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

Our earlier studies have identified oligomycin sensitivity-conferring prote in (OSCP), a subunit of proton F0F1-ATPase/ATP synthase in the mitochondria l inner membranes, as a new estradiol binding protein. This finding suggest s that mitochondrial ATPase/ATP synthase could be a potential target for es tradiol or compounds with similar structures. Here, we report that estradio l and several other compounds inhibited F0F1-ATPase activity of detergent-s olubilized rat brain mitochondrial preparations in a following decreasing o rder: diethylstilbestrol (half-inhibition concentration, IC50 of 10-25 mu M ) > alpha-zearalenol, 4-hydroxyestradiol (IC50 of 55 mu M) > 2-hydroxyestra diol (IC50 of 110 mu M), 17 beta-estradiol, 17 alpha-estradiol > beta-zeara lanol > estriol, testosterone, 16 alpha-hydroxyestrone > corticosterone, pr ogesterone, dehydroepiandrosterone, dehydroepiandrosterone 3-sulfate, chole sterol (less than 10% inhibition at 140 mu M). On the other hand, Na+,K+-AT Pase 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 > 4hy droxyestradiol > progesterone > alpha-zearalenol, while other compounds had little effect (less than 5%). The data indicate that the ubiquitous mitoch ondrial F0F1-ATPase is a specific target site for estradiol and related est rogenic compounds; however, under this in vitro condition, the effect seems to require pharmacological concentrations. (C) 1999 Elsevier Science B.V. All rights reserved.