Anti-Oxidant, Anti-Inflammatory and Anti-Allergic Activities of Luteolin

Abstract

Luteolin is a flavone which occurs in medicinal plants as well as in some vegetables and spices. It is a natural anti-oxidant with less pro-oxidant potential than the flavonol quercetin, the best studied flavonoid, but apparently with a better safety profile. It displays excellent radical scavenging and cytoprotective properties, especially when tested in complex biological systems where it can interact with other anti-oxidants like vitamins. Luteolin displays specific anti-inflammatory effects at micromolar concentrations which are only partly explained by its anti-oxidant capacities. The anti-inflammatory activity includes activation of anti-oxidative enzymes, suppression of the NFκB pathway and inhibition of pro-inflammatory substances. In vivo, luteolin reduced increased vascular permeability and was effective in animal models of inflammation after parenteral and oral application. Although luteolin is only a minor component in our nutrition (less than 1 mg/day) epidemiological studies indicate that it has the potential to protect from diseases associated with inflammatory processes such as cardiovascular disease. Luteolin often occurs in the form of glycosides in plants, but these are cleaved and the aglycones are conjugated and metabolized after nutritional uptake which has to be considered when evaluating in vitro studies. Some data for oral and topical bioavailability exist, but more quantitative research in this field is needed to evaluate the physiological and therapeutical potential of luteolin.

