title: Effects of estradiol metabolites on cAMP production and degradation.
abstract: (Full text is available at http://www.manu.edu.mk/prilozi). 17beta-Estradiol is metabolized to 2-hydroxyestradiol, and 2-hydroxyestradiol is converted to 2-methoxyestradiol. These steroids reduce proliferation of, migration of and collagen production by vascular smooth muscle cells with an order of potency of 2-methoxyestradiol > 2-hydroxyestradiol > 17beta-estradiol, i.e. the converse of their estrogenic potency. Since cAMP also inhibits cell growth, it is conceivable that these steroids alter cAMP synthesis or degradation, and this hypothesis was addressed in this study. In cultured preglomerular vascular smooth muscle cells pretreated with a high concentration of a broad spectrum phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine, 1 mM) to eliminate phosphodiesterase activity as a confounding variable, high (100 microM), but not low (10 microM), concentrations of 17beta-estradiol, 2-hydroxyestradiol and 2-methoxyestradiol attenuated isoproterenol-induced cAMP by 15%, 19% and 55%, respectively. 2-Hydroxyestradiol (100 microM) also attenuated forskolin-induced cAMP by 31% in cells treated with 3-isobutyl-1-methylxanthine. In cells not pretreated with 3-isobutyl-1-methylxanthine and using concentrations of steroids (10 microM) that did not interfere with adenylyl cyclase, 17beta-estradiol decreased by 34%, 2-hydroxyestradiol did not alter and 2-methoxyestradiol increased by 60% isoproterenol-induced cAMP. These results indicate that in preglomerular vascular smooth muscle cells, high concentrations of 2-hydrxoyestradiol markedly inhibit adenylyl cyclase whereas 17beta-estradiol and 2-methoxestradiol only modestly inhibit adenylyl cyclase even at high concentrations. Our results also indicate that lower concentrations of 17beta-estradiol, 2-hydroxyestradiol and 2-methoxyestradiol activate, have no effect on and inhibit, respectively, phosphordiesterase activity. The effects of these compounds on phosphodiesterase activity may account in part for the greater potency of 2-methoxyestradiol as an anti-growth compound compared with 17beta-estradiol and 2-hydroxyestradiol. Key words: Estradiol, Estradiol metabolites, 2-Methoxyestradiol, Cyclic adenosine monophosphate.
authors.affiliation: Center for Clinical Pharmacology, Departments of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, USA.
authors.forename: P S
authors.initials: PS
authors.lastname: Tofovic
authors.forename: B M
authors.initials: BM
authors.lastname: Rosado
authors.forename: K R
authors.initials: KR
authors.lastname: Dubey
authors.forename: Z
authors.initials: Z
authors.lastname: Mi
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Jackson
mesh_terms: D000077584:2-Methoxyestradiol; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000098:blood supply; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR
chemical_list: D010726:Phosphodiesterase Inhibitors; D004958:Estradiol; D000077584:2-Methoxyestradiol; C001390:2-hydroxyestradiol; D000242:Cyclic AMP