Inhibition of mitochondrial respiration and production of toxic oxygen radicals by flavonoids (original) (raw)
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Biochemical …, 1986
AbWact-A series of fourteen Aavonoids 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 Is values toward succinoxidase activity, flavonoids with a catechol moiety on the b ring exhibited the following general order of potency: chalcone > flavone > flavonol > dihydroflavonol > an~~anidin. Catechins were inactive. In a series of 3,5,7-~hy~ox~avones containing various configurations of the b ring hydroxyl groups, it was found that the flavonoids possessing adjacent trihydroxyl (p~og~o1) and b ring o~h~hyd~~~~te~ol~ configtrratio~~s were the most potent inhibitors of succinoxidase, followed by those with rne~-hy~o~1, rnonoh~~o~l and ~y~o~~t~ co~gurations. Four of the fifteen flavonoids tested exhibited su~trate-~de~ndent, K~-sensitive respiration. Two tIavon& with a pyro@ol caption, my&&n and quercetagetia, produced the largest respiratory bursts and were found to auto-oxidise. Evidence is presented that the mitochondriaf respiratory bursts induced by both flavonols and their auto-oxidation resulted in the veneration of 02 and HzOz.
The effect of flavonoids on rat heart mitochondrial function
Biomedicine & Pharmacotherapy, 2006
In this study the effects of flavonoids (quercetin and its derivatives as rutin, hyperoside, quercitrin) on the oxidative phosphorylation in rat heart mitochondria were investigated. We found that all investigated flavonoids possessed uncoupling activity. Thus, quercetin, rutin, and quercitrin in dose-dependent manner induced a stimulation of the State 2 respiration rate by 10-110% with pyruvate + malate as substrate. The maximal stimulation of the State 2 respiration rate was obtained at 1.08 ng/ml of quercetin, 15.2 ng/ml of hyperoside and 44.4 ng/ml of rutin. Quercitrin had clearly lower effects. The State 3 respiration rate was also affected by flavonoids. Quercetin (from 1.08 ng/ml), hyperoside (from 10 ng/ml) and rutin (from 60 ng/ml) caused the decrease in State 3 respiration rate by 16-51%. We assume, that partial mitochondrial uncoupling (without affecting the State 3 respiration rate) induced by flavonoids could have a cardioprotective effect, and that mitochondria could be involved in the mechanism of this process.
The interaction of flavonoids with mitochondria: effects on energetic processes
Chemico-Biological Interactions, 2005
The study addressed aspects of energetics of isolated rat liver mitochondria exposed to the flavonoids quercetin, taxifolin, catechin and galangin, taking into account influences of the 2,3 double bond/3-OH group and 4-oxo function on the C-ring, and o-di-OH on the Bring of their structures, as well as mitochondrial mechanisms potentially involved in cell necrosis and apoptosis. The major findings/hypothesis, were: The 2,3 double bond/3-OH group in conjugation with the 4-oxo function on the C-ring in the flavonoid structure seems favour the interaction of these compounds with the mitochondrial membrane, decreasing its fluidity either inhibiting the respiratory chain of mitochondria or causing uncoupling; while the o-di-OH on the Bring seems favour the respiratory chain inhibition, the absence of this structure seems favour the uncoupling activity. The flavonoids not affecting the respiration of mitochondria, induced MPT. The ability of flavonoids to induce the release of mitochondria-accumulated Ca 2+ correlated well with their ability to affect mitochondrial respiration on the one hand, and their inability to induce MPT, on the other. The flavonoids causing substantial respiratory chain inhibition or mitochondrial uncoupling, quercetin and galangin, respectively, also decreased the mitochondrial ATP levels, thus suggesting an apparent higher potential for necrosis induction in relation to the flavonoids inducing MPT, taxifolin and cathechin, which did not decrease significantly the ATP levels, rather suggesting an apparent higher potential for apoptosis induction.
Antioxidant activity of flavonoids in isolated mitochondria
Phytotherapy Research, 2008
Mitochondria are important intracellular sources and targets of reactive oxygen species (ROS), while flavonoids, a large group of secondary plant metabolites, are important antioxidants. Following our previous study on the energetics of mitochondria exposed to the flavonoids quercetin, taxifolin, catechin and galangin, the present work addressed the antioxidant activity of these compounds (1–50 µmol/L) on Fe2+/citrate-mediated membrane lipid peroxidation (LPO) in isolated rat liver mitochondria, running in parallel studies of their antioxidant activity in non-organelle systems. Only quercetin inhibited the respiratory chain of mitochondria and only galangin caused uncoupling. Quercetin and galangin were far more potent than taxifolin and catechin in affording protection against LPO (IC50 = 1.23 ± 0.27 and 2.39 ± 0.79 µmol/L, respectively), although only quercetin was an effective scavenger of both 2,2-diphenyl-1-picrylhydrazyl (DPPH) and superoxide radicals. These results, together with the previous study, suggest that the 2,3-double bond in conjugation with the 4-oxo function in the flavonoid structure are major determinants of the antioxidant activity of flavonoids in mitochondria, the presence of an o-di-OH structure on the B-ring, as occurs in quercetin, favours this activity via superoxide scavenging, while the absence of this structural feature in galangin, favours it via a decrease in membrane fluidity and/or mitochondrial uncoupling. Copyright © 2008 John Wiley & Sons, Ltd.
