Antioxidant and prooxidant behavior of flavonoids: structure-activity relationships.

The antioxidant and prooxidant behavior of flavonoids and the related activity-structure relationships were investigated in this study using the oxygen radical absorbance capacity assay. Three different reactive species were used in the assay: 2,2'-azobis(2-amidino-propane) dihydrochloride, a peroxyl radical generator; Cu(2+)-H2O2, mainly a hydroxyl radical generator; and Cu2+, a transition metal. Flavonoids including flavones, isoflavones, and flavanones acted as antioxidants against peroxyl and hydroxyl radicals and served as prooxidants in the presence of Cu2+. Both the antioxidant and the copper-initiated prooxidant activities of a flavonoid depend upon the number of hydroxyl substitutions in its backbone structure, which has neither antioxidant nor prooxidant action. In general, the more hydroxyl substitutions, the stronger the antioxidant and prooxidant activities. The flavonoids that contain multiple hydroxyl substitutions showed antiperoxyl radical activities several times stronger than Trolox, an alpha-to copherol analogue. The single hydroxyl substitution at position 5 provides no activity, whereas the di-OH substitution at 3' and 4' is particularly important to the peroxyl radical absorbing activity of a flavonoid. The conjugation between rings A and B does not affect the antioxidant activity but is very important for the copper-initiated prooxidant action of a flavonoid. The O-methylation of the hydroxyl substitutions inactivates both the antioxidant and the prooxidant activities of the flavonoids.

[1]  S. Renaud,et al.  Wine, alcohol, platelets, and the French paradox for coronary heart disease , 1992, The Lancet.

[2]  B. Halliwell,et al.  Inhibition of mammalian 5-lipoxygenase and cyclo-oxygenase by flavonoids and phenolic dietary additives. Relationship to antioxidant activity and to iron ion-reducing ability. , 1991, Biochemical pharmacology.

[3]  E. Niki,et al.  Interaction of α-tocopherol with copper and its effect on lipid peroxidation , 1994 .

[4]  E. Oliveros,et al.  Antioxidant activity of flavonoids: Efficiency of singlet oxygen (1Δg) quenching , 1993 .

[5]  S. Sahu,et al.  Kaempferol-induced nuclear DNA damage and lipid peroxidation. , 1994, Cancer letters.

[6]  O. Texier,et al.  Quercetin metabolites in plasma of rats fed diets containing rutin or quercetin. , 1995, The Journal of nutrition.

[7]  J. Pommery,et al.  Antioxidant properties of hydroxy-flavones. , 1996, Free radical biology & medicine.

[8]  E. Feskens,et al.  Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study , 1993, The Lancet.

[9]  A. Glazer [14] Phycoerythrin fluorescence-based assay for reactive oxygen species , 1990 .

[10]  C. Rice-Evans,et al.  A novel method for measuring antioxidant capacity and its application to monitoring the antioxidant status in premature neonates. , 1993, Clinical science.

[11]  M. Suschetet,et al.  Heterogenous effects of natural flavonoids on monooxygenase activities in human and rat liver microsomes. , 1995, Toxicology and applied pharmacology.

[12]  F. Marcheselli,et al.  Melatonin: a peroxyl radical scavenger more effective than vitamin E. , 1994, Life sciences.

[13]  J. P. Brown,et al.  A review of the genetic effects of naturally occurring flavonoids, anthraquinones and related compounds. , 1980, Mutation research.

[14]  S. Maxwell,et al.  Enhanced chemiluminescent assay for antioxidant capacity in biological fluids , 1992 .

[15]  K. Ingold,et al.  Antioxidant activity of phenols related to vitamin E. Are there chain-breaking antioxidants better than .alpha.-tocopherol? , 1983 .

[16]  K. Ingold,et al.  Quantitative measurement of the total, peroxyl radical‐trapping antioxidant capability of human blood plasma by controlled peroxidation , 1985, FEBS letters.

