CC BY
85
UDC 615.322 : 615.015.44
FLAVONOIDS AS ADVANCED NATURAL ANTIOXIDANTS
Altai State Medical University, Barnaul Ya.F. Zverev, V.M. Bryukhanov
The article presents the description of the main mechanisms of the antioxidant effect of flavonoids. Numerous in vitro experiments showed that can be classified as non-enzymatic antioxidants capable of direct or indirect reducing or preventing cell damage caused by free radicals. Key words: flavonoids, antioxidants, pharmacology
Flavonoids are polyphenolic compounds which have, as it is seen in Fig. 1, 15 carbon atoms forming two aromatic rings (A and B) connected by a 3-carbon bridge (ring C).
10
5 4
Figure 1.
Chemical structure of flavonoids
Being secondary metabolites these compounds (mostly in the form of glycosides) are found in all parts of plants where they perform a range of important functions determining pigmentation, smell, taste, growth and reproduction of plants. Flavonoids take part in providing natural immunity and resistance of plants to various bacterial, fungal and viral pathogens and also in providing protection from herbivorous animals and insects. Besides, some chloroplast-produced flavonoids are involved in transporting electrons during photosynthesis and they show antioxidant properties against ultraviolet radiation. Today about 10,000 flavonoids are identified and a major part of them is divided into 6 subclasses: flavonols, flavones, flavan-3-ols (including proanthocyanidins), anthocyanidins, flavanones and isoflavones (Fig. 2).
o
Flavonfis
o
Flavanones
Figure 2.
Chemical structure of active subclasses of flavonoids
Interest in flavonoids as in antioxidants developed in mid-1990s and was largely determined by such an alimentary phenomenon as the French paradox that was later applied to other Mediterranean nations [1]. A number of epidemiological researches showed that despite of greasy food consumption, often low physical activity and prevalence of smoking dietary habits of residents of these countries directly correlate with relatively low level of cardiovascular diseases and high life expectancy. The study of diets of these countries' residents revealed the presence of a large number of various flavonoid compounds, mainly in vegetables, fruit, red wine and red grapes [2-7]. Recent years gave rise to discussion of the similar Asian paradox which is typical of residents of Japan and other countries in Southeast Asia and which is determined by the consumption of fish and seafood and also of products of vegetable origin, primarily of soy [8,9]. However, it is believed that the biggest role in the varied influence of flavonoids on human organism is played by their antioxidant properties.
A large number of mostly in vitro studies show that flavonoids can be classified as non-enzymatic antioxidants capable of direct or indirect reducing or preventing cell damage caused by free radicals [6]. By the assumption made by the authors mentioned above flavonoids can realize their antioxidant effect with the help of the following mechanisms:
1. Direct scavenging of reactive oxygen species (ROS);
2. Activation of antioxidant enzymes;
3. Transition metal chelation;
4. Reduction of alpha-tocopheryl radicals;
5. Oxidase inhibition;
6. Reduction of nitric-oxide-related oxidative stress and reactive-nitrogen-species-related (RNS-related) oxidative stress;
7. Increasing of plasma level of uric acid;
8. Boosting of antioxidant properties of low-molecular-weight antioxidants.
Taking into consideration all the mechanisms mentioned above we turn our attention to those we find essential.
