Flavonoid inhibition of the human neutrophil NADPH-oxidase (original) (raw)
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Flavonoids Inhibit the Respiratory Burst of Neutrophils in Mammals
Oxidative Medicine and Cellular Longevity, 2012
Neutrophils represent the front-line defence cells in protecting organisms against infection and play an irreplaceable role in the proper performance of the immune system. As early as within the first minutes of stimulation, neutrophilic NADPH oxidase is activated, and cells release large quantities of highly toxic reactive oxygen species (ROS). These oxidants can be highly toxic not only for infectious agents but also for neighboring host tissues. Since flavonoids exhibit antioxidant and anti-inflammatory effects, they are subjects of interest for pharmacological modulation of ROS production. The present paper summarizes contemporary knowledge on the effects of various flavonoids on the respiratory burst of mammalian neutrophils. It can be summarized that the inhibitory effects of flavonoids on the respiratory burst of phagocytes are mediated via inhibition of enzymes involved in cell signaling as well as via modulation of redox status. However, the effects of flavonoids are even more complex, and several sites of action, depending upon the flavonoid structure and way of application, are included.
Archives of Biochemistry and Biophysics, 2001
The effects of three aglycon flavonols (myricetin, quercetin, and kaempferol) and the natural glycoside rutin on superoxide anion radical generating systems were investigated. Quercetin, myricetin, and kaempferol inhibited the formation of uric acid from xanthine by xanthine oxidase, while rutin was ineffective. The generation of superoxide anion radicals by this system was determined by either reduction of cytochrome c or Pholasin luminescence. A scavenging of superoxide was only observed for myricetin and to a small extent for rutin. All flavonols tested inhibited the Pholasin luminescence of fMet-Leu-Phe-stimulated neutrophils. Rutin influenced the oxidative burst of neutrophils in the same way as wortmannin and LY294002, two inhibitors of the phosphoinositide 3-kinase ␥. Indeed, rutin inhibited the activity of this enzyme, whereas the three other flavonols showed no effect. Thus, an inhibition of enzymes involved in signaling rather than a scavenging of superoxide anion radicals dominates in fMet-Leu-Phe-stimulated neutrophils exposed to flavonols.
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.
Flavonoid impairment of neutrophil response
Biochemical Pharmacology, 1986
Flavonoids are a class of phenolic plant pigments which impair the oxidative burst of neutrophils to an extent dependent on their hydrophobicity. The distribution of quercetin and of morin in nitrogen-cavitated neutrophils paralleled their respective hydrophobic characteristics and respiratory burst inhibition. While both flavonoids were localized primarily in the specific granule membrane of neutrophils, the amount of quercetin was considerably greater than that of morin. We here demonstrate inhibition of the initial stimulation response, depolarization of the membrane potential as monitored by fluorescence of the membrane probe diSC ,-(5), and of the respiratory burst, monitored by following the destruction of d&C,-(5), a reaction mediated by the H,O, produced in the burst. The flavonoids-. I. kaempferol, morin, quercetin, or fisetin were preincubated with human neutrophils at a concentration of 100 fl per 2 x lo6 cells/ml for 2-3 min and subsequently stimulated with 1 pgg/ml of the tumor promoter phorbol myristate acetate (PMA) or with 60 ng/ml of immune complex. The effect of each compound differed, i.e. depolarization was enhanced by some and inhibited by others, while Hz02 generation was inhibited by each, supporting our previous findings that membrane potential depolarization and the respiratory burst are dissociable events. Concentration-response experiments, performed at flavonoid concentrations between 12.5 and 5CO@l to determine the lcso values of these compounds for depolarization and burst activation, indicated that none of the flavonoids affected the resting potential, while all perturbed the stimulus-coupled response, the direction and extent of the perturbation depending upon the stimulus, and the function assessed. These data show that the effects of flavonoids on human neutrophils are complex and suggest several sites of action depending upon the flavonoid's subcellular distribution and pathway of stimulation.
