Effects of synthetic and naturally occurring flavonoids on Na+,K+-ATPase: aspects of the structure-activity relationship and action mechanism.
A comparative study was made of the effects of 15 synthetic and naturally occurring flavonoids on the hydrolytic activity of Na+, K+-adenosine triphosphatase (ATPase). Twelve of the flavonoids examined were mono-hydroxy or mono-methoxy derivatives. All inhibited Na+, K+-ATPase from dog kidney cortex when present at concentrations from 40-1000 microM. Flavones possessing cyclohexyl instead of the phenyl group (i.e., 2-cyclohexyl-benzopyran-4-one derivatives), were the most potent with IC50 at 257-320 microM. Structure-activity relationships were observed among the following mono-substituted flavones as: i) 2-cyclohexyl-benzopyran-4-one much greater than 2-phenyl-benzopyran-4-one; ii) 2-cyclohexyl-7-hydroxybenzopyran-4-one greater than 2-cyclohexyl-6-hydroxybenzopyran-4-one greater than 2-cyclohexyl-5-hydroxybenzopyran-4-one. Some flavonoids showing potent inhibitory activity were also examined for ouabain-displacement activity on human erythrocytes. Hardly any of the flavonoids were able to block [3H]ouabain binding to erythrocytes. These results suggest that the mechanism by which flavonoid block Na+, K+-ATPase is not related to the cardiac glycoside-specific binding site(s) of this enzyme.
Hirano
T
T
Division of Clinical Pharmacology, Tokyo College of Pharmacy, Japan.
Oka
K
K
Akiba
M
M
D000818:Animals; D004285:Dogs; D005419:Flavonoids / Q000494:pharmacology*; D066298:In Vitro Techniques; D007672:Kidney Cortex / Q000187:drug effects / Q000201:enzymology; D010042:Ouabain / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D005419:Flavonoids; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase