Browse > Article

Flavonoids Differentially Modulate Nitric Oxide Production Pathways in Lipopolysaccharide-Activated RAW264.7 Cells  

Kim Ae Ra (College of Pharmacy, Pusan National University)
Cho Jae Youl (School of Biotechnology and Bioengineering, Kangwon National University)
Zou Yani (College of Pharmacy, Pusan National University)
Choi Jae Sue (Faculty of Food Science and Biotechnology, Pukyong National University)
Chung Hae Young (College of Pharmacy, Pusan National University)
Publication Information
Archives of Pharmacal Research / v.28, no.3, 2005 , pp. 297-304 More about this Journal
Abstract
Naturally occurring flavonoids are known to modulate various inflammatory and immune processes. Based on structural property, in this study, molecular mechanism of flavonoids in modulating nitric oxide (NO) production and its signaling pathway were investigated using lipopolysaccharide (LPS)-activated RAW264.7 cells. Although flavonol-typed flavonoids (kaempferol and quercetin) more potently scavenged reactivity of nitric oxide ($\cdot$NO) as well as peroxynitrite (ONOO$\kappa$) than isoflavones (genistein and genistin), kaempferol, quercetin and genistein showed a little difference in inhibition of both inducible NO synthase expression and NO production, with IC$_{50}$ values of 13.9, 20.1 and 26.8 $\mu$M. However, there was a striking pattern related to structural feature in modulation of LPS-mediated signaling pathways. Thus, flavonols only inhibited transcription factor AP-1 activation, whereas isoflavones suppressed the DNA binding activation of NF-$\kappa$B and C/EBP$\beta$. Therefore, these data suggest that structural feature may be linked to decide drugs target molecule in LPS-mediated signaling pathways, rather than its potency.
Keywords
Citations & Related Records
Times Cited By KSCI : 1  (Citation Analysis)
Times Cited By Web Of Science : 12  (Related Records In Web of Science)
Times Cited By SCOPUS : 11
연도 인용수 순위
1 Cho, J. Y., Kim, P. S., Park, J., Chae, S. H., Yoo. E. S., Baik, K. U., and Park, M. H., Inhibitory effect of medicinal plants on TNF-$\alpha$ production from LPS-stimulated RAW264.7 cells. Nat. Prod. Sci., 5, 12-19 (1999)
2 Cushman, M., Nagarathnam, D., Burg, D. L., and Geahlen, R. L., Synthesis and protein-tyrosine kinase inhibitory activities of flavonoid analogues. J. Med. Chem., 34, 798-806 (1991)   DOI   PUBMED
3 Faulkner, K. M., Liochev, S. I., and Fridovich, I., Stable Mn(III) porphyrins mimic superoxide dismutase in vitro and substitute for it in vivo. J. Biol. Chem., 269: 23471-23476 (1994)
4 Guha, M. and Mackman, N. LPS induction of gene expression in human monocytes. Cell Signal., 13, 85-94 (2001)   DOI   ScienceOn
5 Kooy, N., Royall, J., Ischiropoulos, H., and Beckman, J., Peroxynitrite-mediated oxidation of dihydrorhodamine 123. Free Radic. Res. Commun.,16, 149-156 (1994)
6 Le Marchand, L., Cancer preventive effects of flavonoids-a review. Biomed. Pharmacother., 56, 296-301 (2002)   DOI   ScienceOn
7 Liang, Y., Huang, Y., Tsai, S., Lin-Shiau, S., Chwn, C., and Lin, J., Suppression of inducible cyclooxygenase and inducible nitric oxide synthase by apigenin and related flavonoids in mouse macrophages. Carcinogenesis, 20, 1945-1952 (1999)   DOI   ScienceOn