[17]  F. Ursini,et al.  Prooxidant role of vitamin E in copper induced lipid peroxidation , 1993, FEBS letters.

[18]  G. Wong,et al.  Quercetin and rutin as inhibitors of azoxymethanol-induced colonic neoplasia. , 1991, Carcinogenesis.

[19]  J. Liehr,et al.  Catechol-O-methyltransferase-catalyzed rapid O-methylation of mutagenic flavonoids. Metabolic inactivation as a possible reason for their lack of carcinogenicity in vivo. , 1994, The Journal of biological chemistry.

[20]  R. Pardini,et al.  Inhibition of the mitochondrial NADH-oxidase (NADH-coenzyme Q oxido-reductase) enzyme system by flavonoids: a structure-activity study. , 1987, Biochemical pharmacology.

[21]  A. Saija,et al.  Flavonoids as antioxidant agents: importance of their interaction with biomembranes. , 1995, Free radical biology & medicine.

[22]  C. Corsaro,et al.  In vitro scavenger activity of some flavonoids and melanins against O2-(.). , 1991, Free radical biology & medicine.

[23]  C. Rice-Evans,et al.  The relative antioxidant activities of plant-derived polyphenolic flavonoids. , 1995, Free radical research.

[24]  Y Hanasaki,et al.  The correlation between active oxygens scavenging and antioxidative effects of flavonoids. , 1994, Free radical biology & medicine.

[25]  O. Schimmer,et al.  Induction of sister-chromatid exchanges (SCE), polyploidy, and micronuclei by plant flavonoids in human lymphocyte cultures. A comparative study of 19 flavonoids. , 1991, Mutation research.

[26]  D. Steinberg,et al.  A role for endothelial cell lipoxygenase in the oxidative modification of low density lipoprotein. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[27]  J. Terao,et al.  Protective effect of epicatechin, epicatechin gallate, and quercetin on lipid peroxidation in phospholipid bilayers. , 1994, Archives of biochemistry and biophysics.

[28]  J. Terao,et al.  Antioxidative activity of quercetin and quercetin monoglucosides in solution and phospholipid bilayers. , 1995, Biochimica et biophysica acta.

[29]  E. Giroux,et al.  Inhibition of lipid peroxidation promoted by iron(III) and ascorbate. , 1992, Archives of biochemistry and biophysics.

[30]  R. Geahlen,et al.  Synthesis and protein-tyrosine kinase inhibitory activities of flavonoid analogues. , 1991, Journal of medicinal chemistry.

[31]  V. Mišík,et al.  Redox intermediates of flavonoids and caffeic acid esters from propolis: an EPR spectroscopy and cyclic voltammetry study. , 1995, Free radical biology & medicine.

[32]  C. Teng,et al.  Inhibition of platelet aggregation by some flavonoids. , 1991, Thrombosis research.

[33]  B. Halliwell,et al.  The definition and measurement of antioxidants in biological systems. , 1995, Free radical biology & medicine.

[34]  C. Beauloye,et al.  Effect of various flavonoids on lysosomes subjected to an oxidative or an osmotic stress. , 1992, Biochemical pharmacology.

[35]  R. Pardini,et al.  Inhibition of mitochondrial respiration and cyanide-stimulated generation of reactive oxygen species by selected flavonoids. , 1994, Biochemical pharmacology.

[36]  S. Sahu,et al.  Interactions of flavonoids, trace metals, and oxygen: nuclear DNA damage and lipid peroxidation induced by myricetin. , 1993, Cancer letters.

[37]  K. Ingold,et al.  ANTIOXIDANT ACTIVITY OF PHENOLS RELATED TO VITAMIN E. ARE THERE CHAIN-BREAKING ANTIOXIDANTS BETTER THAN α-TOCOPHEROL? , 1983 .

[38]  G. Lescoat,et al.  Antioxidant and iron-chelating activities of the flavonoids catechin, quercetin and diosmetin on iron-loaded rat hepatocyte cultures. , 1993, Biochemical pharmacology.

