Aalt Bast

Health effects of quercetin : from antioxidant to nutraceutical

Quercetin, a member of the flavonoids family, is one of the most prominent dietary antioxidants. It is ubiquitously present in foods including vegetables, fruit, tea and wine as well as countless food supplements and is claimed to exert beneficial health effects. This includes protection against various diseases such as osteoporosis, certain forms of cancer, pulmonary and cardiovascular diseases but also against aging. Especially the ability of quercetin to scavenge highly reactive species such as peroxynitrite and the hydroxyl radical is suggested to be involved in these possible beneficial health effects. Consequently, numerous studies have been performed to gather scientific evidence for these beneficial health claims as well as data regarding the exact mechanism of action and possible toxicological aspects of this flavonoid. The purpose of this review is to evaluate these studies in order to elucidate the possible health-beneficial effects of the antioxidant quercetin. Firstly, the definitions as well as the most important aspects regarding free radicals, antioxidants and oxidative stress will be discussed as background information. Subsequently, the mechanism by which quercetin may operate as an antioxidant (tested in vitro) as well as the potential use of this antioxidant as a nutraceutical (tested both ex vivo and in vivo) will be discussed.

The pharmacology of the antioxidant lipoic acid

1. Lipoic acid is an example of an existing drug whose therapeutic effect has been related to its antioxidant activity. 2. Antioxidant activity is a relative concept: it depends on the kind of oxidative stress and the kind of oxidizable substrate (e.g., DNA, lipid, protein). 3. In vitro, the final antioxidant activity of lipoic acid is determined by its concentration and by its antioxidant properties. Four antioxidant properties of lipoic acid have been studied: its metal chelating capacity, its ability to scavenge reactive oxygen species (ROS), its ability to regenerate endogenous antioxidants and its ability to repair oxidative damage. 4. Dihydrolipoic acid (DHLA), formed by reduction of lipoic acid, has more antioxidant properties than does lipoic acid. Both DHLA and lipoic acid have metal-chelating capacity and scavenge ROS, whereas only DHLA is able to regenerate endogenous antioxidants and to repair oxidative damage. 5. As a metal chelator, lipoic acid was shown to provide antioxidant activity by chelating Fe2+ and Cu2+; DHLA can do so by chelating Cd2+. 6. As scavengers of ROS, lipoic acid and DHLA display antioxidant activity in most experiments, whereas, in particular cases, pro-oxidant activity has been observed. However, lipoic acid can act as an antioxidant against the pro-oxidant activity produced by DHLA. 7. DHLA has the capacity to regenerate the endogenous antioxidants vitamin E, vitamin C and glutathione. 8. DHLA can provide peptide methionine sulfoxide reductase with reducing equivalents. This enhances the repair of oxidatively damaged proteins such as alpha-1 antiprotease. 9. Through the lipoamide dehydrogenase-dependent reduction of lipoic acid, the cell can draw on its NADH pool for antioxidant activity additionally to its NADPH pool, which is usually consumed during oxidative stress. 10. Within drug-related antioxidant pharmacology, lipoic acid is a model compound that enhances understanding of the mode of action of antioxidants in drug therapy.

Flavonoids can replace α-tocopherol as an antioxidant

Endogenous antioxidants such as the lipid‐soluble vitamin E protect the cell membranes from oxidative damage. Glutathione seems to be able to regenerate α‐tocopherol via a so‐called free radical reductase. The transient protection by reduced glutathione (GSH) against lipid peroxidation in control liver microsomes is not observed in microsomes deficient in α‐tocopherol. Introduction of antioxidant flavonoids, such as 7‐monohydroxyethylrutoside, fisetin or naringenin, into the deficient microsomes restored the GSH‐dependent protection, suggesting that flavonoids can take over the role of α‐tocopherol as a chain‐breaking antioxidant in liver microsomal membranes.