Archives of Biochemistry and Biophysics, 2001
The effect of three flavonoids, 5,7,3,4-tetrahydoxy-3-methoxy flavone (THMF), luteolin, and quercetin, on the stimulus-induced superoxide generation and tyrosyl phosphorylation of proteins in human neutrophils were investigated. When the cells were preincubated with these flavonoids, the superoxide generation induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP) was significantly suppressed, showing a dependence on amounts of the flavonoid. The suppressing effect of the flavonoid was THMF > luteolin > quercetin. These flavonoids also suppressed the superoxide generation induced by phorbol 12-myristate 13acetate. In this case also, THMF was more effective than luteolin and quercetin. On the other hand, the superoxide generation induced by arachidonic acid was markedly suppressed by quercetin. The suppressing effect was quercetin Ͼ Ͼ THMF > luteolin. THMF, luteolin, and quercetin significantly suppressed tyrosyl phosphorylation of 80.1-, 58.0-, and 45.0-kDa proteins in fMLP-treated human neutrophils. The suppression depended on the concentration of the flavonoids, and the inhibition of tyrosyl phosphorylation was in parallel to that of the fMLP-induced superoxide generation, respectively. While luteolin and quercetin showed a weak hemolytic activity at 2.5 mM, THMF showed almost no hemolytic activity even at 5 mM, suggesting an advantage of THMF for its clinical use.
Inhibition of mitochondrial respiration and production of toxic oxygen radicals by flavonoids
Biochemical Pharmacology, 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.
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.
Appraisal of the Antichemotactic Activity of Flavonoids on Polymorphonuclear Neutrophils
Planta Medica, 2011
Introduction ! Flavonoids are polyphenolic compounds of relatively low molecular weight, with a common benzo-γ-pyrone structure, and are ubiquitous in the plant kingdom. These substances have attracted much attention for displaying a wide range of biological effects exerted at the biochemical level . Many diets are rich in flavonoids and, consequently, interest in the study of flavonoids is growing, with these substances being the major active nutraceutical ingredients in plants that are consumed on a daily basis. Although the potential biological effects of flavonoids are widely recognized, their role in the diet is controversial because information on their bioavailability is scarce and contradictory . Thus, many studies suggest that some isolated flavonoids may significantly affect immune functions and they have been shown to exert potent anti-inflammatory activities, when evaluated in several animal models, as described in detail by other authors [4, 5]. As such, many flavonoid-containing plants, parts of which are used in folk medicine, may be employed as anti-inflammatory agents . Considering that the investigation of chemotactic ability plays an important role in the study of new anti-inflammatory agents , in the current study we investigated the inhibition of polymorphonuclear neutrophil (PMN) chemotaxis by isolated flavonoids in an in vitro model employing a modified Boyden chamber. The chemoattractants used were LPS (lipopolysaccharide from Escherichia coli) and fMLP (formyl-Met-Leu-Phe). This assay was undertaken in order to compare the antichemotactic effect of 25 different flavonoids belonging to the flavone, flavonol and flavanone classes (l " , which differ by the type and number of substituents.
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.
Natural Science, 2012
The effects of eleven flavonoids on lipid peroxidation, protein degradation, deformability and osmotic fragility of human erythrocytes exposed in vitro to 10 mM H 2 O 2 for 60 min at 37˚C have been studied. The following flavonoids; quercetin, rutin and morin significantly protected erythrocytes against lipid peroxidation caused by H 2 O 2. This inhibition of lipid peroxidation could be explained by the presence of at least two hydroxyl groups in ring B of the flavonoid structure, regardless of their positions. However, the flavonoids; quercetin, 3,5,7-trihydroxy-4'-methoxy flavone-7-rutinoside and 3-hydroxy flavone significantly protected erythrocytes against protein degradation. This inhibition could also be explained by the presence of a hydroxyl group at C-3 in ring C of the flavonoid structure. Quercetin and 3,5,7-trihydroxy-4'-methoxy flavone-7-rutinoside significantly protected erythrocytes against loss of deformability and increased osmotic fragility, indicating that the loss of erythrocyte deformability and the increase in osmotic fragility of erythrocytes exposed to H 2 O 2 are related to protein degradation rather than to lipid peroxidation. The other flavonoids (chrysin, 2-carboxy ethyl dihydroxy flavone, apigenin, cirsimaritin, α-naphto flavone and flavanone) failed to protect erythrocytes against the observed oxidative damages. The results demonstrate the importance of the chemical groups substituted on the basic skeleton of the flavonoids in dictating the type of antioxidant activity, and also demonstrate the hemorheological potentials of flavonoids that have particular protein-antioxidant activities.