DOI QR코드

DOI QR Code

Luteolin and luteolin-7-O-glucoside protect against acute liver injury through regulation of inflammatory mediators and antioxidative enzymes in GalN/LPS-induced hepatitic ICR mice

  • Received : 2019.04.23
  • Accepted : 2019.07.15
  • Published : 2019.12.01

Abstract

BACKGROUND/OBJECTIVES: Anti-inflammatory and antioxidative activities of luteolin and luteolin-7-O-glucoside were compared in galactosamine (GalN)/lipopolysaccharide (LPS)-induced hepatitic ICR mice. MATERIALS/METHODS: Male ICR mice (6 weeks old) were divided into 4 groups: normal control, GalN/LPS, luteolin, and luteolin-7-O-glucoside groups. The latter two groups were administered luteolin or luteolin-7-O-glucoside (50 mg/kg BW) daily by gavage for 3 weeks after which hepatitis was induced by intraperitoneal injection of GalN and LPS (1 g/kg BW and $10{\mu}g/kg\;BW$, respectively). RESULTS: GalN/LPS produced acute hepatic injury by a sharp increase in serum AST, ALT, and $TNF-{\alpha}$ levels, increases that were ameliorated in the experimental groups. In addition, markedly increased expressions of cyclooxygenase (COX)-2 and its transcription factors, nuclear factor $(NF)-{\kappa}B$ and activator protein (AP)-1, were also significantly attenuated in the experimental groups. Compared to luteolin-7-O-glucoside, luteolin more potently ameliorated the levels of inflammatory mediators. Phase II enzymes levels and NF-E2 p45-related factor (Nrf)-2 activation that were decreased by GalN/LPS were increased by luteolin and luteolin-7-O-glucoside administration. In addition, compared to luteolin, luteolin-7-O-glucoside acted as a more potent inducer of changes in phase II enzymes. Liver histopathology results were consistent with the mediator and enzyme results. CONCLUSION: Luteolin and luteolin-7-O-glucoside protect against GalN/LPS-induced hepatotoxicity through the regulation of inflammatory mediators and phase II enzymes.