Abbreviations

Akt:serine/threonin protein kinase B

COX-2:cyclooxygenase-2

CVD:cardiovascular disease

DPPH:2,2-diphenyl-1-picrylhydrazyl

EAE:experimental autoimmune encephalomyelitis

EGCG:epigallocatechin 3-gallate

fMLP:fMetLeuPhe, formyl peptide

GSH:glutathione

IFN-γ:interferon γ

IκB:Inhibitor of kappa B

IL:interleukin

iNOS:inducible nitric oxygen synthase

IP-10:inducible nitric oxygen synthase

IRF:interferon regulatory factor

LPS:lipopolysaccharide

LysoPAF AcTF:1-lysophospholipide acetyltransferase

MAPK:mitogen-activated protein kinase

M-CSF:macrophage colony-stimulating factor

NFκB:nuclear factor kappa B

8-OHdG:8-hydroxy-2′-deoxyguanosine

PGE₂:prostaglandin E₂

PMA:phorbol myristate acetate

ROS:reactive oxygen species

TEAC:trolox equivalent anti-oxidant capacity

TNF-α:tumor necrosis factor-α

luteolin - flavonoids - Reseda luteola L. - Resedaceae - free radical scavengers

References

• 1 USDA databank for the flavonoid content of selected foods, 2nd release 2007. Available at http://www.ars.usda.gov/nutrientdata Accessed June 13, 2008
• 2 Schempp C M, Wähling A, Lange E. Method for the production of flavonoid-containing compositions and use thereof. European patent EP 1 648 566 B1 2008
• 3 Heilmann J, Merfort I. Aktueller Kenntnisstand zum Metabolismus von Flavonoiden. II. Resorption und Metabolismus von Flavonen, Flavanonen, Flavanen, Procyanidinen und Isoflavonoiden.  Pharm Unserer Zeit. 1998;  27 173-83
• 4 Huang D, Ou B, Prior R L. The chemistry behind antioxidant capacity assays.  J Agric Food Chem. 2005;  53 1841-56
• 5 Apak R, Güçlü K, Demirata B, Ozyürek M, Celik S E, Bektaşoglu B. et al . Comparative evaluation of various total antioxidant capacity assays applied to phenolic compounds with the CUPRAC assay.  Molecules. 2007;  12 1496-547
• 6 Havsteen B H. The biochemistry and medical significance of the flavonoids.  Pharmacol Ther. 2002;  96 67-202
• 7 Heim K E, Tagliaferro A R, Bobilya D J. Flavonoid antioxidants: chemistry, metabolism and structure-activity relationships.  J Nutr Biochem. 2002;  13 572-84
• 8 Belyakov V A, Roginsky V A, Bors W. Rate constant for the reaction of peroxyl free radical with flavonoids and related compounds as determined by the kinetic chemoluminescence method. J Chem Soc [Perkin 2] 1995: 2319-36
• 9 Jovanovic S V, Steenken S, Hara Y, Simic M G. Reduction potential of flavonoid and model phenoxyl radicals. Which ring in flavonoids is responsible for antioxidant activity?. J Chem Soc [Perkin 2] 1996: 2497-504
• 10 Rice-Evans C A, Miller N J, Paganga G. Structure-antioxidant activity relationships of flavonoids and phenolic acids.  Free Radic Biol Med. 1996;  20 933-1056
• 11 Brown J E, Khodr H, Hider R C, Rice-Evans C A. Structural dependence of flavonoid interactions with Cu²⁺ ions: implications for their antioxidant properties.  Biochem J. 1998;  330 1173-8
• 12 Pietta P G. Flavonoids as antioxidants.  J Nat Prod. 2000;  63 1035-42
• 13 Romanová D, Vachálková A, Cipák L, Ovesná Z, Rauko P. Study of antioxidant effect of apigenin, luteolin and quercetin by DNA protective method.  Neoplasma. 2001;  48 104-7
• 14 Galvez J, de la Cruz J P, Zarzuelo A, Sanchez de la Cuesta F. Flavonoid inhibition of enzymic and nonenzymic lipid peroxidation in rat liver differs from its influence on the glutathione-related enzymes.  Pharmacology. 1995;  51 27-33
• 15 Shimoi K, Masuda S, Shen B, Furugori M, Kinae N. Radioprotective effect of antioxidative flavonoids in gamma-ray irradiated mice.  Carcinogenesis. 1994;  15 2669-72
• 16 Gal S, Lichtenberg D, Bor A, Pinchuk I. Copper-induced peroxidation of phosphatidylserine-containing liposomes is inhibited by nanomolar concentrations of specific antioxidants.  Chem Phys Lipids. 2007;  150 86-203