The ability of some flavonoids to "kill" ROS comes from peculiarities in their chemical structure and it is conditioned by the need to either give away a hydrogen atom or to become electron donors. As
a result of these reactions free radical neutralization takes place. The antioxidants, in their turn, take on free radical properties after giving away a hydrogen atom or an electron. However, free radical molecules formed this way are significantly more stable in comparison with the free radicals being neutralized that makes interaction with substrate unlikely [10-12]. Although, there is another point of view, according to which a produced intermediate phenoxy radical is not stable and one of the peculiarities of this compound is the ability of unpaired electron delocalization, i.e. the process of attaching this electron to an aromatic ring forming a range of resonance structures. Thus, a formed radical can be reactive with other free radicals [13]. It is not improbable that this is how pro-oxidant properties appear in some flavonoids. It is believed that the mechanism of giving away a hydrogen atom is very important because the process of electron transfer needs more energy [14]. However, the ability of scavenging of free radicals is largely determined by the number of hydroxyl groups and their position in a flavonoid molecule. Taking the foregoing into consideration we should note that the consensus about free radical fixation by flavonoids that is built today was firstly suggested as a hypothesis by W.Bors et al. as early as in 1990 and later it was endorsed by many researches [6,1518]. The suggested hypothesis includes three main features that are showed in Fig. 3.
Easier electron derealization
Figure 3.
Mechanism of free radical fixation by flavonoids
According to Fig. 3: 1. Hydroxyl groups 3' and 4' attached to the ring B (catechol structure) are the main feature of flavonoids that is necessary for "killing" free radicals. Moreover, apparently hydroxyl groups at the ring B play the most significant role in scavenging ROS while similar substitutes in the rings A and C have far less antioxidant activity [19-21].
2. Double bond 2, 3 in conjunction with 4-oxo (ketonic) group in the ring C provides electron delocalization from the ring B. It is known that electron delocalization in aromatic rings stabilizes produced free radicals (apparently, by resonance) when a flavonoid interacts with ROS [17].
3. Hydroxyl groups attached to the rings A and C in positions 3, 5 and 7 in conjunction with 4-oxo group also increase antioxidant activity of flavonoids probably by providing hydrogen fixation to the oxo-group [6,22].
In vitro experiments revealed that the flavonoids which have all the mentioned features of chemical structure are also the most capable of "killing" free radicals. Flavonols quercetin and myricetin and also flavan-3-ols epicatechin-gallate, epigallocatechin and especially epigallocatechin-gallate belong to such polyphenols. Moreover, a hydroxyl group in position 3 plays an important role in increasing antiradical activity, giving additional activity to flavonols and flavan-3-ols [10].
At the same time, it is fair to say that antioxidant activity is common for aglycones but not for glycosylated or conjugated flavonoid derivatives. It appears that such difference can take place according to the fact that glycosylation, glucuronidation, sulphation and methylation results in substitution of hydroxyl groups at aromatic rings which are responsible for interaction with free radicals and due to this process antioxidant activity may decrease [23].
Of greater importance in the antioxidant mechanism of flavonoids is transition metal chelation. Flavonoids easily fixate ions of such transition metals as ferrum and cuprum which contribute to free radical production initiating peroxidation. According to many researches, metal chelation is the most effective way of flavonoid inhibition of peroxidation [10].
It is well known that generation of superoxide radical 02- takes place when affected by NAD(P) H oxidases and cytoplasmic xanthine oxidase localized in many cells. In this case oxygen can transform into superoxide radical according to the equation:
02 + Fe2+n^n Cu+—>02- + Fe3+n^n Cu2+ The generated superoxide radical rapidly dismutates forming hydrogen peroxide H2O2 which is not a free radical itself but rapidly transforms into the most reactive oxyradical -hydroxyl radical HO^ - according to the well-known Fenton reaction:
Fe2+n^n Cu+ + H2O2 —> Fe3+n^n Cu2+ + OH- + HO-The source material for this reaction is excess ferrum the amount of which exceeds the amount of Fe3+ bound to transferrin, a protein that transports ferrum [24]. Besides, superoxide radical provides releasing Fe2+ from ferritin and dehydratases containing iron-sulphur clasters by Fe3+ reduction and it is also capable of ferrum or cuprum reduction in the following reaction:
02-- + Fe3+n^n Cu2+ —> O2 + Fe2+n^n Cu+, providing reduced transition metal ions for the reactions with H2O2 [17,25].