Keywords

References

  1. Fei J, Liang B, Jiang C, Ni H, Wang L. Luteolin inhibits IL-$1{\beta}$-induced inflammation in rat chondrocytes and attenuates osteoarthritis progression in a rat model. Biomed Pharmacother 2019;109:1586-92. https://doi.org/10.1016/j.biopha.2018.09.161
  2. Seelinger G, Merfort I, Schempp CM. Anti-oxidant, anti-inflammatory and anti-allergic activities of luteolin. Planta Med 2008;74:1667-77. https://doi.org/10.1055/s-0028-1088314
  3. Richelle M, Pridmore-Merten S, Bodenstab S, Enslen M, Offord EA. Hydrolysis of isoflavone glycosides to aglycones by beta-glycosidase does not alter plasma and urine isoflavone pharmacokinetics in postmenopausal women. J Nutr 2002;132:2587-92. https://doi.org/10.1093/jn/132.9.2587
  4. Izumi T, Piskula MK, Osawa S, Obata A, Tobe K, Saito M, Kataoka S, Kubota Y, Kikuchi M. Soy isoflavone aglycones are absorbed faster and in higher amounts than their glucosides in humans. J Nutr 2000;130:1695-9. https://doi.org/10.1093/jn/130.7.1695
  5. Kano M, Takayanagi T, Harada K, Sawada S, Ishikawa F. Bioavailability of isoflavones after ingestion of soy beverages in healthy adults. J Nutr 2006;136:2291-6. https://doi.org/10.1093/jn/136.9.2291
  6. Andlauer W, Kolb J, Furst P. Isoflavones from tofu are absorbed and metabolized in the isolated rat small intestine. J Nutr 2000;130:3021-7. https://doi.org/10.1093/jn/130.12.3021
  7. Rowland I, Faughnan M, Hoey L, Wahala K, Williamson G, Cassidy A. Bioavailability of phyto-oestrogens. Br J Nutr 2003;89 Suppl 1:S45-58. https://doi.org/10.1079/BJN2002796
  8. Kure A, Nakagawa K, Kondo M, Kato S, Kimura F, Watanabe A, Shoji N, Hatanaka S, Tsushida T, Miyazawa T. Metabolic fate of luteolin in rats: its relationship to anti-inflammatory effect. J Agric Food Chem 2016;64:4246-54. https://doi.org/10.1021/acs.jafc.6b00964
  9. Zhou P, Li LP, Luo SQ, Jiang HD, 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. https://doi.org/10.1021/jf072612+
  10. Piskula MK. Factors affecting flavonoids absorption. Biofactors 2000;12:175-80. https://doi.org/10.1002/biof.5520120128
  11. Zubik L, Meydani M. Bioavailability of soybean isoflavones from aglycone and glucoside forms in American women. Am J Clin Nutr 2003;77:1459-65. https://doi.org/10.1093/ajcn/77.6.1459
  12. Kemelo MK, Wojnarova L, Kutinova Canova N, Farghali H. D-galactosamine/lipopolysaccharide-induced hepatotoxicity downregulates sirtuin 1 in rat liver: role of sirtuin 1 modulation in hepatoprotection. Physiol Res 2014;63:615-23.
  13. Ferencikova R, Cervinkova Z, Drahota Z. Hepatotoxic effect of D-galactosamine and protective role of lipid emulsion. Physiol Res 2003;52:73-8.
  14. Surh YJ, Chun KS, Cha HH, Han SS, Keum YS, Park KK, Lee SS. Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutat Res 2001;480-481:243-68. https://doi.org/10.1016/S0027-5107(01)00183-X
  15. Fujioka S, Niu J, Schmidt C, Sclabas GM, Peng B, Uwagawa T, Li Z, Evans DB, Abbruzzese JL, Chiao PJ. NF-kappaB and AP-1 connection: mechanism of NF-kappaB-dependent regulation of AP-1 activity. Mol Cell Biol 2004;24:7806-19. https://doi.org/10.1128/MCB.24.17.7806-7819.2004
  16. Sajadimajd S, Khazaei M. Oxidative stress and cancer: the role of Nrf2. Curr Cancer Drug Targets 2018;18:538-57. https://doi.org/10.2174/1568009617666171002144228
  17. Zhang M, An C, Gao Y, Leak RK, Chen J, Zhang F. Emerging roles of Nrf2 and phase II antioxidant enzymes in neuroprotection. Prog Neurobiol 2013;100:30-47. https://doi.org/10.1016/j.pneurobio.2012.09.003
  18. Mao J, Yi M, Wang R, Huang Y, Chen M. Protective effects of costunolide against D-galactosamine and lipopolysaccharide-induced acute liver injury in mice. Front Pharmacol 2018;9:1469. https://doi.org/10.3389/fphar.2018.01469
  19. Aziz N, Kim MY, Cho JY. Anti-inflammatory effects of luteolin: a review of in vitro, in vivo, and in silico studies. J Ethnopharmacol 2018;225:342-58. https://doi.org/10.1016/j.jep.2018.05.019
  20. Jia Z, Nallasamy P, Liu D, Shah H, Li JZ, Chitrakar R, Si H, McCormick J, Zhu H, Zhen W, Li Y. Luteolin protects against vascular inflammation in mice and TNF-alpha-induced monocyte adhesion to endothelial cells via suppressing $I{\kappa}B{\alpha}/NF-{\kappa}B$ signaling pathway. J Nutr Biochem 2015;26:293-302. https://doi.org/10.1016/j.jnutbio.2014.11.008
  21. Park CM, Song YS. Luteolin and luteolin-7-O-glucoside inhibit lipopolysaccharide-induced inflammatory responses through modulation of $NF-{\kappa}B$/AP-1/PI3K-Akt signaling cascades in RAW 264.7 cells. Nutr Res Pract 2013;7:423-9. https://doi.org/10.4162/nrp.2013.7.6.423
  22. Song YS, Park CM. Luteolin and luteolin-7-O-glucoside strengthen antioxidative potential through the modulation of Nrf2/MAPK mediated HO-1 signaling cascade in RAW 264.7 cells. Food Chem Toxicol 2014;65:70-5. https://doi.org/10.1016/j.fct.2013.12.017
  23. Lee WC, Jung HA, Choi JS, Kim YS, Lee SM. Protective effects of luteolin against apoptotic liver damage induced by D-galactosamine/lipopolysaccharide in mice. J Nat Prod 2011;74:1916-21. https://doi.org/10.1021/np2003935
  24. Hossen MJ, Yang WS, Kim D, Aravinthan A, Kim JH, Cho JY. Thymoquinone: an IRAK1 inhibitor with in vivo and in vitro anti-inflammatory activities. Sci Rep 2017;7:42995. https://doi.org/10.1038/srep42995
  25. Wu YH, Hu SQ, Liu J, Cao HC, Xu W, Li YJ, Li LJ. Nature and mechanisms of hepatocyte apoptosis induced by D-galactosamine/lipopolysaccharide challenge in mice. Int J Mol Med 2014;33:1498-506. https://doi.org/10.3892/ijmm.2014.1730
  26. Shanmugam S, Thangaraj P, Lima BD, Chandran R, de Souza Araujo AA, Narain N, Serafini MR, Junior LJ. Effects of luteolin and quercetin 3-${\beta}$-d-glucoside identified from Passiflora subpeltata leaves against acetaminophen induced hepatotoxicity in rats. Biomed Pharmacother 2016;83:1278-85. https://doi.org/10.1016/j.biopha.2016.08.044
  27. Jiang W, Sun R, Wei H, Tian Z. Toll-like receptor 3 ligand attenuates LPS-induced liver injury by down-regulation of toll-like receptor 4 expression on macrophages. Proc Natl Acad Sci U S A 2005;102:17077-82. https://doi.org/10.1073/pnas.0504570102
  28. Nowak M, Gaines GC, Rosenberg J, Minter R, Bahjat FR, Rectenwald J, MacKay SL, Edwards CK 3rd, Moldawer LL. LPS-induced liver injury in D-galactosamine-sensitized mice requires secreted $TNF-{\alpha}$ and the TNF-p55 receptor. Am J Physiol Regul Integr Comp Physiol 2000;278:R1202-9. https://doi.org/10.1152/ajpregu.2000.278.5.R1202
  29. Hossen MJ, Kim MY, Kim JH, Cho JY. AP-1-targeted inhibition of macrophage function and lipopolysaccharide/D-galactosamineinduced hepatitis by Phyllanthus acidus methanolic extract. Am J Chin Med 2015;43:1137-58. https://doi.org/10.1142/S0192415X15500652
  30. Dejager L, Libert C. Tumor necrosis factor alpha mediates the lethal hepatotoxic effects of poly(I:C) in D-galactosamine-sensitized mice. Cytokine 2008;42:55-61. https://doi.org/10.1016/j.cyto.2008.01.014
  31. Kim YW, West XZ, Byzova TV. Inflammation and oxidative stress in angiogenesis and vascular disease. J Mol Med (Berl) 2013;91:323-8. https://doi.org/10.1007/s00109-013-1007-3
  32. Lee JP, Li YC, Chen HY, Lin RH, Huang SS, Chen HL, Kuan PC, Liao MF, Chen CJ, Kuan YH. Protective effects of luteolin against lipopolysaccharide-induced acute lung injury involves inhibition of MEK/ERK and PI3K/Akt pathways in neutrophils. Acta Pharmacol Sin 2010;31:831-8. https://doi.org/10.1038/aps.2010.62
  33. Park CM, Jin KS, Cho CW, Lee YW, Huh GH, Cha YS, Song YS. Luteolin inhibits inflammatory responses by down-regulating the JNK- $NF{\kappa}B$ and AP-1 pathways in $TNF-{\alpha}$ activated HepG2 cells. Food Sci Biotechnol 2012;21:279-83. https://doi.org/10.1007/s10068-012-0037-x
  34. Shimoi K, Okada H, Furugori M, Goda T, Takase S, Suzuki M, Hara Y, Yamamoto H, Kinae N. Intestinal absorption of luteolin and luteolin 7-O-beta-glucoside in rats and humans. FEBS Lett 1998;438:220-4. https://doi.org/10.1016/S0014-5793(98)01304-0
  35. Murota K, Shimizu S, Miyamoto S, Izumi T, Obata A, Kikuchi M, Terao J. Unique uptake and transport of isoflavone aglycones by human intestinal caco-2 cells: comparison of isoflavonoids and flavonoids. J Nutr 2002;132:1956-61. https://doi.org/10.1093/jn/132.7.1956
  36. Hollman PC, Katan MB. Health effects and bioavailability of dietary flavonols. Free Radic Res 1999;31 Suppl:S75-80. https://doi.org/10.1080/10715769900301351
  37. Ross JA, Kasum CM. Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu Rev Nutr 2002;22:19-34. https://doi.org/10.1146/annurev.nutr.22.111401.144957

