Inhibition of mitochondrial respiration and production of toxic oxygen radicals by flavonoids (original) (raw)
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.
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:
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.
2017
1 Department of Biochemistry, Cell and Molecular Biology, School of Biological Sciences, College of Basic and Applied Sciences, University of Ghana, Legon, P. O. Box LG54, Legon, Accra, Ghana. 2 Department of Chemistry,School of Physical and Mathematical Sciences, College of Basic and Applied Science, University of Ghana, Legon, Accra, Ghana. 3 Department of Physiology, Development and Neuroscience, University of Cambridge, UK.
Structureactivity relationship of flavonoids with superoxide scavenging activity
Biological Trace Element Research, 1995
The superoxide scavenging activities of 12 flavonoids were measured. The superoxide anions were generated by a hypoxanthine-xanthine oxidase system and measured by the nitrite method. The results showed that the scavenging ability enhanced with an increasing number of hydroxyl groups in rings B. Substitution at C3 position with a hydroxyl group increased the activity. Compared to a methoxyl group or a glycoside in this position, a free hydroxyl group showed the highest activity. A saturated C2−C3 bond showed a higher activity than a unsaturated bond. The absence of a carbonyl group at C4 position increased the activity.
The Journal of Nutritional Biochemistry, 2010
Quercetin uptake in Jurkat cells is extremely rapid and associated with a remarkable accumulation of the flavonoid, dependent on its binding to intracellular components. Cell-associated quercetin is biologically active, quantitatively consumed to promote survival in the presence of reactive species, such as peroxynitrite (ONOO − ), or reduction of extracellular oxidants via activation of plasma membrane oxidoreductases. In alternative, quercetin is very slowly released upon post-incubation in drug-free medium, an event significantly accelerated by extracellular albumin. Quercetin uptake is also observed in isolated mitochondria, resulting in an enormous accumulation of the flavonoid, consumed under conditions associated with prevention of lipid peroxidation induced by ONOO − . Interestingly, remarkable quercetin accumulation is also detected in the mitochondria isolated from quercetin-pre-loaded cells, and exposure to either ONOO − or extracellular oxidants caused the parallel loss of both the mitochondrial and cytosolic fractions of the flavonoid. In conclusion, Jurkat cells accumulate large amounts of quercetin and even larger amounts of the flavonoid further accumulate in their mitochondria. Intramitochondrial quercetin appears to be functional for prevention of mitochondrial damage as well as for redistribution to the cytosol, when the fraction of the flavonoid therein retained is progressively consumed either by cell-permeant oxidants or by activation of plasma membrane oxidoreductases.
The production of reactive oxygen species by dietary flavonols
Free Radical Biology and Medicine, 1990
Flavonols are a group of naturally occurring compounds which are widely distributed in nature where they are found glycosylated primarily in vegetables and fruits. A number of studies have found both anti-and prooxidant effects for many of these compounds. The most widely studied because of their ubiquitous nature have been quercetin, a B-dihydroxylated and myricetin, a B-trihydroxylated flavonol. Some of their prooxidant properties have been attributed to the fact that they can undergo autooxidation when dissolved in aqueous buffer. Studying a number of factors affecting autooxidation, we found the rate of autooxidation for both quercetin and myricetin to be highly pH dependent with no autooxidation detected for quereetin at physiologic pH. Both the addition of iron for the two flavonols and the addition of iron followed by SOD for quercetin increased the rate of autooxidation substantially, Neither kaempferol, a monohydroxylated flavonol nor rutin, a glycosylated quercetin showed any ability to autooxidize. The results with rutin differ from what we expected based on the Bring structural similarity to quercetin. The autooxidation of quercetin and myricetin was further studied by electron spin resonance spectroscopy (ESR). Whereas quercetin produced a characteristic DMPO-OH radical, it was not detected below a pH of 9. However, the addition of iron allowed the signal to be detected at a pH as low as 8.0. On the other hand, myricetin autooxidation yielded a semiquinone signal which upon the addition of iron, converted to a DMPO-OH signal detected at a pH of 7.5. In a microsome-NADPH system, quercetin produced an increase in oxygen utilization and with ESR, an ethanol-derived radical signal which could be completely suppressed by catalase indicating the dependence of the signal on hydrogen peroxide. These studies demonstrate that the extracellular production of active oxygen species by dietary flavonols is not likely to occur in vivo but the potential for intracellular redox cycling may have toxicologic significance.
Direct activation of the mitochondrial calcium uniporter by natural plant flavonoids
Biochemical Journal, 2004
During cell activation, mitochondria play an important role in Ca 2+ homoeostasis due to the presence of a fast and specific Ca 2+ channel in its inner membrane, the mitochondrial Ca 2+ uniporter. This channel allows mitochondria to buffer local cytosolic [Ca 2+ ] changes and controls the intramitochondrial Ca 2+ levels, thus modulating a variety of phenomena from respiratory rate to apoptosis. We have described recently that SB202190, an inhibitor of p38 MAPK (mitogen-activated protein kinase), strongly activated the uniporter. We show in the present study that a series of natural plant flavonoids, widely distributed in foods, produced also a strong stimulation of the mitochondrial Ca 2+ uniporter. This effect was of the same magnitude as that induced by SB202190 (an approx. 20-fold increase in the mitochondrial Ca 2+ uptake rate), developed without measurable delay and was rapidly reversible. In intact cells, the mitochondrial Ca 2+ peak induced by histamine was also largely increased by the flavonoids. Stimulation of the uniporter by either flavonoids or SB202190 did not require ATP, suggesting a direct effect on the uniporter or an associated protein which is not mediated by protein phosphorylation. The most active compound, kaempferol, increased the rate of mitochondrial Ca 2+ uptake by 85 + − 15 % (mean + − S.E.M., n = 4) and the histamine-induced mitochondrial Ca 2+ peak by 139 + − 19 % (mean + − S.E.M., n = 5) at a concentration of 1 µM. Given that flavonoids can reach this concentration range in plasma after ingestion of flavonoid-rich food, these compounds could be modulating the uniporter under physiological conditions.