Oxidative stress induced by transition ions leads to massive protein, lipid and especially nucleus damage when DNA molecules have positional linkage to various transition metals. It leads to the separation of DNA strands, nucleotide damage followed by malignant transformation, gene mutation or apoptosis. In this case the metal-induced production of hydroxyl radical HO^ has the most negative effect [25-31].
Therefore, fixation of transition metals (mostly ferrum and cuprum) catalyzing free radical production and initiating oxidative stress is the most significant antioxidant mechanism. Thus, the propensity of flavonoids for transition metal chelation seems to be very important.
Today it is well known that many flavonoids are capable of transition metal chelation but this mechanism is less well understood than the mechanism of direct scavenging of free radicals. In spite of the significant difference in the level of metal-chelating activity, a range of general molecular features of the effect under discussion has been detected [25,32].
HO" \
I 1
Figure 4
Transition metal chelation by flavonoids
It is notable that these reactions involve the same chemical structure components (mainly catechol structure of the ring B) as in the reactions of scavenging of free radicals (Fig. 4):
1. Apparently, hydroxyl groups 3' and 4' in the ring B play an important role.
2. Hydroxyl groups in positions 3 and 5 in conjunction with 4-oxo group in the ring C are also significant [10,32,33].
In order to prove the mechanisms mentioned above we should note that cyclic voltammetry showed that flavonoids luteolin and quercetin which have a catechol fragment in their molecules appeared to be more powerful inhibitors of the Fenton reaction than baicilein and naringenin which lack this structural fragment [34]. The
leading role of the catechol group at the ring B in iron fixation in comparison with the ring A was also confirmed by other researches [35-37]. The role of hydroxyls in positions 3 and 5 in conjunction with 4-oxo group during the process of iron chelation was also experimentally demonstrated [38]. Among the studied flavonoids the most capable of metal chelation is, apparently, quercetin. This polyphenolic compound as well as sulfonic water-soluble derivatives appeared to be capable of forming complexes not only with ferrum and cuprum but also with other metals including cadmium and crome that gives us an opportunity to consider quercetin not only an antioxidant but also a potential antidote for intoxication with the corresponding metal salts [6,39-41]. Sufficiently high level of antioxidant activity has also been found in rutin, naringenin, morin and some other flavonoids during the reactions of metal complexes formation [10].
Another mechanism providing positive effects of flavonoids on oxidative stress is the increasing of activity of antioxidant enzymes which, as it is known, are the main protection factor against electrophilic toxic agents. Numerous in vitro experiments show that these plant polyphenols are capable of activating NAD(P)H:quinone oxidoreductase (NQO1), superoxide dismutase (SOD), catalase (KAT), hemoxygenase-1 (HO-1) and also three glutathione-related enzymes: glutathione peroxidase (GPx), glutathione reductase (GR), glutathione-S-transferase (GST). It provides an indirect antioxidant effect in flavonoids [42]. This mechanism was found in representatives of all flavonoid subclasses [4346]. A clear antioxidant effect in various cell cultures expressing such antioxidant enzymes as GPx, GR, GST, SOD, KAT was observed when using quercetin, catechine, myricetin, luteolin, naringenin, apigenin, tangeritin, genistein, cocoa flavonoids [47-52].
Today it is believed that the flavonoid stimulation of antioxidant enzymes is mainly provided by the interaction with such a transcriptional factor as Nrf2. The redox-sensitive signaling system Keap1/ Nrf2/ARE controls intracellular homeostasis through the immune response, apoptosis and cell cycle genes expression providing contribution to the processes of inflammation, carcinogenesis and protection against various stress agents including reactive oxygen species [53-63].
Through this signaling pathway the antioxidant enzymes genes expression is activated due to the interaction between a transcriptional factor Nrf2 and a cis-regulatory antioxidant response element (ARE).
