4-Hydroxytamoxifen

4-Hydroxytamoxifen is an orally active, selective estrogen receptor modulator (SERM). 4-Hydroxytamoxifen is a major metabolite of tamoxifen and a selective estrogen receptor antagonist^[1]. 4-Hydroxytamoxifen has the superoxide anion radical-scavenging activity, the antioxidative characteristics of 4-Hydroxytamoxifen can attenuate the methamphetamine(MA)-induced dopaminergic toxicity^[2].

4-Hydroxytamoxifen decreased the transcriptional activity of ERRγ by more than 75%, with an EC₅₀ value of 2μM^[3]. In vitro, MPNST cells were treated with 8-12μM 4-Hydroxytamoxifen for 48 hours,  concentration-dependently increased in caspase 3-like enzymatic activity. 4-Hydroxytamoxifen also triggers autophagic death in MPNST cells^[4]. In vitro, 2 or 10µM 4-Hydroxytamoxifen abolished the generation of action potentials and repolarized the membrane potential in rat pancreatic beta-cells stimulated by 16mM glucose in 2min. 4-Hydroxytamoxifen impaired beta-cell electrical and secretory activity by inhibiting calcium and anion channel currents^[5].

In vivo, αMHC-MerCreMer mice were treated with 20mg/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 40mg/kg 4-Hydroxytamoxifen also did not impair cardiac function^[6]. In vivo, treatment with 6µg/0.1mL/day subcutaneously of 4-Hydroxytamoxifen significantly mitigated MA-induced nigrostriatal dopamine (DA) and 3,4-dihydroxyphenylaceticacid (DOPAC) depletions in both male and female mice^[2].

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].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.[3].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.

[4].Kohli L, et al. 4-Hydroxytamoxifen induces autophagic death through K-Ras degradation. Cancer Res. 2013 Jul 15;73(14):4395-405. 

[5].Best L. Inhibition of glucose-induced electrical activity by 4-hydroxytamoxifen in rat pancreatic beta-cells. Cell Signal. 2002 Jan;14(1):69-73.

[6].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.