• 17 Hirano R, Sasamoto W, Matsumoto A, Itakura H, Igarashi O, Kondo K. Antioxidant ability of various flavonoids against DPPH radicals and LDL oxidation.  J Nutr Sci Vitaminol (Tokyo). 2001;  47 357-62
• 18 Horváthová K, Novotný L, Vachálková A. The free radical scavenging activity of four flavonoids determined by the comet assay.  Neoplasma. 2003;  50 291-5
• 19 Horváthová K, Novotný L, Tóthová D, Vachálková A. Determination of free radical scavenging activity of quercetin, rutin, luteolin and apigenin in H₂O₂-treated human ML cells K562.  Neoplasma. 2004;  51 395-9
• 20 Horváthová K, Chalupa L, Sebova D, Tóthová D, Vachálková A. Protective effect of quercetin and luteolin in human melanoma HMB-2 cells.  Mutat Res. 2005;  565 105-12
• 21 Noroozi M, Angerson W J, Lean M E. Effects of flavonoids and vitamin C on oxidative DNA damage to human lymphocytes.  Am J Clin Nutr. 1998;  67 1210-8
• 22 Steffan B. Inhaltsstoffe aus Pflanzen der indonesischen Volksmedizin (Jamu): Isolierung, Identifizierung, und Charakterisierung der antioxidativen Eigenschaften [dissertation]. Düsseldorf; Heinrich Heine Universität 2005
• 23 Pérez-García F, Adzet T, Canigueral S. Activity of artichoke leaf extract on reactive oxygen species in human leukocytes.  Free Radic Res. 2000;  33 661-5
• 24 Kohen R, Nyska A. Oxidation of biological systems: oxidative stress phenomena, antioxidants, redox reactions, and methods for their quantification.  Toxicol Pathol. 2002;  30 620-50
• 25 Gebhardt R, Rexhepaj R, Fausel M. Vergleich der antioxidativen und hepatoprotektiven Wirkung von Flavonoiden aus Blattextrakten der Artischocke (Cynara scolymus) an Hepatocytenkulturen unter Einwirkung toxischer Hydroperoxide. Phytopharmakaforschung 2000, Tagung der Ges Phytotherapie und Ges Arzneipflanzenforschung Bonn; 1998
• 26 Wolfe K L, Liu R H. Cellular antioxidant activity (CAA) assay for assessing antioxidants, foods, and dietary supplements.  J Agric Food Chem. 2007;  55 8896-907
• 27 Harris G K, Qian Y, Leonard S S, Sbarra D C, Shi X. Luteolin and chrysin differentially inhibit cyclooxygenase-2 expression and scavenge reactive oxygen species but similarly inhibit prostaglandin-E2 formation in RAW 264.7 cells.  J Nutr. 2006;  136 1517-21
• 28 Wang X G, Chen G Y, Chen M P. Effect of luteolin on COX-2 and mPGES-1 expression in LPS-induced RAW264.7 cells.  Zhong yao cai - J Chin Med Mater. 2008;  30 1263-6
• 29 Psotová J, Chlopcíková S, Miketová P, Hrbác J, Simánek V. Chemoprotective effect of plant phenolics against anthracycline-induced toxicity on rat cardiomyocytes. Part III. Apigenin, baicalelin, kaempferol, luteolin and quercetin.  Phytother Res. 2004;  18 516-21
• 30 Kanazawa K, Uehara M, Yanagitani H, Hashimoto T. Bioavailable flavonoids to suppress the formation of 8-OHdG in HepG2 cells.  Arch Biochem Biophys. 2006;  455 197-203
• 31 Qiusheng Z, Yuntao Z, Rongliang Z, Dean G, Changling L. Effects of verbascoside and luteolin on oxidative damage in brain of heroin treated mice.  Pharmazie. 2005;  60 539-43
• 32 Ruiz P A, Haller D. Functional diversity of flavonoids in the inhibition of the proinflammatory NF-kappaB, IRF, and Akt signaling pathways in murine intestinal epithelial cells.  J Nutr. 2006;  136 664-71
• 33 Kim J S, Lee H J, Lee M H, Kim J, Jin C, Ryu J H. Luteolin inhibits LPS-stimulated inducible nitric oxide synthase expression in BV-2 microglial cells.  Planta Med. 2006;  72 65-8
• 34 Comalada M, Ballester I, Bailón E, Sierra S, Xaus J, Gálvez J. et al . Inhibition of pro-inflammatory markers in primary bone marrow-derived mouse macrophages by naturally occurring flavonoids: analysis of the structure-activity relationship.  Biochem Pharmacol. 2006;  72 010-21
• 35 Kim E K, Kwon K B, Song M Y, Han M J, Lee J H, Lee Y R. Flavonoids protect against cytokine-induced pancreatic beta-cell damage through suppression of nuclear factor kappaB activation.  Pancreas. 2007;  35 1-9
