Binding of spironolactone metabolites in vivo to renal mineralocorticoid receptors in guinea pigs.
Spironolactone (SL) is a mineralocorticoid antagonist used clinically to treat hypertension and congestive heart failure. Its mechanism of action involves competitive binding to aldosterone receptors in the kidneys, resulting in diuresis. It is known that the actions of SL are mediated by metabolites of the drug, but the active metabolites have not been definitively identified. Accordingly, studies were done to determine which metabolites bind to renal mineralocorticoid receptors after SL administration to guinea pigs. The major metabolite found in the steroid receptor fraction of kidney cytosol was 7 alpha-thiomethyl-SL (TM). Incubation of kidney cytosol with varying concentrations (0-100 pmol/l) of aldosterone resulted in the concentration-dependent displacement of TM from the steroid receptor fraction. The steroid receptor fraction from renal nuclei of SL-treated animals contained approximately equal concentrations of TM, 7 alpha-thio-SL (TH), and canrenone (CAN). Incubation of kidney nuclei with aldosterone caused a concentration-dependent displacement of all three metabolites. The results indicate that TM is the major SL metabolite that interacts with cytosolic mineralocorticoid receptors in kidneys, but that TH and CAN may contribute to nuclear receptor binding.
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Department of Pharmacology and Toxicology, Philadelphia College of Pharmacy and Science, West Point, PA.
Colby
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D000450:Aldosterone / Q000378:metabolism*; D000818:Animals; D001667:Binding, Competitive; D002192:Canrenone / Q000378:metabolism; D006168:Guinea Pigs; D007668:Kidney / Q000378:metabolism*; D008297:Male; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D013148:Spironolactone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism*
D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; C046564:7-thiomethylspirolactone; D000450:Aldosterone; D002192:Canrenone