2-Hydroxyestradiol

2-Hydroxyestradiol (2-OHE2), also known as estra-1,3,5(10)-triene-2,3,17β-triol, is an endogenous steroid, catechol estrogen, and metabolite of estradiol, as well as a positional isomer of estriol. Transformation of estradiol to 2-hydroxyestradiol is a major metabolic pathway of estradiol in the liver. CYP1A2 and CYP3A4 are the major enzymes catalyzing the 2-hydroxylation of estradiol. Conversion of estradiol into 2-hydroxyestradiol has also been detected in the uterus, breast, kidney, brain, and pituitary gland, as well as the placenta, and may similarly be mediated by cytochrome P450 enzymes. Although estradiol is extensively converted into 2-hydroxyestradiol, circulating levels of 2-hydroxyestradiol and levels of 2-hydroxyestradiol in various tissues are very low. This may be due to rapid conjugation (O-methylation, glucuronidation, sulfonation) of 2-hydroxyestradiol followed by urinary excretion. 2-Hydroxyestradiol has approximately 7% and 11% of the affinity of estradiol at the estrogen receptors (ERs) ERα and ERβ, respectively. It dissociates from the estrogen receptors more rapidly than does estradiol. The steroid is only very weakly estrogenic, and is able to antagonize the estrogenic effects of estradiol, indicating that its intrinsic activity at the estrogen receptor is less than that of estradiol and hence that it possesses the profile of a selective estrogen receptor modulator. It shows estrogenic activity in human breast cancer cells. In addition to its activity at the nuclear ERs, 2-hydroxyestradiol is an antagonist of the G protein-coupled estrogen receptor (GPER) (100–1,000 μM). 2-Hydroxyestradiol is a catechol estrogen and in this regard bears some structural resemblance to the catecholamines dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline). In accordance, 2-hydroxyestradiol has been found to interact with catecholamine systems. The steroid is known to compete with catecholamines for binding to catechol O-methyltransferase and tyrosine hydroxylase and to directly and competitively inhibit these enzymes.