• 36 Xagorari A, Papapetropoulos A, Mauromatis A, Economou M, Fotsis T, Roussos C. Luteolin inhibits an endotoxin-stimulated phosphorylation cascade and proinflammatory cytokine production in macrophages.  J Pharmacol Exp Ther. 2001;  296 181-7
• 37 Hirano T, Higa S, Arimitsu J, Naka T, Shima Y, Ohshima S. et al . Flavonoids such as luteolin, fisetin and apigenin are inhibitors of interleukin-4 and interleukin-13 production by activated human basophils.  Arch Allergy Immunol. 2004;  134 135-40
• 38 Kawai M, Hirano T, Higa S, Arimitsu J, Maruta M, Kuwahara Y. et al . Flavonoids and related compounds as anti-allergic substances.  Allergol Int. 2007;  56 113-23
• 39 Park K Y, Lee S H, Min B K, Lee K S, Choi J S, Chung S R. et al . Inhibitory effect of luteolin 4′-O-glucoside from Kummerowia striata and other flavonoids on interleukin-5 bioactivity.  Planta Med. 1999;  65 457-9
• 40 Hirano T, Arimitsu J, Higa S, Naka T, Ogata A, Shima Y. et al . Luteolin, a flavonoid, inhibits CD40 ligand expression by activated human basophils.  Int Arch Allergy Immunol. 2006;  140 150-6
• 41 Cheong H, Ryu S Y, Oak M H, Cheon S H, Yoo G S, Kim K M. Studies of structure activity relationship of flavonoids for the anti-allergic actions.  Arch Pharm Res. 1998;  21 78-80
• 42 Hougee S, Sanders A, Faber J, Graus Y M, van den Berg W B, Garssen J. et al . Decreased pro-inflammatory cytokine production by LPS-stimulated PBMC upon in vitro incubation with the flavonoids apigenin, luteolin or chrysin, due to selective elimination of monocytes/macrophages.  Biochem Pharmacol. 2005;  69 241-8
• 43 Kim H K, Cheon B S, Kim Y H, Kim S Y, Kim H P. Effects of naturally occurring flavonoids on nitric oxide production in the macrophage cell line RAW 264.7 and their structure-activity relationships.  Biochem Pharmacol. 1999;  58 759-65
• 44 Verbeek R, Plomp A C, van Tol E A, van Noort J M. The flavones luteolin and apigenin inhibit in vitro antigen-specific proliferation and interferon-gamma production by murine and human autoimmune T cells.  Biochem Pharmacol. 2004;  68 621-9
• 45 Verbeek R, van Tol E A, van Noort J M. Oral flavonoids delay recovery from experimental autoimmune encephalomyelitis in SJL mice.  Biochem Pharmacol. 2005;  70 220-8
• 46 Kuppusamy U R, Khoo H E, Das N P. Structure-activity studies of flavonoids as inhibitors of hyaluronidase.  Biochem Pharmacol. 1990;  40 397-401
• 47 Hertel W, Peschel G, Ozegowski J H, Müller P J. Inhibitory effects of triterpenes and flavonoids on the enzymatic activity of hyaluronic acid-splitting enzymes.  Arch Pharm (Weinheim). 2006;  339 313-8
• 48 Choi E M. Modulatory effects of luteolin on osteoblastic function and inflammatory mediators in osteoblastic MC3T3-E1 cells.  Cell Biol Int. 2007;  31 870-7
• 49 Yanoshita R, Chang H W, Son K H, Kudo I, Samejima Y. Inhibition of lysoPAF acetyltransferase activity by flavonoids.  Inflamm Res. 1996;  45 546-9
• 50 Baolin L, Weiwei W, Ning T. Topical application of luteolin inhibits scratching behavior associated with allergic cutaneous reaction in mice.  Planta Med. 2005;  71 424-8
• 51 Kimata M, Inagaki N, Nagai H. Effects of luteolin and other flavonoids on IgE-mediated allergic reactions.  Planta Med. 2000;  66 25-9
• 52 Kimata M, Shichijo M, Miura T, Serizawa I, Inagaki N, Nagai H. Effects of luteolin, quercetin and baicalein on immunoglobulin E-mediated mediator release from human cultured mast cells.  Clin Exp Allergy. 2000;  30 501-8
• 53 Ueda H, Yamazaki C, Yamazaki M. Luteolin as an anti-inflammatory and anti-allergic constituent of Perilla frutescens. .  Biol Pharm Bull. 2002;  25 1197-202
• 54 Hendriks J J, Alblas J, van der Pol S M, van Tol E A, Dijkstra C D, de Vries H E. Flavonoids influence monocytic GTPase activity and are protective in experimental allergic encephalitis.  J Exp Med. 2004;  200 1667-72