Cysteine remains in the structure of Keap1 function, apparently, as redox-sensors and some flavonoids may perform chemical modification of
cysteine thiols. It makes dissociation of Nrf2 from Keapl and its further nuclear translocation easier [42,64]. It was discovered that when in the nucleus Nrf2 factor links to ARE in a promoter region in many genes including the ones coding the expression of antioxidant enzymes in some types of cells and tissues [53,54,65-68]. Experiments with Nrf2 knockout mice showed the broken induction of detoxifying enzymes and redox-regulating proteins [69].
At the same time, it should not go unmentioned that many flavonoids have certain pro-oxidant activity. It is not improbable that this activity is proportional to the number of hydroxyl groups in flavonoid molecules [70]. These are the hydroxyl groups at aromatic rings that contribute to the higher production of hydroxyl radicals from hydrogen peroxide through the Felton reaction [6]. Furthermore, it is showed that some flavonoids can reduce transition metals: Fe3+ to Fe2+ and Cu2+ to Cu+, providing reduced metals for further interaction with H2O2 [31,70,71]. Pro-oxidant features were found in baicilein, epigallocatechin (EGC), epigallocatechin gallate (EGCG), quercetin, morin, myricetin, catechine and other flavonoids [25,72-74]. It is interesting to note that the same flavonoids can have both antioxidant and pro-oxidant features that can be determined by different environmental conditions and the concentration used [6,25,31,74-76].
How should we deal with the discovered pro-oxidant features of flavonoids? This question remains understudied and quite debating. However, the opinions vary from the need for careful usage of large doses of flavonoids to rather easy attitude towards their pro-oxidant activity [6,77,78]. It should not go unmentioned that there is a point of view according to which slight oxidative stress induced by some flavonoids activates antioxidant defense through stimulating antioxidant enzymes expression and thus activates cell transduction and general cytoprotection [6,79,80].
References
1. Burr M.L. Explaining the French paradox. J. R. Soc. Health.1995; 115: 217-219.
2. Renaud S., de Lorgeril M. Wine, alcohol, platelets, and French paradox for coronary heart disease. Lancet. 1992; 339: 1523-1526.
3. de Lange D.W., Verhoef S., Gorter G. et al. Polyphenolic grape extract inhibits platelet activation through PECAM-1: An explanation for the French paradox. Alcohol Clin. Exp. Res. 2007; 31: 1308-1314.
4. Lachman J., Sulc M., Schilla M. Comparison of the total antioxidant status of Bohemian wines during the wine-making process. Food Chem. 2007; 103: 802-807.
5. Lachman J., Sulc M. Antioxidants and
antioxidant activity of red and white wines affected by winemaking and other extrinsic and intrinsic factors. Red wine and health. Ed. by P. O'Byrne. Nova Science Publishers; New York, 2009; 91-141.
6. Prochazkova D., Bousova I., Wilhelmova N. Antioxidant and prooxidant properties of flavonoids. Fitoterapia. 2011; 82: 513-523.
7. Galinski C.N., Zwicker J.I., Kennedy D.R. Revisiting the mechanistic basis of the French Paradox: Red wine inhibits the activity of protein disulfide isomerase in vitro. Thromb. Res. 2016; 137: 169-173.
8. Yamori Y. Food factors for atherosclerosis prevention: Asian perspective derived from analyses of worldwide dietary biomarkers. Exp. Clin. Cardiol. 2006; 11 (2): 94-98.
9. Nagura J., Iso H., Watanabe Y. et al. Fruit, vegetable and bean intake and mortality from cardiovascular disease among Japanese men and women: The JACC Study. Br. J. Nutr. 2009; 102: 285-292.
10. Tarakhovsky Yu.S., Kim Yu.A., Abdrasilov B.S., Muzafarov Ye.N. Flavonoidy: biokhimiya, biofizika, meditsina. Pushchino, 2013; 310.
11. Leopoldini M., Marino T., Russo N., Toscano M. Antioxidant properties of phenolic compounds: H-atom versus electron transfer. J. Phys. Chem. A. 2004; 108: 4916-4922.
