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 mu M) > alpha-zearalenol, 4-hydroxyestradiol (IC50 of 55 mu M) > 2-hydroxyestradiol (IC50 of 110 mu M), 17 beta-estradiol, 17 alpha-estradiol > beta-zearalanol > estriol, testosterone, 16 alpha-hydroxyestrone > corticosterone, progesterone, dehydroepiandrosterone, dehydroepiandrosterone 3-sulfate, cholesterol (less than 10% inhibition at 140 mu M). On the other hand, Na+,K+-ATPase of porcine cortex showed different sensitivity to the compounds tested above. At 70 mu M, the rank of inhibitory potency in decreasing order was as follows: 2-hydroxyestradiol (IC50 of 70 mu M) > diethylstilbestrol > 4hydroxyestradiol > 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. (C) 1999 Elsevier Science B.V. All rights reserved.