An Essential Difference between the Flavonoids MonoHER and Quercetin in Their Interplay with the Endogenous Antioxidant Network

Department of Pharmacology and Toxicology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, Maastricht, The Netherlands.
PLoS ONE (Impact Factor: 3.53). 11/2010; 5(11):e13880. DOI: 10.1371/journal.pone.0013880
Source: PubMed

ABSTRACT Antioxidants can scavenge highly reactive radicals. As a result the antioxidants are converted into oxidation products that might cause damage to vital cellular components. To prevent this damage, the human body possesses an intricate network of antioxidants that pass over the reactivity from one antioxidant to another in a controlled way. The aim of the present study was to investigate how the semi-synthetic flavonoid 7-mono-O-(β-hydroxyethyl)-rutoside (monoHER), a potential protective agent against doxorubicin-induced cardiotoxicity, fits into this antioxidant network. This position was compared with that of the well-known flavonoid quercetin. The present study shows that the oxidation products of both monoHER and quercetin are reactive towards thiol groups of both GSH and proteins. However, in human blood plasma, oxidized quercetin easily reacts with protein thiols, whereas oxidized monoHER does not react with plasma protein thiols. Our results indicate that this can be explained by the presence of ascorbate in plasma; ascorbate is able to reduce oxidized monoHER to the parent compound monoHER before oxidized monoHER can react with thiols. This is a major difference with oxidized quercetin that preferentially reacts with thiols rather than ascorbate. The difference in selectivity between monoHER and quercetin originates from an intrinsic difference in the chemical nature of their oxidation products, which was corroborated by molecular quantum chemical calculations. These findings point towards an essential difference between structurally closely related flavonoids in their interplay with the endogenous antioxidant network. The advantage of monoHER is that it can safely channel the reactivity of radicals into the antioxidant network where the reactivity is completely neutralized.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Reactive oxygen species (ROS) can react with any cellular component leading to oxidative damage. As an adaptive response to ROS, cells activate Nrf2 which enforces the endogenous antioxidant defense. Exogenous antioxidants directly neutralize the ROS and prevent the oxidative damage. This protection against ROS might backfire, because the adaptive response of the cell is prevented. The flavonoid monoHER efficiently scavenges ROS. In this study the effect of monoHER on the oxidative stress as well as the adaptive response was investigated. It was found that monoHER protected against oxidative stress caused in HUVECs by H2O2, while monoHER did not prevent the induction of the adaptive response, including the nuclear translocation of Nrf2 as well as the upregulation of HO-1 gene expression. Remarkably, monoHER added to HUVECs which were not subjected to oxidative stress did not cause an adaptive response. The concept that emerges is that by scavenging ROS, the oxidized monoHER formed channels the reactivity selectively to thiol groups. Oxidized monoHER adducts Keap1, which can set the innate Nrf2 machinery into motion and enforce the endogenous antioxidant defense. In this way monoHER acts as a double-edged sword in cells subjected to oxidative stress; the antioxidant offers direct protection and induces adaptation.
    07/2014; DOI:10.1016/j.phanu.2014.05.003
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Flavonoids have been studied intensely for their ability to act as anti-carcinogenic, anti-inflammatory, anti-viral and anti-aging agents and are often marketed as supplements related to their anti-inflammatory activity. Previous studies have primarily focused on the effects of polar natural flavonoids. We examined the activity of novel hydrophobic and lipophilic flavonols against human DU-145 and PC-3 prostate cancer cell lines. All flavonol analogs were more active than the naturally occurring flavonols quercetin, kaempferol, kaempferide and galangin. The most potent analogs were 6.5-fold more active against DU-145 and PC-3 cells than quercetin and fell within the biologically relevant concentration range (low micromolar). We also evaluated the potential toxic effects of flavonol analogs on normal cells, an assessment that has frequently been ignored when studying the anticancer effects of flavonoids. During these analyses, we discovered that various metabolic and DNA staining assays were unreliable methods for assessing cell viability of flavonoids. Flavonoids reduce colorimetric dyes such as MTT and Alamar Blue in the absence of cells. We showed that flavonol-treated prostate cancer cells were stained less intensely with crystal violet than untreated cells at non-toxic concentrations. The trypan blue exclusion assay was selected as a reliable alternative for measuring cell viability.
    International Journal of Oncology 05/2014; 45(2). DOI:10.3892/ijo.2014.2452 · 2.77 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Anthracycline chemotherapy is often used in the treatment of various malignancies. Its application, however, encounters several limitations due to development of serious side effects, mainly cardiotoxicity and may be ineffective due to multidrug resistance (MDR). Many different compounds have been evaluated as poorly effective in the protection against anthracycline side effects and in the prevention from MDR. Thus, continuous investigational efforts are necessary to find valuable protectants and the flavonoid quercetin (Q) seems to be a promising candidate. It is present in relatively high amounts in a human diet and the lack of its toxicity, including genotoxicity has been confirmed. The structure of Q favours its high antioxidant activity, the potential to inhibit the activity of oxidative enzymes and to interact with membrane transporter proteins responsible for development of MDR, e.g. P-glycoprotein. Furthermore, Q can influence cellular signalling and gene expression, and thus, alter response to exogenous genotoxicants and oxidative stress in normal cells. It accounts for its chemopreventive and anticancer properties. Overall, these properties might indicate the possibility of application of Q as cardioprotectant during anthracycline chemotherapy. Moreover, numerous biological properties displayed by Q might possibly result in the reversal of MDR in tumour cells and improve the efficacy of chemotherapy. However, these beneficial effects towards anthracycline-induced complications of chemotherapy have to be further explored and confirmed both in animal and clinical studies. Concurrently, investigations aimed at improvement of the bioavailability of Q and further elucidation of its metabolism after application in combination with anthracyclines are needed.
    Biomedecine [?] Pharmacotherapy 10/2014; 68(8). DOI:10.1016/j.biopha.2014.10.013 · 2.11 Impact Factor

Full-text (2 Sources)

Available from
Aug 5, 2014