Interaction of progestins with steroid receptors in human uterus.
Norethindrone (17beta-hydroxy-19-nor-17alpha-pregn-4-en-20-yn-3-one) and norethindrone acetate (17beta-acetoxy-19-nor-17alpha-pregn-4-en-20-yn-3-one) interfered to a varying degree, by competitive inhibition, with the binding of progesterone and oestradiol to respective cytoplasmic receptors in the human uterus. Progesterone binding to 4S macromolecule was saturable and co-specific for progestins. Competitors like norgestrel (17beta-hydroxy-18-methyl-19-nor-17alpha-pregn-4-en-20-yn-3-one), 19-norprogesterone, medroxyprogesterone acetate (17alpha-acetoxy-6alpha-methylpregn-4-ene-3,20-dione) and compound R(5020) (17,21-dimethyl-19-norpregna-4,9-diene-3,20-dione) possessed higher binding affinities for the progestin receptor. The dissociation constant (K(d)) for the progesterone-receptor interaction was 0.6-1.6nm and the receptor concentration ranged between 6600 and 8200 sites/cell. Norethindrone and norethindrone acetate competed for the progesterone receptor with inhibition constants (K(i)) of 6.8 and 72nm respectively. Gradient displacement and competitive-receptor assays indicated that norethindrone acetate-binding affinity for progestin receptor was approximately one-tenth that of norethindrone and progesterone. The progestins also inhibited oestradiol binding to 4.6S oestrogenic receptor by 8-12%, involving interaction at the oestradiol-binding site with a calculated K(i) value of 0.5-0.8mum. The competitive interaction of progestins with steroid receptors may be of putative importance in explaining the progestin action at the target site.
D000085:Acetates; D001667:Binding, Competitive; D002499:Centrifugation, Density Gradient; D003600:Cytosol / Q000378:metabolism; D004965:Estrogen Antagonists / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D009640:Norethindrone / Q000378:metabolism*; D011374:Progesterone / Q000037:antagonists & inhibitors; D011960:Receptors, Estrogen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism*; D014599:Uterus / Q000378:metabolism*
D000085:Acetates; D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D011374:Progesterone; D009640:Norethindrone