Structure-antioxidant activity relationships of flavonoids and phenolic acids

http://www.dietcan.net/docs/Polifenoles%20en%20alimentos%20y%20biodisponibilidad.pdf

Polyphenols: food sources and bioavailability

Flavonoids are nearly ubiquitous in plants and are recognized as the pigments responsible for the colors of leaves, especially in autumn. They are rich in seeds, citrus fruits, olive oil, tea, and red wine. They are low molecular weight compounds composed of a three-ring structure with various substitutions. This basic structure is shared by tocopherols (vitamin E). Flavonoids can be subdivided according to the presence of an oxy group at position 4, a double bond between carbon atoms 2 and 3, or a hydroxyl group in position 3 of the C (middle) ring. These characteristics appear to also be required for best activity, especially antioxidant and antiproliferative, in the systems studied. The particular hydroxylation pattern of the B ring of the flavonoles increases their activities, especially in inhibition of mast cell secretion. Certain plants and spices containing flavonoids have been used for thousands of years in traditional Eastern medicine. In spite of the voluminous literature available, however, Western medicine has not yet used flavonoids therapeutically, even though their safety record is exceptional. Suggestions are made where such possibilities may be worth pursuing.

The Effects of Plant Flavonoids on Mammalian Cells:Implications for Inflammation, Heart Disease, and Cancer

Antimicrobial activity of flavonoids

In diverse organisms, calorie restriction slows the pace of ageing and increases maximum lifespan. In the budding yeast Saccharomyces cerevisiae, calorie restriction extends lifespan by increasing the activity of Sir2 (ref. 1), a member of the conserved sirtuin family of NAD(+)-dependent protein deacetylases. Included in this family are SIR-2.1, a Caenorhabditis elegans enzyme that regulates lifespan, and SIRT1, a human deacetylase that promotes cell survival by negatively regulating the p53 tumour suppressor. Here we report the discovery of three classes of small molecules that activate sirtuins. We show that the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD(+), and increases cell survival by stimulating SIRT1-dependent deacetylation of p53. In yeast, resveratrol mimics calorie restriction by stimulating Sir2, increasing DNA stability and extending lifespan by 70%. We discuss possible evolutionary origins of this phenomenon and suggest new lines of research into the therapeutic use of sirtuin activators.

Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan

The occurrence of reactive oxygen species (ROS), termed as prooxidants, is a characteristic of normal aerobic organisms. The term “reactive oxygen species” collectively denotes oxygen-centered radicals such as superoxide (O2·-)and hydroxyl (·OH), as well as nonradical species derived from oxygen, such as hydrogen peroxide (H2O2), singlet oxygen (1ΔgO2) and hypochlorous acid (HOC1). Radical reactions are central to the maintenance of homeostasis in biological systems. Radical species perform a cardinal role in many physiological processes such as cytochrome P450-mediated oxidative transformation reactions, a plethora of enzymic oxidation reactions, oxidative phosphorylation, regulation of the tone of smooth muscle, and killing of microorganisms.1–3 Excessive generation of free radicals can have deleterious biological consequences.4–6 Organisms are equipped with an armamentarium of defense systems, termed antioxidants in order to safeguard them against the onslaught of ROS.1–3,7 When the generation of prooxidants overwhelms the capacity of antioxidant defense systems oxidative stress ensues. This can cause tissue damage leading to pathophysiological events. ROS play a pivotal role in the action of numerous foreign compounds (xenobiotics). Their increased production seems to accompany most forms of tissue injury.4,5 Whether sustained and increased production of ROS is a primary event in human disease progression or a secondary consequence of tissue injury has been discussed.5,6 Whatever may be the case, the formation of free radicals has been implicated in a multitude of disease states ranging from inflammatory/immune injury to myocardial infarction and cancer.

Free Radical Scavenging and Antioxidant Activity of Plant Flavonoids

Quercetin exhibits antitumor activity. We investigated the effect of quercetin on the in vitro and in vivo growth of two squamous cell carcinoma cell lines and a normal human lung fibroblast-like cell line. The in vivo effect was evaluated using implantable cell growth chambers implanted subcutaneously in immunocompetent rats. Quercetin was injected intraperitoneally, and multiple dosages were tested. Cells were counted on days 1, 3, 5, and 7, and growth curves were constructed. Quercetin caused inhibition of growth in both squamous cell carcinoma lines. Effect on the fibroblast-like human lung cells was noted only at the maximum concentration. Significant growth inhibition of squamous cell carcinoma was observed in implantable cell growth chambers retrieved 3 days after quercetin treatment. Quercetin appears to possess a cytotoxic effect on squamous cell carcinoma of head and neck origin both in vivo and in vitro. The inhibitory effect on malignant cells appears to be selective and dose-dependent.

The effects of the bioflavonoid quercetin on squamous cell carcinoma of head and neck origin

We investigated the antiproliferative effect of two polyhydroxylated (quercetin and taxifolin) and two polymethoxylated (nobiletin and tangeretin) flavonoids against three cell lines in tissue culture. Tangeretin and nobiletin markedly inhibited the proliferation of a squamous cell carcinoma (HTB 43) and a gliosarcoma (9L) cell line at 2-8 micrograms/ml concentrations. Quercetin displayed no effect on 9L cell growth at these concentrations, while at 8 micrograms/ml it inhibited HTB 43 cell growth. Taxifolin slightly inhibited HTB 43 cell growth at 8 micrograms/ml, while moderately inhibiting HTB 43 cell growth at 2-8 micrograms/ml. The proliferation of a human lung fibroblast-like cell line (CCL 135) was relatively insensitive to low concentrations of the above flavonoids.

Differential inhibition of proliferation of human squamous cell carcinoma, gliosarcoma and embryonic fibroblast-like lung cells in culture by plant flavonoids.

We examined the effects of flavone and two polyhydroxylated plant flavonoids (quercetin and fisetin), either singly or in combination with ascorbic acid, on the growth of a human squamous cell carcinoma cell line (HTB 43) in vitro. Fisetin and quercetin significantly impaired cell growth in the presence of ascorbic acid. Exposure of cells to ascorbic acid (2 micrograms/ml) and 2 micrograms/ml of either fisetin or quercetin resulted in 61 and 45% inhibition of cell growth, respectively, in 72 h, while treatment with ascorbic acid alone had no effect on cellular proliferation. Flavone and ascorbic acid, either as single agents or in combination, exhibited no significant inhibition at any of the concentrations tested. The enhancement of the antiproliferative effect of the above flavonoids by ascorbic acid may be due to its ability to protect these compounds against oxidative degradation.

Chithan Kandaswami

Papers

The Effects of Plant Flavonoids on Mammalian Cells:Implications for Inflammation, Heart Disease, and Cancer

Free Radical Scavenging and Antioxidant Activity of Plant Flavonoids

The effects of the bioflavonoid quercetin on squamous cell carcinoma of head and neck origin

Differential inhibition of proliferation of human squamous cell carcinoma, gliosarcoma and embryonic fibroblast-like lung cells in culture by plant flavonoids.

Ascorbic acid-enhanced antiproliferative effect of flavonoids on squamous cell carcinoma in vitro.