Rapid inhibition of rat brain mitochondrial proton F0F1-ATPase activity by estrogens: comparison with Na +, K +-ATPase of porcine cortex

• Published in: European journal of pharmacology Vol. 368; no. 1; pp. 95 - 102
• Main Authors: Zheng, Jianbiao, Ramirez, Victor D.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 26.02.1999; Elsevier
• Subjects: Animals; Biological and medical sciences; Brain - drug effects; Brain - enzymology; Catecholestrogen; Cholesterol - pharmacology; Corticosterone - pharmacology; Dehydroepiandrosterone - pharmacology; Detergents; Diethylstilbestrol - pharmacology; Enzyme Inhibitors - pharmacology; Estrogen; Estrogens - pharmacology; F0F1-ATPase; Female; Hormones. Endocrine system; Hydroxyestrones - pharmacology; Medical sciences; Microsomes - drug effects; Microsomes - enzymology; Mitochondria - drug effects; Mitochondria - enzymology; Mitochondrion; Na +, K +-ATPase; Oligomycin; Ouabain - pharmacology; Pharmacology. Drug treatments; Progesterone - pharmacology; Proton-Translocating ATPases - antagonists & inhibitors; Proton-Translocating ATPases - metabolism; Rats; Rats, Sprague-Dawley; Sodium-Potassium-Exchanging ATPase - antagonists & inhibitors; Solubility; Swine; Testosterone - pharmacology; Zeranol - pharmacology; Mitochondrion; Oligomycin; F0F1-ATPase; Na +, K +-ATPase; Catecholestrogen; Estrogen; Enzyme; Adenosinetriphosphatase; Central nervous system; K; Estradiol; In vitro; Site of action; Binding protein; Mitochondria; Na; Enzymatic activity; Animal; Hydrolases; exchanging ATPase; Mechanism of action; Brain (vertebrata)
• DOI: 10.1016/S0014-2999(99)00012-6
• ISSN: 0014-2999

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, IC 50 of 10–25 μM)>α-zearalenol, 4-hydroxyestradiol (IC 50 of 55 μM)>2-hydroxyestradiol (IC 50 of 110 μM), 17β-estradiol, 17α-estradiol>β-zearalanol>estriol, testosterone, 16α-hydroxyestrone>corticosterone, progesterone, dehydroepiandrosterone, dehydroepiandrosterone 3-sulfate, cholesterol (less than 10% inhibition at 140 μM). On the other hand, Na +, K +-ATPase of porcine cortex showed different sensitivity to the compounds tested above. At 70 μM, the rank of inhibitory potency in decreasing order was as follows: 2-hydroxyestradiol (IC 50 of 70 μM)>diethylstilbestrol>4-hydroxyestradiol>progesterone>α-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.