4-Hydroxytamoxifen

4-hydroxytamoxifen is a major metabolite of tamoxifen and selective estrogen receptor antagonist. It potentiated the protective effects of estradiol against the MA-induced nigrostriatal DA depletion.^[1] 4-Hydroxytamoxifen has the superoxide anion radical-scavenging activity, the antioxidative characteristics of 4-Hydroxytamoxifen can attenuate the MA-induced dopaminergic toxicity.^[4]

In vitro, 4-Hydroxytamoxifen decreased the transcriptional activity of ERRγ by more than 75%, with an EC50 value of 2 μM.^[5] In MPNST cells were treated with 8-12 μM 4-Hydroxytamoxifen after 48 hours, there has a concentration-dependent increase in caspase 3-like enzymatic activity. 4-Hydroxytamoxifen also triggers autophagic death in MPNST cells.^[2] In vitro study it indicated that 10 or 2 μM 4-hydroxytamoxifen abolished the generation of action potentials and repolarized the membrane potential in rat pancreatic beta-cells stimulated by 16 mM glucose. 4-hydroxytamoxifen impairs beta-cell electrical and secretory activity by inhibiting calcium and anion channel currents.^[6]

In vivo experiment it shown that αMHC-MerCreMer mice were treated 20 mg/kg 4-hydroxytamoxifen intraperitoneally for 5 consecutive days, neither cardiac function nor cardiac energetic status in αMHC-MerCreMer mice was disturbed. In addition, the injection of 40 mg/kg 4-hydroxytamoxifen also did not impair cardiac function.^[3] In vivo efficacy test it demonstrated that treatment with 6 μg/0.1 mL/day subcutaneously of 4-Hydroxytamoxifen significantly mitigated MA-induced nigrostriatal DA and DOPAC depletions in both male and female mice.^[4]

References:
[1].Yu L.,?et al.?(2002a)?Ovarian hormones do not attenuate methamphetamine-induced dopaminergic neurotoxicity in mice gonadectomized at 4 weeks postpartum.?Neuroendocrinology?75,?282–287.
[2].Kohli L, et al. 4-Hydroxytamoxifen induces autophagic death through K-Ras degradation. Cancer Res. 2013 Jul 15;73(14):4395-405.
[3].Heinen A, et al. 4-hydroxytamoxifen does not deteriorate cardiac function in cardiomyocyte-specific MerCreMer transgenic mice. Basic Res Cardiol. 2021 Feb 5;116(1):8.
[4].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.
[5].Coward P, et al. 4-Hydroxytamoxifen binds to and deactivates the estrogen-related receptor gamma. Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8880-4.
[6].Best L. Inhibition of glucose-induced electrical activity by 4-hydroxytamoxifen in rat pancreatic beta-cells. Cell Signal. 2002 Jan;14(1):69-73.

4-hydroxytamoxifen 是他莫昔芬和选择性雌激素受体拮抗剂的主要代谢产物。它增强了雌二醇对MA诱导的黑质纹状体DA耗竭的保护作用。^[1] 4-Hydroxytamoxifen具有超氧阴离子自由基清除活性，4-Hydroxytamoxifen的抗氧化特性可以减弱MA-诱导多巴胺能毒性。^[4]

在体外，4-Hydroxytamoxifen 使 ERRγ 的转录活性降低了 75% 以上，EC50 值为 2 μM。^[5] 在 MPNST 细胞中，用 8-12 μM 4 处理- 48 小时后，羟基他莫昔芬会出现 caspase 3 样酶活性的浓度依赖性增加。 4-羟基他莫昔芬还会引发 MPNST 细胞的自噬性死亡。^[2] 体外研究表明，10 或 2 μM 4-羟基他莫昔芬可消除大鼠胰腺 β- 细胞中动作电位的产生并使膜电位复极化。 16 mM 葡萄糖刺激的细胞。 4-羟基三苯氧胺通过抑制钙和阴离子通道电流来损害 β 细胞的电活动和分泌活动。^[6]

体内实验表明，αMHC-MerCreMer 小鼠连续 5 天腹膜内注射 20 mg/kg 4-羟基三苯氧胺，αMHC-MerCreMer 小鼠的心脏功能和心脏能量状态均未受到干扰。此外，注射40 mg/kg 4-羟基他莫昔芬也没有损害心脏功能。^[3] 体内药效试验表明，皮下注射6 μg/0.1 mL/天的4-羟他莫昔芬显着减轻雄性和雌性小鼠中 MA 诱导的黑质纹状体 DA 和 DOPAC 耗竭。^[4]