12. Leopoldini M., Russo N., Toscano M. The molecular basis of working mechanism of natural polyphenolic antioxidants. Food Chem. 2011; 125 (2): 288-306.
13. Azarova O.V., Galaktionova L.P. Flavonoids: anti-inflammatory mechanism. Khimija Rastitel'nogo Syr'ja. 2012; 4: 61-78.
14. Li A-N., Li S., Zhang Y-J. et al. Resources and biological activities of natural polyphenols. Nutrients. 2014; 6 (12): 6020-6047.
15. Bors W., Heller W., Michel C., Saran M. Flavonoids as antioxidants: Determination of radical-scavenging efficiencies. Methods in Enzymology. Ed. by Packer I., Glazer A. N. Academic Press; San Diego. 1990; 186: 343-355.
16. Landete J.M. Updated knowledge about polyphenols: Functions, bioavailability, metabolism, and health. Crit. Rev. Food Sci. Nutr. 2012; 52 (10): 936-948.
17. Bubols G.B., da Rocha V.D., Medina-Remon A. et al. The antioxidant activity of coumarins and flavonoids. Mini-Rev. Med. Chem. 2013; 13: 318-334.
18. Lago J.H.G., Toledo-Arruda A.C., Mernak M. et al. Structure-activity association of flavonoids in lung diseases. Molecules. 2014; 19: 3570-3595.
19. Burda S., Oleczek W. Antioxidant and antiradical activities of flavonoids. Agric. Food Chem. 2001; 49; 2774-2779.
20. Taubert D., Breitenbach T., Lazar A. et al. Reaction rate constants of superoxide scavenging by plant antioxidants. Free Radic. Biol. Med. 2003; 35: 1599-1607.
21. Amic D., Davidovic-Amic D., Beslo D. et al. SAR and QSAR of the antioxidant activity of flavonoids. Curr. Med. Chem. 2007; 14: 827-845.
22. Croft K.D. The chemistry and biological effects of flavonoids and phenolic acids. Ann. NY Acad. Sci. 2006; 854: 435-442.
23. Rice-Evans C.A., Miller N.J., Paganga G. Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic. Biol. Med. 1996; 20: 933-956.
24. Hentze M.W., Muckenthaler M.U., Galy B., Camaschella C. Two to tango: Regulation of Mammalian iron metabolism. Cell. 2010; 142 (1): 24-38.
25. Perron N.R., Brumaghim J.L. A review of the antioxidant mechanisms of polyphenol compounds related to iron binding Cell. Biochem. Biophys. 2009; 53: 75-100.
26. Hoffmann M.E., Mello-Filho A.C., Meneghini R. Correlation between cytotoxic effect of hydrogen peroxide and yield of DNA strand breaks in cells of different species. Biochim. Biophys. Acta. 1984; 781: 234-238.
27. Imlay J.A., Linn S. DNA damage and oxygen radical toxicity. Science. 1988; 240: 1302-1309.
28. Mello-Filho A.C., Meneghini R. Iron is the intracellular metal involved in the production of DNA damage by oxygen radicals. Mutat. Res. 1991; 251: 109-113.
29. Henle E.S., Han Z., Tang N. et al. Sequence-specific DNA cleavage by Fe2+-mediated Fenton reaction has possible biological implications. J. Biol. Chem. 1999; 274: 962971.
30. Rai P., Wemmer D. E., Linn S. Preferential binding and structural distortion by Fe2+ at RGGG-containing DNA sequences correlates with enhanced oxidative cleavage at such sequences. Nucl. Acid. Res. 2005; 33: P. 497-510.
31. Perron N.R., García C.R., Pinzón J.R. et al. Antioxidant and prooxidant effects of polyphenol compounds on copper-mediated DNA damage. J. Inorg. Biochem. 2011; 105: 745-753.
