减少 CRISPR 介导的基因编辑中的脱靶效应[2]。(Z)-4-Hydroxytamoxifen是他莫昔芬的代谢产物,靶向雌激素受体,特别是在乳腺癌细胞中,在乳腺组织中充当拮抗剂,在子宫内膜等其他组织中充当激动剂。这种双重作用使其成为治疗和化学预防雌激素受体阳性乳腺癌的关键药物[3]。

在体外,(Z)-4-Hydroxytamoxifen (1-100nM)处理未成熟大鼠垂体细胞6天,抑制雌二醇刺激的PRL 合成,比他莫昔芬更有效[4]。 (Z)-4-Hydroxytamoxifen低浓度 (0.01-1.00 nM) 在没有雌二醇的情况下,会显著刺激MCF-7细胞集落形成[5]。

在体内,(Z)-4-Hydroxytamoxifen (0.2、1 、5 µg/d,p.o.) 引起未成熟大鼠子宫湿重出现剂量相关降低现象[1]。(Z)-4-Hydroxytamoxifen(6 µg/0.1 mL/day,s.c.)可有效减轻完整和去腺切除的两性 C57BL/6 J 小鼠中甲基苯丙胺诱导的黑质纹状体多巴胺消耗,且不会改变纹状体中的多巴胺水平[6]。