8 Mathy-Hartert, M., Deby-Dupont, G. P., Reginster, J. Y., Ayache, N., Pujol, J. P., and Henrotin, Y. E., Regulation by reactive oxygen species of interleukin-1beta, nitric oxide and prostaglandin E(2) production by human chondrocytes. Osteoarthritis Cartilage, 10, 547-555 (2002)   DOI   ScienceOn
9 Nagata, N., Momose, K., and Ishida, Y., Inhibitory effects of catecholamines and anti-oxidants on the fluorescence reaction of 4,5-diaminofluorescein, DAF-2, a novel indicator of nitric oxide. J. Biochem., 125, 658-661 (1999)   DOI
10 Olszanecki, R., Gebska, A., Kozlovski, V. I., and Gryglewski, R. J., Flavonoids and nitric oxide synthase. J. Physiol. Pharmacol., 53, 571-584 (2002)
11 Shen, S. C., Lee, W. R., Lin, H. Y., Huang, H. C., Ko, C. H., Yang, L. L., and Chen, Y. C., In vitro and in vivo inhibitory activities of rutin, wogonin, and quercetin on lipopolysaccharideinduced nitric oxide and prostaglandin E(2) production. Eur. J. Pharmacol., 446, 187-194 (2002)   DOI   PUBMED   ScienceOn
12 Tada, H., Shiho, O., Kuroshima, K., Koyama, M., and Tsukamoto, K., An improved colorimetric assay for interleukin 2. J. Immunol. Methods, 93, 157-165 (1986)   DOI   ScienceOn
13 Wheeler, A. P. and Bernard, G. R., Treating patients with severe sepsis. N. Engl. J. Med., 340, 207-214 (1999)   DOI   ScienceOn
14 Ohshima, H., Yoshie, Y., Auriol, S., and Gilibert, I., Antioxidant and pro-oxidant actions of flavonoids: effects on DNA damage induced by nitric oxide, peroxynitrite and nitroxyl anion. Free Radic. Biol. Med., 25, 1057-1065 (1998)   DOI   ScienceOn
15 Carter, A. B., Knudtson, K. L., Monick, M. M., and Hunninghake, G. W., The p38 mitogen-activated protein kinase is required for NF-kappaB-dependent gene expression. The role of TATA-binding protein (TBP). J. Biol. Chem., 274, 30858- 30863 (1999a)   DOI
16 Carter, A. B., Monick, M. M., and Hunninghake, G. W., Both Erk and p38 kinases are necessary for cytokine gene transcription. Am. J. Respir. Cell Mol. Biol., 20, 751-758 (1999b)   DOI   ScienceOn
17 Cobb, M. and Goldsmith, E., How MAP kinases are regulated. J. Biol. Chem., 270, 14843-14846 (1999)
18 Heijnen, C. G., Haenen, G. R., van Acker, F. A., van der Vijgh, W. J., and Bast, A., Flavonoids as peroxynitrite scavengers: the role of the hydroxyl groups. Toxicol. In Vitro, 15, 3-6 (2001)   DOI   ScienceOn
19 Jung, H. A., Kim, A. R., Chung, H. Y., and Choi, J. S., In vitro antioxidant activity of some selected Prunus species in Korea. Arch. Pharm. Res., 25, 865-872 (2002)   DOI   ScienceOn
20 Matsuda, H., Morikawa, T., Ando, S., Toguchida, I., and Yoshikawa, M., Structural requirements of flavonoids for nitric oxide production inhibitory activity and mechanism of action. Bioorg. Med. Chem., 11, 1995-2000 (2003)   DOI   ScienceOn
21 Akiyama, T., Ishida, J., Nakagawa, S., Ogawara, H., Watanabe, S., Itoh, N., Shibuya, M., and Fukami, Y., Genistein, a specific inhibitor of tyrosine-specific protein kinases. J. Biol. Chem., 262: 5592-5595 (1987)
22 Huie, R. and Padmaja, S., The reaction of NO and superoxide. Free Radic. Res. Commun., 18, 195-199 (1993)   DOI