• 55 Kotanidou A, Xagorari A, Bagli E, Kitsanta P, Fotsis T, Papapetropoulos A. et al . Luteolin reduces lipopolysaccharide-induced lethal toxicity and expression of proinflammatory molecules in mice.  Am J Respir Crit Care Med. 2002;  165 818-23
• 56 Kumazawa Y, Kawaguchi K, Takimoto H. Immunomodulating effects of flavonoids on acute and chronic inflammatory responses caused by tumor necrosis factor alpha.  Curr Pharm Des. 2006;  12 4271-9
• 57 Ziyan L, Yongmei Z, Nan Z, Ning T, Baolin L. Evaluation of the anti-inflammatory activity of luteolin in experimental animal models.  Planta Med. 2007;  73 221-6
• 58 Zhou P, Li L P, Luo S Q, Jiang H D, Zeng S. Intestinal absorption of luteolin from peanut hull extract is more efficient than that from individual pure luteolin.  J Agric Food Chem. 2008;  56 296-300
• 59 Wittemer S M, Ploch M, Windeck T, Müller S C, Drewelow B, Derendorf H. et al . Bioavailability and pharmacokinetics of caffeoylquinic acids and flavonoids after oral administration of Artichoke leaf extracts in humans.  Phytomedicine. 2005;  12 28-38
• 60 Brown J E, Rice-Evans C A. Luteolin-rich artichoke extract protects low density lipoprotein from oxidation in vitro. .  Free Radic Res. 1998;  29 247-55
• 61 Boersma M G, van der Woude H, Bogaards J, Boeren S, Vervoort J, Cnubben N H. et al . Regioselectivity of phase II metabolism of luteolin and quercetin by UDP-glucuronosyl transferases.  Chem Res Toxicol. 2002;  15 662-70
• 62 Shimoi K, Nakayama T. Glucuronidase deconjugation in inflammation.  Methods Enzymol. 2005;  400 263-72
• 63 Merfort I, Heilmann J, Hagedorn-Leweke U, Lippold B C. In vivo skin penetration studies on chamomile flavones.  Pharmazie. 1994;  49 509-11
• 64 Chavant L, Combie H, Crs J. Memorandum: new dietary ingredients.  Plant Med Phytother. 1975;  9 267-72
• 65 ai L M, Cheng H, Li W P, Liu S Q, Chen M X, Xu S Y. Memorandum: new dietary ingredients.  Acta Anhui Med Univ. 1985;  20 1-3
• 66 Mittra B, Saha A, Chowdhury A R, Pal C, Mandal S, Mukhopadhyay S. et al . Luteolin, an abundant dietary component is a potent anti-leishmanial agent that acts by inducing topoisomerase II-mediated kinetoplast DNA cleavage leading to apoptosis.  Mol Med. 2000;  6 527-41
• 67 Czeczot H, Tudek B, Kusztelak J, Szymczyk T, Dobrowolska B, Glinkowska G. et al . Isolation and studies of the mutagenic activity in the Ames test of flavonoids naturally occurring in medical herbs.  Mutat Res. 1990;  240 209-16
• 68 Choi J S, Park K Y, Moon S H, Rhee S H, Young H S. Antimutagenic effect of plant flavonoids in the Salmonella assay system.  Arch Pharm Res. 1994;  17 71-5
• 69 Kawanishi S, Oikawa S, Murata M. Evaluation for safety of antioxidant chemopreventive agents.  Antioxid Redox Signal. 2005;  7 1728-39
• 70 Middleton E J r, Kandaswami C, Theoharides T C. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer.  Pharmacol Rev. 2000;  52 673-751
• 71 Knekt P, Jarvinen R, Reunanen A, Maatela J. Flavonoid intake and coronary mortality in Finland: a cohort study.  BMJ. 1996;  312 478-81
• 72 Knekt P, Isotupa S, Rissanen H, Heliövaara M, Järvinen R, Häkkinen S. et al . Quercetin intake and the incidence of cerebrovascular disease.  Eur J Clin Nutr. 2000;  54 415-7
• 73 Marniemi J, Alanen E, Impivaara O, Seppänen R, Hakala P, Rajala T. et al . Dietary and serum vitamins and minerals as predictors of myocardial infarction and stroke in elderly subjects.  Nutr Metab Cardiovasc Dis. 2005;  15 188-97
• 74 Mink P J, Scrafford C G, Barraj L M, Harnack L, Hong C P, Nettleton J A. et al . Flavonoid intake and cardiovascular disease mortality: a prospective study in postmenopausal women.  Am J Clin Nutr. 2007;  85 895-909
• 75 Yochum L, Kushi L H, Meyer K, Folsom A R. Dietary flavonoid intake and risk of cardiovascular disease in postmenopausal women.  Am J Epidemiol. 1999;  149 943-9
