A 17β-Estradiol Metabolite With Gender-Independent Therapeutic Potential
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See related article, pp 1104–1112
Observational studies in humans and experimental studies in animals provide evidence that estrogens protect postmenopausal women against cardiovascular disease.1 However, results from randomized clinical trials do not support this contention.1 The reason(s) for the disparity in the outcome remains unclear and unresolved. Multiple factors, including type of estrogen used, interaction with progesterone, age of subjects, the status of vascular disease, and the timing of treatment, have been hypothesized to contribute to lack of protective actions in the clinical trials.1,2
On the basis of the conventional mechanism, major focus has been directed toward the role of estrogen receptors in mediating cardiovascular effects of estrogen, and much less attention placed on the contribution, consequence, and importance of estrogen metabolism in defining the protective actions of estrogen, particularly, 17β-estradiol. In this issue Pingili et al3 demonstrate that 2-methoxyestradiol, an endogenous 17β-estradiol metabolite, attenuates angiotensin II–induced hypertension and renal dysfunction in intact male and ovariectomized female CYP1B1+/+ mice.3 Previously, using CYP1B1−/− mice and pharmacological CYP1B1 inhibitor, their team demonstrated that conversion of endogenous 17β-estradiol to 2-methoxyestradiol is essential for counteracting angiotensin II–induced hypertension and end-organ damage (renal and cardiovascular) in female mice.4 Collectively, their findings provide credence to the original hypothesis that 2-methoxyestradiol mediates the protective actions of 17β-estradiol on cardiovascular and renal system.2
Aromatase metabolizes testosterone to 17β-estradiol, whereas multiple CYP450-isoforms (CYP1A1, CYP1A2, CYP1B1, and CYP3A4) convert 17β-estradiol to several metabolites.5 The CYP1B1 isozyme is largely extrahepatic and dynamically expressed …