32. Galleano M., Verstraeten S.V., Oteiza P.I., Fraga C.G. Antioxidant actions of flavonoids: Thermodynamic and kinetic analysis. Arch. Biochem. Biophys. 2010; 501: 23-30.
33. van Acker S.A., van den Berg D.J., Tromp M. N. et al. Structural aspects of antioxidant activity of flavonoids. Free Radic. Biol. Med. 1996; 20 (3): P. 331-342.
34. Cheng I.F., Breen K. On the ability of four flavonoids, baicilein, luteolin, naringenin, and quercetin, to suppress the Fenton reaction of the iron-ATP complex. BioMetals. 2000; 13; 77-83.
35. Jovanovic S.V., Steenken S., Hara Y., Simic M.G. Reduction potentials of flavonoid and model phenoxyl radicals. Which ring in flavonoids is responsible for antioxidant activity? J. Chem. Soc. Perkin Transactions. 1996; 2: 2497-2504.
36. Arora A., Nair M.G., Strasburg G.M. Structure-activity relationships for antioxidant activities of a series of flavonoids in a liposomal system. Free Rad. Biol. Med. 1998; 24: 1355-1363.
37. Brown J.E., Khodr H., Hider R.C., Rice-Evans C. Structural dependence of flavonoid interactions with Cu2+ ions: Implications for their antioxidant properties. Biochem. J. 1998; 330: 1173-1178.
38. Khokhar S., Apenten R.K.O. Iron binding characteristics of phenolic compounds: Some tentative structure-activity relations. Food Chem. 2003; 81: 133-140.
39. Kopacz M., Kuzniar A. Complexes of cadmium (II), mercury (II), and lead (II) with quercetin-5'-sulfonic acid (QSA). Pol. J. Chem. 2003; 77: 1777-1786.
40. Szelag A., Magdalan J., Kopacz M. et al. Assessment of efficacy of quercetin-5'-sulfonic acid sodium salt in the treatment of acute chromium poisoning: Experimental studies. Pol. J. Pharmacol. 2003; 55: 10971103.
41. Chlebda E., Magdalan J., Merwid-Lad A. et al. Influence of water-soluble flavonoids, quercetin-5'-sulfonic acid sodium salt and morin-5'-sulfonic acid sodium salt, on antioxidant parameters in the subacute cadmium intoxication mouse model. Exp. Toxicol. Pathol. 2010; 62: 105-108.
42. Hu M-L. Dietary polyphenols as antioxidants and anticancer agents: More questions than answers. Chang Gung Med. J. 2011; 34: 449-460.
43. Shih P.H., Yeh C.T., Yen G.C. Anthocyanins induce activation of phase II enzymes through the antioxidant response element pathway against oxidative stress-induced apoptosis. J. Agric. Food Chem. 2007; 55 (23): 9427-9435.
44. Bhamre S., Sahoo D., Tibshirani R. et al. Gene expression changes induced by genistein in the prostate cancer cell line LNCaP. Open Prost. Cancer J. 2010; 3: 86-98.
45. Ding W., Liu Y. Genistein attenuates genioglossus muscle fatigue under chronic intermittent hypoxia by down-regulation of oxidative stress level and up-regulation antioxidant enzyme activity through ERK1/2 signaling pathway. Oral. Dis. 2011; 17: 677-684.
46. Lionetto M.G., Giordano M.E., Calisi A. et al. Effect of the daily ingestion of a purified anthocyanin extract from grape skin on rat serum antioxidant capacity. Physiol. Res. 2011; 26: 106-112.
47. Khan S.G., Katiyar S.K., Agarwal R., Mukhtar H. Enhancement of antioxidant and phase II enzymes by oral feeding of green tea polyphenols in drinking water to SKH-1 hair less mice: Possible role of cancer chemoprevention. Cancer Res. 1992; 52: 4050-4052.
