Development of biological assays for the identification of selective inhibitors of estradiol formation from estrone in rat liver preparations

Abstract

Estradiol (E2) is the most important estrogen in humans. Besides its physiological effects it is involved in the initiation and progression of estrogen dependent diseases like breast cancer and endometriosis. Common endocrine therapies have a strong influence on systemic E2 action and thus cause the corresponding side effects. For an optimisation of therapy in estrogen dependent diseases there is need for new innovative approaches. 17β-Hydroxysteroid dehydrogenase type 1 (17βHSD1) is considered as a promising target in therapy, because it catalyses the reduction of estrone (E1) to E2 (last step of E2-biosynthesis) and is often overexpressed in diseased tissue. Highly active and selective inhibitors of the human 17βHSD1 with promising properties for further preclinical development have been identified in our group. Further investigations have looked at the demonstration of efficacy in an appropriate animal experiment. For this reason, adequate tests for the assessment of the inhibitors in other species have to be established. Here we describe the development of two assays for determination of E2-activation and -inactivation, respectively, as well as the identification of inhibitors of E2-formation in rat liver preparations and their evaluation for selectivity.