Inhibition of mitochondrial respiration and cyanide-stimulated generation of reactive oxygen species by selected flavonoids.
A continuation of our structure-activity study on flavonoids possessing varied hydroxyl ring configurations was conducted. We tested six additional flavonoids for their ability to inhibit beef heart mitochondrial succinoxidase and NADH-oxidase activities. In every case, the IC50 observed for the NADH-oxidase enzyme system was lower than for succinoxidase activity, demonstrating a primary site of inhibition in the complex I (NADH-coenzyme Q reductase) portion of the respiratory chain. The order of potency for inhibition of NADH-oxidase activity was robinetin, rhamnetin, eupatorin, baicalein, 7,8-dihydroxyflavone, and norwogonin with IC50 values of 19, 42, 43, 77, 277 and 340 nmol/mg protein, respectively. Flavonoids with adjacent tri-hydroxyl or para-dihydroxyl groups exhibited a substantial rate of auto-oxidation which was accelerated by the addition of cyanide (CN-). Flavonoids possessing a catechol configuration exhibited a slow rate of auto-oxidation in buffer that was stimulated by the addition of CN-. The addition of superoxide dismutase (SOD) and catalase in the auto-oxidation experiments each decreased the rate of oxygen consumption, indicating that O2- and H2O2 are generated during auto-oxidation. In the CN(-)-stimulated oxidation experiments, the addition of SOD also slowed the rate of oxygen consumption. These findings demonstrate that the CN-/flavonoid interaction generated O2- non-enzymatically, which could have biological implications.
Hodnick
W F
WF
Allie M. Lee Laboratory for Cancer Research, Department of Biochemistry, University of Nevada-Reno 89557.
Duval
D L
DL
Pardini
R S
RS
D000818:Animals; D002417:Cattle; D003486:Cyanides / Q000494:pharmacology*; D044950:Flavanones; D005419:Flavonoids / Q000494:pharmacology*; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D010101:Oxygen Consumption; D011794:Quercetin / Q000031:analogs & derivatives / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000378:metabolism
D003486:Cyanides; D044950:Flavanones; D005419:Flavonoids; D009097:Multienzyme Complexes; D017382:Reactive Oxygen Species; D013481:Superoxides; C006680:baicalein; C063423:rhamnetin; D011794:Quercetin; D010088:Oxidoreductases; C022691:succinate oxidase; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; C040014:robinetin