Cited by

  1. Luteolin-7-O-Glucoside Inhibits Oral Cancer Cell Migration and Invasion by Regulating Matrix Metalloproteinase-2 Expression and Extracellular Signal-Regulated Kinase Pathway vol.10, pp.4, 2020, https://doi.org/10.3390/biom10040502
  2. Paving Luteolin Therapeutic Potentialities and Agro-Food-Pharma Applications: Emphasis on In Vivo Pharmacological Effects and Bioavailability Traits vol.2021, 2019, https://doi.org/10.1155/2021/1987588
  3. Protective Effect of Luteolin on D-Galactosamine (D-Gal)/Lipopolysaccharide (LPS) Induced Hepatic Injury by in Mice vol.2021, 2021, https://doi.org/10.1155/2021/2252705
  4. Network Pharmacology-Based Identification of Potential Targets of Lonicerae japonicae Flos Acting on Anti-Inflammatory Effects vol.2021, 2019, https://doi.org/10.1155/2021/5507003
  5. Luteolin Alleviates Methamphetamine-Induced Hepatotoxicity by Suppressing the p53 Pathway-Mediated Apoptosis, Autophagy, and Inflammation in Rats vol.12, 2021, https://doi.org/10.3389/fphar.2021.641917
  6. Beyond the Liver: Liver-Eye Communication in Clinical and Experimental Aspects vol.8, 2019, https://doi.org/10.3389/fmolb.2021.823277
  7. Polyphenols as anticancer agents: Toxicological concern to healthy cells vol.35, pp.11, 2019, https://doi.org/10.1002/ptr.7216