48. Breinholt V., L^uridsen S. T., Dragsted L. D. Differ
49. ential effects of dietary flavonoids on drug metabolizing and antioxidant enzymes in female rat. Xenobiotica. 1999; 29: 12271240.
50. Nagata H., Takekoshi S., Takagi T. et al. Antioxidative action of flavonoids, quercetin and catechin, mediated by the activation of glutathione peroxidase. Tokai J. Exp. Clin. Med. 1999; 24(1): 1-11.
51. Jung U.J., Kim H.J., Lee J.S. et al. Naringin supplementation lowers plasma lipids and enhances erytrocyte antioxidant enzyme activities in hypercholesterolemic subjects. Clin. Nutr. 2003; 22: 561-568.
52. Leung H.W. C., Kuo C.L., Yang W.H. et al. Antioxidant enzymes activity involvement in luteolin-induced human lung squamous carcinoma CH27 cell apoptosis. Eur. J. Pharmacol. 2006; 534: 12-18.
53. Martin M.Â., Serrano A.B.G., Ramos S. et al. Cocoa flavonoids up-regulate antioxidant enzyme activity via the ERK1/2 pathway to protect against oxidative stress-induced apoptosis in HepG2 cells. J. Nutr. Biochem. 2010; 21:196-205.
54. Lekhovich V.V., Vavilin V.A., Zenkov N.K., Menshchikova Ye.B. Active Defense Under Oxidative Stress. The Antioxidant Responsive Element. Biokhimiya. 2006; 71 (9): 1183-1198.
55. Turpayev K.T. Role of Transcription Factor AP-1 in Integration of Cell Signaling Systems. Mol. biol. 2006; 40: 945-961.
56. Menshchikova Ye.B., Tkachev V.O., Zenkov N.K. Redox-dependent Signaling System Nrf2/ARE in Inflammation. Mol. biol. 2010; 44(2): 1-17.
57. Tchechushkov A.V., Tkachev V.O., Zenkov N.K., Menshchikova Ye.B. Redox-
sensitive Signaling System Keap1/Nrf2/ ARE in Differentiation and Activation of T Lymphocytes. Byulleten SO RAMN. 2012; 32 (5): 21-27.
58. Gershtein Ye.S., Shcherbakov A.M., Oshkina N.Ye. et al. Key NF-kB System Components in Tumors of Breast Cancer Patients. Vestnik TGU. 2013; 18 (6): 3292-3297.
59. Zenkov N.K., Menshchikova Ye.B., Tkachev V.O. Keap1/Nrf2/ARE Redox-sensitive Signaling System as a Pharmacological Target. Biokhimiya. 2013; 78 (1): 27-47.
60. Lemza A.Ye. The Role of Signaling System of the Antioxidant-response Element in Phenolic Antioxidants Inflammation Modulating. [dissertation]. Novosibirsk, 2014.
61. Flohe L., Brigelius-Flohe R., Saliou C. et al. Redox regulation of NF-kappa B activation. Free Radic. Biol. Med. 1997; 22: 1115-1126.
62. Chen L.F., Greene W.C. Shaping the nuclear action of NF-kappa B. Nat. Rev. Mol. Cell. Biol. 2004; 5: 392-401.
63. Surh Y.J. NF-kappa B and Nrf2 as potential chemopreventive targets of some anti-inflammatory and antioxidative phytonutrients with anti-inflammatory and antioxidative activities. Asia Pac. J. Clin. Nutr. 2008; 17 (1): 269-272.
64. Tusi S.K., Ansari N., Amini M. et al. Attenuation of NF-kappaB and activation of Nrf2 signaling by 1,2,4-triazine derivatives, protects neuron-like PC12 cells against apoptosis. Apoptosis. 2010; 15: 738-751.
65. Dinkova-Kostova A.T. Sulfhydryl groups of Keap 1 are the sensor regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. // Proc. Natl. Acad. Sci. U S A. 2002; 99: 10908-10913.
