Stereospecificity of the intracellular binding of norethisterone and its a-ring reduced metabolites

Abstract

The interaction of norethisterone (NET) and four A-ring reduced metabolites of NET with cytosol receptors for progesterone (PR), androgen (AR), and estrogen (ER) was investigated. Cytosol preparations from: (a) uteri of adult estrogen-primed castrated rats, (b) ventral prostates of adult castrated rats and (c) uteri of immature rats were used as the source of PR, AR, and ER respectively. 3H-Labeled ORG-2058, R-1881, and 17β-estradiol were used as the radioligands. The results of competitive studies disclosed that: (a) the most efficient competitor for PR binding sites was NET (Ki = 1.1 × 10−7M) followed by 5α-dihydro NET (5α-NET), whereas the 3α,5α; 3β,5α and 3α,5β-tetrahydro NET derivatives were ineffective (b) the most efficient competitor for AR binding sites was 5α-NET (Ki = 1 × 10−8), immediately followed by NET, while the three tetrahydro NET derivatives were not competitors and (c) remarkable competition for ER binding sites was only exhibited by the 3β,5α-tetrahydro NET derivative (Ki = 4.6 × 10−8M) and to a lesser extent by its 3α,5α-epimeric alcohol, while NET and 5α-NET were completely ineffective. These findings demonstrate the stereospecificity of the intracellular binding of NET and its reduced metabolites with cytosol steroid putative receptors, and provide biochemical support to the understanding of the variety of hormone-like effects observed after the in vivo administration of NET.