23 Hertog, M. G., Kromhout, D., Aravanis, C., Blackburn, H., Buzina, R., Fidanza, F., Giampaoli, S., Jansen, A., Menotti, A., and Nedeljkovic, S., Flavonoid intake and long-term risk of coronary heart disease and cancer in the seven countries study. Arch. Intern. Med., 155, 381-386 (1995)   DOI   ScienceOn
24 Kroncke, K., Fehsel, K., and Kolb-Bachofen, V., Inducible nitric oxide synthase in human disease. Clin. Exp. Immunol., 113, 147-156 (1998)   DOI   PUBMED
25 Lopez-Lazaro, M., Flavonoids as anticancer agents: structureactivity relationship study. Curr. Med. Chem. Anti-Canc., Agents 2, 691-714 (2002)   DOI   ScienceOn
26 Middleton, E. Jr., Kandaswami, C., and Theoharides, T. C., The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol. Rev., 52, 673-751 (2000)
27 Kimura, S., Watanabe, K., Yajiri, Y., Motegi, T., Masuya, Y., Shibuki, K., Uchiyama, S., Homma, T., and Takahashi, H., Cerebrospinal fluid nitric oxide metabolites in painful diseases. Neuro. Report, 10, 275-279 (1999)   DOI   ScienceOn
28 Cho, J. Y., Kim, P. S., Park, J., Yoo, E. S., Baik, K. U., Kim, Y. K., and Park, M. H., Inhibitor of tumor necrosis factor-alpha production in lipopolysaccharide-stimulated RAW264.7 cells from Amorpha fruticosa. J. Ethnopharmacol., 70, 127-133 (2000)   DOI   ScienceOn
29 Haenen, G., Paquay, J., Korthouwer, R., and Bast, A., Peroxynitrite scavenging by flavonoids. Biochem. Biophys. Res. Commun., 23, 591-593 (1997)   DOI   ScienceOn
30 Kim, H. J., Yu, B. P., and Chung, H.Y., Molecular exploration of age-related NF-kappaB/IKK downregulation by calorie restriction in rat kidney. Free Radic. Biol. Med., 32, 991-1005 (2002)   DOI   ScienceOn
31 Stuehr, D., Mammalian nitric oxide synthase. Biochem. Biophys. Acta, 1441, 217-230 (1999)
32 Klotz, L. O. and Sies, H., Defenses against peroxynitrite: selenocompounds and flavonoids. Toxicol. Lett., 140-141, 125-132 (2003)   DOI   ScienceOn
33 Choi, J. S., Chung, H. Y., Kang, S. S., Jung, M. J., Kim, J. W., No, J. K., and Jung, H. A., The structure-activity relationship of flavonoids as scavengers of peroxynitrite. Phytother. Res., 16, 232-235 (2002)   DOI   ScienceOn
34 Rice-Evans, C. A., Miller, N. J., and Paganga, G., Structureantioxidant activity relationships of flavonoids and phenolic acids. Free Radic. Biol. Med., 20, 933-956 (1996)   DOI   ScienceOn
35 Mavis, R. and Stellwagen, E., Purification and subunit structure of glutathione reductase from bakers yeast. J. Biol. Chem., 243, 809-814 (1968)
36 Geahlen, R. L., Koonchanok, N. M., McLaughlin, J. L., and Pratt, D. E., Inhibition of protein-tyrosine kinase activity by flavanoids and related compounds. J. Nat. Prod., 52, 982- 986 (1989)   DOI   PUBMED
37 Agullo, G., Gamet-Payrastre, L., Manenti, S., Viala, C., Remesy, C., Chap, H., and Payrastre, B., Relationship between flavonoid structure and inhibition of phosphatidylinositol 3- kinase: a comparison with tyrosine kinase and protein kinase C inhibition. Biochem. Pharmacol., 53, 1649-1657 (1997)   DOI   ScienceOn
38 Kim, H. K., Cheon, B. S., Kim, Y. H., Kim, S. Y., and 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., 58, 759-765 (1999)   DOI   PUBMED   ScienceOn