66. Kobayashi T., Ohta T., Yamamoto M. Unique function of the Nrf2-Keap1 pathway in the inducible expression of antioxidant and detoxifying enzymes. Methods Enzymol. 2004; 378: 273-286.
67. Zhang D.D. The Nrf2-Keap1-ARE signaling pathway: The regulation and dual function of Nrf2 in cancer. Antioxid. Redox Signal. 2010; 13 (11): 1623-1626.
68. Malloy M.T., McIntosh D.J., Walters T.S. et al. Trafficking of the transcription factor Nrf2 to promyelocytic leukemia-nuclear bodies implications for degradation of NRF2 in the nucleus. J. Biol. Chem. 2013; 288 (20): 14569-14583.
69. Atia A., Alrawaiq N., Abdullah A. A review of NAD(P)H: quinine oxidoreductase 1 (NQO1); a multifunctional antioxidant enzyme. J. Appl. Pharm. Sci. 2014; 4(12): 118-122.
70. Ramos-Gomez M., Kwak M.K., Dolan P.M. et al. Sensitivity of carcinogenesis in increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc. Natl. Acad. Sci. U S A. 2001; 98: 3410-3415.
71. Cao S., Sofic E., Prior R.L. Antioxidant and prooxidant behavior of flavonoids: Structure - activity relationships. Free Radic. Biol. Med. 1997; 22: 749-760.
72. Ryan P., Hynes M.J. The kinetics and mechanisms of the complex formation and antioxidant behaviour of the polyphenols EGCg and ECG with iron (III). J. Inorg. Biochem. 2007; 101: 585-593.
73. Puppo A. Effect of flavonoids on hydroxyl radical formation by Fenton-type reactions: Influence of the iron chelator. Phytochemistry. 1992; 31: 85-88.
74. Schweigert N., Zehnder A.J.B., Eggen R.I.L. Clinical properties of catechol and their molecular modes of toxic action in cells, from microorganisms to mammals. Envir. Microbiol. 2001; 3: 81-91.
75. Yen G.C., Duh P.D., Tsai H.L., Huang S.L. Pro-oxidative properties of flavonoids in human lymphocytes. Biosci. Biotechnol. Biochem. 2003; 67: 1215-1222.
76. Laughton M.J., Halliwell B., Evans P.J. et al. Antioxidant and pro-oxidant actions of the plant phenolics quercetin, gossypol and myricetin: Effects of lipid peroxidation,
hydroxyl radical generation and bleomycin-dependent damage to DNA. Biochem. Pharmacol. 1989; 38: 2859-2864.
77. Wilms L.C., Kleinjans J.C., Moonen E.J., Briede J.J. Discriminative protection against hydroxyl and superoxide anion radicals by quercetin in human leucocytes in vitro. Toxicol. in Vitro. 2008; 22: 301-307.
78. Elbling L., Weiss R.M., Teufelhofer O. et al. Green tea extract and (-)-epigallocatechin-3 gallate, the major tea catechin, exert oxidant but lack antioxidant activities. FASEB J. 2005; 19 (7): 807-809.
79. Lambert J.D., Sang S., Yang C.S. Possible controversy over dietary polyphenols: Benefits vs risks. Chem. Res. Toxicol. 2007; 20(4): 583-585.
80. Khurtsilava O.G., Pluzhnikov N.N., Nakatis Ya.A., ed. Oxidative Stress and Inflammation: Pathogenic Partnership. SPb, 2012.
81. Halliwell B. Are polyphenols antioxidants or pro-oxidants? What do we learn from cell culture and in vivo studies? Arch. Biochem. Biophys. 2008; 476: 107-112.
Contacts:
656038, Barnaul, Lenina Prospect, 40.
Altai State Medical University.
Tel.: (3852) 241868.
Email: zver@agmu.ru
