Inhibition of mitochondrial respiration and production of toxic oxygen radicals by flavonoids. A structure-activity study.
A series of fourteen flavonoids were employed in a systematic structure-activity study to assess their abilities to inhibit succinoxidase and generate toxic oxygen species in beef heart mitochondria. By comparing I50 values toward succinoxidase activity, flavonoids with a catechol moiety on the b ring exhibited the following general order of potency: chalcone greater than flavone greater than flavonol greater than dihydroflavonol greater than anthocyanidin. Catechins were inactive. In a series of 3,5,7-trihydroxyflavones containing various configurations of the b ring hydroxyl groups, it was found that the flavonoids possessing adjacent trihydroxy (pyrogallol) and b ring ortho-hydroxy(catechol) configurations were the most potent inhibitors of succinoxidase, followed by those with meta-hydroxyl, monohydroxyl and unhydroxylated configurations. Four of the fifteen flavonoids tested exhibited substrate-independent, KCN-insensitive respiration. Two flavonols with a pyrogallol configuration, myricetin and quercetagetin, produced the largest respiratory bursts and were found to auto-oxidize. Evidence is presented that the mitochondrial respiratory bursts induced by both flavonols and their auto-oxidation resulted in the generation of O-2 and H2O2.
D000818:Animals; D002417:Cattle; D002599:Chalcone / Q000031:analogs & derivatives* / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology*; D005609:Free Radicals; D008929:Mitochondria, Heart / Q000187:drug effects*; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D010100:Oxygen / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D011427:Propiophenones; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship
D005419:Flavonoids; D005609:Free Radicals; D011427:Propiophenones; D002599:Chalcone; D010088:Oxidoreductases; C022691:succinate oxidase; D010100:Oxygen