• 76 Sesso H D, Gaziano J M, Liu S, Buring J E. Flavonoid intake and the risk of cardiovascular disease in women.  Am J Clin Nutr. 2003;  77 1400-8
• 77 Tavani A, Spertini L, Bosetti C, Parpinel M, Gnagnarella P, Bravi F. et al . Intake of specific flavonoids and risk of acute myocardial infarction in Italy.  Public Health Nutr. 2006;  9 369-74
• 78 Quintiery L, Palatini P, Nassi A, Ruzza P, Floreani M. Flavonoids diosmetin and luteolin inhibit midazolam metabolism by human liver microsomes and recombinant CYP 3A4 and CYP 3A5 enzymes.  Biochem Pharmacol. 2008;  75 1426-37
• 79 Wang X, Wang Q, Morris M E. Pharmacokinetic interaction between the flavonoid luteolin and gamma-hydroxybutyrate in rats: potential involvement of monocarboxylate transporters.  AAPS J. 2008;  10 47-55
• 80 Ahlenstiel T, Burkhardt G, Köhler H, Kuhlmann M K. Improved cold preservation of kidney tubular cells by means of adding bioflavonoids to organ preservation solutions.  Transplantation. 2006;  81 231-9
• 81 Chen C Y, Peng W H, Tsai K D, Hsu S L. Luteolin suppresses inflammation-associated gene expression by blocking NF-kappaB and AP-1 activation pathway in mouse alveolar macrophages.  Life Sci. 2007;  81 1602-14
• 82 Gutiérrez-Venegas G, Kawasaki-Cárdenas P, Arroyo-Cruz S R, Maldonado-Frías S. Luteolin inhibits lipopolysaccharide actions on human gingival fibroblasts.  Eur J Pharmacol. 2006;  541 95-105      
• 83 Hirano T, Higa S, Arimitsu J, Naka T, Ogata A, Shima Y. et al . Luteolin, a flavonoid, inhibits AP-1 activation by basophils.  Biochem Biophys Res Commun. 2006;  340 1-7
• 84 Hu C, Kitts D D. Luteolin and luteolin 7-O-glucoside from dandelion flower suppress iNOS and COX-2 in RAW264.7 cells.  Mol Cell Biochem. 2004;  265 107-13
• 85 Kim S H, Shin K J, Kim D, Kim Y H, Han M S, Lee T G. et al . Luteolin inhibits the nuclear factor-kappa B transcriptional activity in Rat-1 fibroblasts.  Biochem Pharmacol. 2003;  66 955-63
• 86 Lu H W, Sugahara K, Sagara Y, Masuoka N, Asaka Y, Manabe M. et al . Effect of three flavonoids, 5,7,3′,4′-tetrahydroxy-3-methoxy flavone, luteolin, and quercetin, on the stimulus-induced superoxide generation and tyrosyl phosphorylation of proteins in human neutrophil.  Arch Biochem Biophys. 2001;  393 73-7
• 87 Odontuya G, Hoult J R, Houghton P J. Structure-activity relationship for anti-inflammatory effect of luteolin and its derived glycosides.  Phytother Res. 2005;  19 782-6
• 88 Park B Y, Min B S, Oh S R, Kim J H, Bae K H, Lee H K. Isolation of flavonoids, a biscoumarin and an amide from the flower buds of Daphne genkwa and the evaluation of their anti-complement activity.  Phytother Res. 2006;  20 610-3
• 89 Pieroni A, Heimler D, Pieters L, van Poel B, Vlietinck A J. In vitro anti-complementary activity of flavonoids from olive (Olea europaea L.) leaves.  Pharmazie. 1996;  51 765-8
• 90 Pieroni A, Pachaly P, Huang Y, Van Poel B, Vlietinck A J. Studies on anti-complementary activity of extracts and isolated flavones from Ligustrum vulgare and Phillyrea latifolia leaves (Oleaceae).  J Ethnopharmacol. 2000;  70 213-7
• 91 Sharma V, Mishra M, Ghosh S, Tewari R, Basu A, Seth P. et al . Modulation of interleukin-1 beta mediated inflammatory response in human astrocytes by flavonoids: implications in neuroprotection.  Brain Res Bull. 2007;  73 55-63
• 92 Theoharides T C, Kempuraj D, Iliopoulou B P. Mast cells, T cells, and inhibition by luteolin: implications for the pathogenesis and treatment of multiple sclerosis.  Adv Exp Med Biol. 2007;  601 423-30
• 93 Ueda H, Yamazaki C, Yamazaki M. A hydroxyl group of flavonoids affects oral anti-inflammatory activity and inhibition of systemic tumor necrosis factor-alpha production.  Biosci Biotechnol Biochem. 2004;  68 119-25