The antioxidant activity of phloretin: the disclosure of a new antioxidant pharmacophore in flavonoids

Phloretin is a dihydrochalcone flavonoid that displays a potent antioxidant activity in peroxynitrite scavenging and the inhibition of lipid peroxidation. Comparison with structurally related compounds revealed that the antioxidant pharmacophore of phloretin is 2,6-dihydroxyacetophenone. The potent activity of 2,6-dihydroxyacetophenone is due to stabilisation of its radical via tautomerisation. The antioxidant pharmacophore in the dihydrochalcone phloretin, i.e., the 2,6-dihydroxyacetophenone group, is different from the antioxidant pharmacophores previously reported in flavonoids.

Use of telemetry to record electrocardiogram and heart rate in freely moving mice

This paper describes for the first time the possibility to record the electrocardiogram (ECG) and heart rate (HR) with a commercially available telemetry and data acquisition system in freely moving mice. The system comprises a telemetry transmitter implanted in the peritoneal cavity and a receiver, placed underneath the home cage, an A/D converter (MacLab) and a Macintosh LC II 4/80 computer with software (MacLab, Chart/Scope). The raw analog ECG data are digitized within the MacLab and can be converted to HR data additionally. The effects of surgery for implanting the transmitter, handling and anesthesia by either Nembutal or a mixture of Hypnorm, Dormicum, and water, on the changes in ECG and HR were examined. The telemetry system for recording the ECG and HR provides an accurate and reliable method for monitoring the direct effects of handling on HR. By using this telemetry system, we maintain that measurements in freely moving animals are more efficient, reliable, and less labor-intensive than the measurement techniques described in the literature thus far.

Butyrate modulates oxidative stress in the colonic mucosa of healthy humans

BACKGROUND & AIMS Butyrate, a short-chain fatty acid produced by colonic microbial fermentation of undigested carbohydrates, has been implicated in the maintenance of colonic health. This study evaluates whether butyrate plays a role in oxidative stress in the healthy colonic mucosa. METHODS A randomized, double blind, cross-over study with 16 healthy volunteers was performed. Treatments consisted of daily rectal administration of a 60 ml enema containing 100 mM sodium butyrate or saline for 2 weeks. After each treatment, a blood sample was taken and mucosal biopsies were obtained from the sigmoid colon. In biopsies, the trolox equivalent antioxidant capacity, activity of glutathione-S-transferase, concentration of uric acid, glutathione (GSH), glutathione disulfide and malondialdehyde, and expression of genes involved in GSH and uric acid metabolism was determined. Secondary outcome parameters were CRP, calprotectin and intestinal fatty acid binding protein in plasma and histological inflammatory scores. RESULTS Butyrate treatment resulted in significantly higher GSH (p<0.05) and lower uric acid (p<0.01) concentrations compared to placebo. Changes in GSH and uric acid were accompanied by increased and decreased expression, respectively, of their rate limiting enzymes determined by RT-PCR. No significant differences were found in other parameters. CONCLUSIONS This study demonstrated that butyrate is able to beneficially affect oxidative stress in the healthy human colon.

In vitro and ex vivo anti-inflammatory activity of quercetin in healthy volunteers

OBJECTIVE Quercetin, a commonly occurring flavonoid and well known antioxidant, has been suggested to possess other beneficial activities. The present study investigated the possible anti-inflammatory effects of physiologically attainable quercetin concentrations. METHODS The effects of quercetin were tested in vitro, i.e., added to blood in the test tube, and ex vivo and in vivo, i.e., in blood taken after 4 wk of administration of quercetin in an intervention study. RESULTS Quercetin dose-dependently inhibited in vitro lipopolysaccharide-induced tumor necrosis factor-alpha production in the blood of healthy volunteers. At a concentration of 1 muM, quercetin caused a 23% reduction. The in vitro lipopolysaccharide-induced interleukin-10 production remained unaffected by quercetin. A 4-wk quercetin intervention resulted in a significant increase in plasma quercetin concentration. The supplementation also increased total plasma antioxidant status but did not affect glutathione, vitamin C, and uric acid plasma concentrations. Basal and ex vivo lipopolysaccharide-induced tumor necrosis factor-alpha levels were not altered by the intervention. CONCLUSION The present study shows that quercetin increases antioxidant capacity in vivo and displays anti-inflammatory effects in vitro, but not in vivo or ex vivo, in the blood of healthy volunteers. This lack of effect is probably due to their low cytokine and high antioxidant levels at baseline, indicating that neither inflammation nor oxidative stress is present. Only in people with increased levels of inflammation and oxidative stress, e.g., patients with a disease of which the pathology is associated with these two processes, might antioxidant supplementation be fruitful.