[39]  W. Klaus,et al.  Effects of different inotropes with antioxidant properties on acute regional myocardial ischemia in isolated rabbit hearts. , 1995, General pharmacology.

[40]  H. Maeda,et al.  Hydroxyl radical production by H2O2 plus Cu,Zn-superoxide dismutase reflects the activity of free copper released from the oxidatively damaged enzyme. , 1992, The Journal of biological chemistry.

[41]  D. Das Naturally occurring flavonoids: structure, chemistry, and high-performance liquid chromatography methods for separation and characterization. , 1994, Methods in enzymology.

[42]  H. Alessio,et al.  Oxygen-radical absorbance capacity assay for antioxidants. , 1993, Free radical biology & medicine.

[43]  J. Dore,et al.  Effects of flavonoids on the release of reactive oxygen species by stimulated human neutrophils. Multivariate analysis of structure-activity relationships (SAR). , 1993, Biochemical pharmacology.

[44]  U. Takahama Inhibition of lipoxygenase-dependent lipid peroxidation by quercetin: Mechanism of antioxidative function , 1985 .

[45]  C. Rice-Evans,et al.  Structure-antioxidant activity relationships of flavonoids and phenolic acids. , 1996, Free radical biology & medicine.

[46]  G. Igile,et al.  Flavonoids from Vernonia amygdalina and their antioxidant activities , 1994 .

[47]  N. Sekar,et al.  Chemopreventive potential of dietary bioflavonoids against 20-methylcholanthrene-induced tumorigenesis. , 1994, Cancer letters.

[48]  J. H. Parish,et al.  Activities of flavonoids for the cleavage of DNA in the presence of Cu(II): correlation with generation of active oxygen species. , 1992, Carcinogenesis.

[49]  T. Whitehead,et al.  Effect of red wine ingestion on the antioxidant capacity of serum. , 1995, Clinical chemistry.

[50]  E. Niki,et al.  α‐Tocopherol mediated peroxidation in the copper (II) and met myoglobininduced oxidation of human low density lipoprotein: The influence of lipid hydroperoxides , 1995, FEBS letters.

[51]  G. Lescoat,et al.  Role of flavonoids and iron chelation in antioxidant action. , 1994, Methods in enzymology.

[52]  W. Jinsart,et al.  Inhibition of wheat embryo calcium-dependent protein kinase and avian myosin light chain kinase by flavonoids and related compounds. , 1991, Biological chemistry Hoppe-Seyler.

[53]  M. Grisham Reactive metabolites of oxygen and nitrogen in biology and medicine , 1992 .

[54]  A. Wu,et al.  Automated assay of oxygen radical absorbance capacity with the COBAS FARA II. , 1995, Clinical chemistry.

[55]  R. Pardini,et al.  Inhibition of mitochondrial NADH oxidase, succinoxidase, and ATPase by naturally occurring flavonoids. , 1987, Journal of natural products.

[56]  W. Bors,et al.  Flavonoids as antioxidants: determination of radical-scavenging efficiencies. , 1990, Methods in enzymology.

[57]  R. Cutler,et al.  High concentrations of antioxidants may not improve defense against oxidative stress. , 1993, Archives of gerontology and geriatrics.

[58]  E. Middleton,et al.  Effects of flavonoids on immune and inflammatory cell functions. , 1992, Biochemical pharmacology.

[59]  Nakayama Tsutomu,et al.  Suppression of active oxygen-induced cytotoricity by flavonoids , 1993 .

[60]  J. Hoult,et al.  Actions of flavonoids and coumarins on lipoxygenase and cyclooxygenase. , 1994, Methods in enzymology.

[61]  M. Alcaraz,et al.  Effects of flavonoids on Naja naja and human recombinant synovial phospholipases A2 and inflammatory responses in mice. , 1994, Life sciences.