2-Hydroxyestradiol

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Background

2-Hydroxyestradiol is an angiogenesis inhibitor via the HIF-1a pathway.
HIF-1a, a basic helix-loop-helix PAS domain containing protein, is reported as the master transcriptional regulator of cellular and developmental response to hypoxia.
In vitro: In vitro evidences suggested that most of the cellular effects of 2-hydroxyestradiol were mediated by 2-methoxyestradiol, a metabolite of 2-hydroxyestradiol as an anti-cancer agent acting as an angiogenesis inhibitor via the HIF-1a pathway. Inhibition of catechol-O-methyltransferase (COMT), the enzyme methylating 2-hydroxyestradiol to 2-methoxyestradiol, blocked the ability of 2-hydroxyestradiol to inhibit growth of vascular smooth muscle cells, cardiac fibroblasts, as well as renal mesangial cells. Moreover, 2-hydroxyestradiol could inhibit vascular smooth muscle cell growth in cells obtained from wild-type mice but not in cells cultured from COMT knockout mice. In contrast to 2OHE, treatment of vascular smooth muscle cells with 2-methoxyestradiol inhibited serum-induced growth of cells from both wild-type and COMTknockout mice [1].
In vivo: Animal study showed that after administration of 2-hydroxyestradiol, plasma levels of 2-hydroxyestradiol declined extremely rapidly. Concomitant with the disappearance of 2-hydroxyestradiol, 2-methoxyestradiol occurred and then declined. After administration of 2-methoxyestradiol, plasma levels of 2MEOE declined with a plasma CL of 50 ml min(-1) kg(-1). We could not detect 2-hydroxyestradiol in plasma from rats receiving 2-methoxyestradiol. Thus, the authors conclude that the conversion of 2-hydroxyestradiol to 2-methoxyestradiol was so efficient, and the administration of 2-hydroxyestradiol is bioequivalent to administration of 2-methoxyestradiol itself [1].
Clinical trial: So far, no clinical study has been conducted.

Reference:[1] Zacharia, L. C.,Piché, C.A.,Fielding, R.M., et al. 2-hydroxyestradiol is a prodrug of 2-methoxyestradiol. Journal of Pharmacology and Experimental Therapeutics 309(3), 1093-1097 (2004).