Chemico-Biological Interactions, 2010
Flavonoids are a large group of polyphenolic compounds that have received considerable attention because of their biological and physiological importance. The flavone (2-phenyl-4H-1-benzopyran-4one) used in this work is found in some cereal grains and generates several biological activities, including: apoptosis induction, cell cycle arrest, caspase activation and inhibition of tumor cell proliferation. However, its effects on the hepatic mitochondrial metabolism are still unknown. We evaluated the effect of flavone on the metabolism of mitochondria isolated from rat liver. Polarographic experiments using 200 mol L −1 flavone and rat liver mitochondria oxidizing glutamate or succinate indicated that both substrates underwent: (i) reduction of state 3 respiration; (ii) stimulation of state 4 respiration; (iii) reduction of the respiratory control coefficient; and (iv) reduction of the ADP/O ratio. An analysis of the activity of enzymatic complexes in the respiratory chain showed that flavone acts between complexes I and III. Flavone reduced the membrane electric potential at doses of 100, 150 and 200 mol L −1 . Flavone at certain doses (75-200 mol L −1 ) reduced mitochondrial swelling in the presence of valinomycin and KNO 3 , suggesting that flavone could induce changes in mitochondrial membrane properties. These results demonstrate that the inhibition of mitochondrial enzymes in the respiratory chain coupled with the effects on membrane properties are promoted by the core structure of flavones, and these effects may be in part responsible for the cytotoxic effects of flavones.
Free Radical Biology and Medicine, 1998
The ability of eight structurally related naturally occurring flavonoids in inhibiting lipid peroxidation and mitochondrial membrane permeability transition (MMPT), as well as respiration and protein sulfhydryl oxidation in rat liver mitochondria, was evaluated. The flavonoids tested exhibited the following order of potency to inhibit ADP/ Fe(II)-induced lipid peroxidation, estimated with the thiobarbituric acid assay:
Inhibition of mitochondrial respiration by model phenolic compounds
Biochemical Pharmacology, 1979
A variety of mode1 phenolic compounds were tested for their ability to inhibit the beef heart mitochon~ial NADH-oxidase and succinoxidase enzyme systems in vitro. Specificaily, we determined the hydroxy and methoxy configurations of the model phenolic compounds that were mandatory for inhibition of mitochondrial respiration. Data are presented that supported the conclusion that the relative potency of inhibition of the beef heart mitochondrial succinoxidase enzyme system was methyl hydroquinone > hydroquinone > 4-methyl catechol > 3-methyl catechol > catechol, whereas o-cresol,p-cresol, resorcinol, 2methyl resorcinol and orcinol were non-i~ibitory. None of the model phenolic compounds tested were inhibitory toward the beef heart mito~hondrial NADH-oxidase enzyme system. These findings indicate that the site of inhibition for the catechol and hydroquinone derivatives is in complex II. Furthermore, it is proposed that a capacity for ortho-or para-quinone formation is mandatory for inhibition of mitochondrial succinoxidase activity by model phenolic compounds.
Flavonoids as superoxide scavengers and antioxidants
Free Radical Biology and Medicine, 1990
The superoxide anions scavenging activity and antioxidation of seven flavonoids-quercetin, rutin, morin, acacetin, hispidulin, hesperidin, and naringin-were studied. The superoxide anions were generated in a phenazin methosulphate-NADH system and were assayed by reduction of nitroblue tetrazolium. The scavenging activity ranked: rutin was the strongest, and quercetin and naringin the second, while morin and hispidulin were very weak. The concentration values yielding 50% inhibition of lipid peroxidation in mouse liver homogenate were in order of 10-6 M for quercetin, rutin, and morin; and of 10-5 M for acacetin and hispidulin, while naringin and hesperidin had no antioxidative action. In comparison with the antioxidative and scavenging activities of flavonoids, there are no correlations.
Phytotherapy Research, 2009
Crataegus (Hawthorn) fruit extracts (CE) are widely used for the treatment of various cardiovascular diseases (arrhythmias, heart failure, myocardial weakness, etc). Despite the fact that many of these diseases are associated with disturbances of mitochondria, no data have been found on the effect of CE on their function. The aim of this study was to perform an oxygraphic investigation of the effect of CE (in concentration range from 70 ng/ml to 13.9 µg/ml of Crataegus phenolic compounds (PC)) and its several pure flavonoids on isolated rat heart mitochondria respiring on pyruvate+malate, succinate and palmitoyl-L-carnitine+malate. CE at doses under 278 ng/ml of PC had no effect on mitochondrial functions. At concentrations from 278 ng/ml to 13.9 µg/ml of PC, CE stimulated State 2 respiration by 11% -34% with all used substrates, and decreased the mitochondrial membrane potential by 1.2-4.4 mV measured with a tetraphenylphosphonium-selective electrode and H 2 O 2 production measured fluorimetrically. Similar uncoupling effects on mitochondrial respiration were observed with several pure CE flavonoids. The highest CE concentration also slightly reduced the maximal ADP-stimulated and uncoupled respiration, which might be due to inhibition of mitochondrial respiratory chain between flavoprotein and cytochrome c. Whether or not the uncoupling and other effects of CE on mitochondria may be realized in vivo remains to be determined.