Rapid inhibition of rat brain mitochondrial proton F0F1-ATPase activity by estrogens: comparison with Na+, K+ -ATPase of porcine cortex.
Our earlier studies have identified oligomycin sensitivity-conferring protein (OSCP), a subunit of proton F0F1-ATPase/ATP synthase in the mitochondrial inner membranes, as a new estradiol binding protein. This finding suggests that mitochondrial ATPase/ATP synthase could be a potential target for estradiol or compounds with similar structures. Here, we report that estradiol and several other compounds inhibited F0F1-ATPase activity of detergent-solubilized rat brain mitochondrial preparations in a following decreasing order: diethylstilbestrol (half-inhibition concentration, IC50 of 10-25 microM) > alpha-zearalenol, 4-hydroxyestradiol (1C50 of 55 microM) >2-hydroxyestradiol (IC50 of 110 microM), 17beta-estradiol, 17alpha-estradiol > beta-zearalanol > estriol, testosterone, 16alpha-hydroxyestrone > corticosterone, progesterone, dehydroepiandrosterone, dehydroepiandrosterone 3-sulfate, cholesterol (less than 10% inhibition at 140 microM). On the other hand, Na+, K+ -ATPase of porcine cortex showed different sensitivity to the compounds tested above. At 70 microM, the rank of inhibitory potency in decreasing order was as follows: 2-hydroxyestradiol (IC50 of 70 microM) > diethylstilbestrol> 4-hydroxyestradiol > progesterone > alpha-zearalenol, while other compounds had little effect (less than 5%). The data indicate that the ubiquitous mitochondrial F0F1-ATPase is a specific target site for estradiol and related estrogenic compounds; however, under this in vitro condition, the effect seems to require pharmacological concentrations.
Zheng
J
J
Department of Molecular and Integrative Physiology and Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana 61801, USA.
Ramirez
V D
VD
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002784:Cholesterol / Q000494:pharmacology; D003345:Corticosterone / Q000494:pharmacology; D003687:Dehydroepiandrosterone / Q000494:pharmacology; D003902:Detergents; D004054:Diethylstilbestrol / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D006894:Hydroxyestrones / Q000494:pharmacology; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D010042:Ouabain / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors; D012995:Solubility; D013552:Swine; D013739:Testosterone / Q000494:pharmacology; D015029:Zeranol / Q000494:pharmacology
D003902:Detergents; D004791:Enzyme Inhibitors; D004967:Estrogens; D006894:Hydroxyestrones; C026702:16-hydroxyestrone; D013739:Testosterone; D003687:Dehydroepiandrosterone; D011374:Progesterone; D010042:Ouabain; D004054:Diethylstilbestrol; D015029:Zeranol; D002784:Cholesterol; D006180:Proton-Translocating ATPases; D000254:Sodium-Potassium-Exchanging ATPase; D003345:Corticosterone