Bioprocessing of Wheat Bran Improves in vitro Bioaccessibility and Colonic Metabolism of Phenolic Compounds

Ferulic acid (FA) is the most abundant phenolic compound in wheat grain, mainly located in the bran. However, its bioaccessibility from the bran matrix is extremely low. Different bioprocessing techniques involving fermentation or enzymatic and fermentation treatments of wheat bran were developed aiming at improving the bioaccessibility of phenolic compounds in bran-containing breads. The bioaccessibility of ferulic acid, p-coumaric acid, and sinapic acid was assessed with an in vitro model of upper gastrointestinal tract (TIM-1). Colonic metabolism of the phenolic compounds in the nonbioaccessible fraction of the breads was studied with an in vitro model of human colon (TIM-2). The most effective treatment was the combination of enzymes and fermentation that increased the bioaccessibility of FA from 1.1% to 5.5%. The major colonic metabolites were 3-(3-hydroxyphenyl)propionic acid and 3-phenylpropionic acid. Bran bioprocessing increases the bioaccessibility of phenolic compounds as well as the colonic end metabolite 3-phenylpropionic acid.

Oxidized quercetin reacts with thiols rather than with ascorbate: implication for quercetin supplementation

When an antioxidant scavenges a reactive species, i.e., when it exerts its antioxidant activity, the antioxidant is converted into potentially harmful oxidation products. In this way, the antioxidant quercetin might yield an ortho-quinone, denoted as QQ, which has four tautomeric forms, i.e., the ortho-quinone and three quinonmethides. We evaluated the interaction of QQ with ascorbate or glutathione (GSH). Ascorbate recycles QQ to the parent compound quercetin, while GSH forms two adducts with QQ, i.e., 6-GSQ and 8-GSQ. When both GSH and ascorbate are present, QQ is converted exclusively into GSQ. In the absence of GSH, protein thiols will be arylated by QQ. This protein arylation is not prevented by ascorbate. Thiol arylation by quinones and quinonmethides can impair several vital enzymes. This implies that the product formed when quercetin displays its antioxidant scavenging effect is toxic in the absence of GSH. Therefore, an adequate GSH level should be maintained when quercetin is supplemented.

Oxidant metabolism in chronic obstructive pulmonary disease

The development and progression of chronic obstructive pulmonary disease (COPD) have been associated with increased oxidative stress or reduced antioxidant resources. Several indicators of oxidative stress, such as hydrogen peroxide exhalation, lipid peroxidation products and degraded proteins, are indeed elevated in COPD patients. As a result, the antioxidant capacity decreases in COPD patients. The fall in antioxidant capacity of blood from COPD patients should not only be regarded as a reflection of the occurrence of oxidative stress but also as evidence that oxidative stress spreads out to the circulation and can therefore generate a systemic effect. COPD is linked to weight loss and in particular to loss in fatfree mass by skeletal muscle wasting. This systemic effect can be mediated by both oxidative stress and oxidative stressmediated processes like apoptosis and inflammation. Furthermore, COPD is a predisposition for lung cancer through several mechanisms including oxidative stress and oxidative stressmediated processes such as inflammation and disruption of genomic integrity. Current therapeutic interventions against the farreaching consequences of the systemic oxidative stress in chronic obstructive pulmonary disease are not yet optimised. A diet designed to reduce chronic metabolic stress might form an effective therapeutic strategy in chronic obstructive pulmonary disease.