Regulation of Nrf2 Mediated Phase II Enzymes by Luteolin in human Hepatocyte

  • Park, Chung Mu (Department of Clinical Laboratory Science, Dong-Eui University)
  • Received : 2014.02.07
  • Accepted : 2014.04.16
  • Published : 2014.06.30

Abstract

This study attempted to confirm the antioxidative potential of luteolin against tert-butyl hydroperoxide (t-BHP) induced oxidative damage and to investigate its molecular mechanism related to glutathione (GSH)-dependent enzymes in HepG2 cells. Treatment with luteolin resulted in attenuation of t-BHP induced generation of reactive oxygen species (ROS) and oxidative stress-mediated cell death. In addition, accelerated expression of GSH-dependent antioxidative enzymes, glutathione peroxidase (GPx) and glutathione reductase (GR), and heme oxygenase (HO)-1, as well as strengthened GSH content was induced by treatment with luteolin, which was in accordance with increased nuclear translocation of nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), a transcription factor for phase 2 enzymes, in a dose-dependent manner. These results suggest that the cytoprotective potential of luteolin against oxidative damage can be attributed to fortified GSH-mediated antioxidative pathway and HO-1 expression through regulation of Nrf2 in HepG2 cells.

Keywords

References

  1. Ashokkumar P, Sudhandiran G. Protective role of luteolin on the status of lipid peroxidation and antioxidant defense against azoxymethane-induced experimental colon carcinogenesis. Biomed Pharmacother. 2008. 62: 590-597. https://doi.org/10.1016/j.biopha.2008.06.031
  2. Baranano DE, Rao M, Ferris CD, Snyder SH. Biliverdin reductase: a major physiologic cytoprotectant. Proc Natl Acad Sci U S A. 2002. 99: 16093-16098. https://doi.org/10.1073/pnas.252626999
  3. Farombi EO, Surh YJ. Heme oxygenase-1 as a potential therapeutic target for hepatoprotection. J Biochem Mol Biol. 2006. 39: 479-491. https://doi.org/10.5483/BMBRep.2006.39.5.479
  4. Harvey CJ, Thimmulappa RK, Singh A, Blake DJ, Ling G, Wakabayashi N, Fujii J, Myers A, Biswal S. Nrf2-regulated glutathione recycling independent of biosynthesis is critical for cell survival during oxidative stress. Free Radic Biol Med. 2009. 46: 443-453. https://doi.org/10.1016/j.freeradbiomed.2008.10.040
  5. Hwang YP, Choi JH, Choi JM, Chung YC, Jeong HG. Protective mechanisms of anthocyanins from purple sweet potato against tert-butyl hydroperoxide-induced hepatotoxicity. Food Chem Toxicol. 2011. 49: 2081-2089. https://doi.org/10.1016/j.fct.2011.05.021
  6. Jaeschke H, Gores GJ, Cederbaum AI, Hinson JA, Pessayre D, Lemasters JJ. Mechanisms of hepatotoxicity. Toxicol Sci. 2002. 65: 166-176. https://doi.org/10.1093/toxsci/65.2.166
  7. Jang S, Kelley KW, Johnson RW. Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1. Proc Natl Acad Sci U S A. 2008. 105: 7534-7539. https://doi.org/10.1073/pnas.0802865105
  8. Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol. 2007. 47: 89-116. https://doi.org/10.1146/annurev.pharmtox.46.120604.141046
  9. Knasmuller S, Mersch-Sundermann V, Kevekordes S, Darroudi F, Huber WW, Hoelzl C, Bichler J, Majer BJ. Use of humanderived liver cell lines for the detection of environmental and dietary genotoxicants; current state of knowledge. Toxicology. 2004. 198: 315-328. https://doi.org/10.1016/j.tox.2004.02.008
  10. Krithika R, Mohankumar R, Verma RJ, Shrivastav PS, Mohamad IL, Gunasekaran P, Narasimhan S. Isolation, characterization and antioxidative effect of phyllanthin against CCl4-induced toxicity in HepG2 cell line. Chem Biol Interact. 2009. 181: 351-358. https://doi.org/10.1016/j.cbi.2009.06.014
  11. Lee JS, Surh YJ. Nrf2 as a novel molecular target for chemoprevention. Cancer Lett. 2005. 224: 171-184. https://doi.org/10.1016/j.canlet.2004.09.042
  12. Lima CF, Fernandes-Ferreira M, Pereira-Wilson C. Phenolic compounds protect HepG2 cells from oxidative damage: relevance of glutathione levels. Life Sci. 2006. 79: 2056-2068. https://doi.org/10.1016/j.lfs.2006.06.042
  13. Mancuso C, Barone E, Guido P, Miceli F, Di Domenico F, Perluigi M, Santangelo R, Preziosi P. Inhibition of lipid peroxidation and protein oxidation by endogenous and exogenous antioxidants in rat brain microsomes in vitro. Neurosci Lett. 2012. 518: 101-105. https://doi.org/10.1016/j.neulet.2012.04.062
  14. Masella R, Di Benedetto R, Vari R, Filesi C, Giovannini C. Novel mechanisms of natural antioxidant compounds in biological systems: involvement of glutathione and glutathione-related enzymes. J Nutr Biochem. 2005. 16: 577-586. https://doi.org/10.1016/j.jnutbio.2005.05.013
  15. Mersch-Sundermann V, Knasmuller S, Wu XJ, Darroudi F, Kassie F. Use of a human-derived liver cell line for the detection of cytoprotective, antigenotoxic and cogenotoxic agents. Toxicology. 2004. 198: 329-340. https://doi.org/10.1016/j.tox.2004.02.009
  16. Nakagawa Y, Suzuki T, Ishii H, Ogata A, Nakae D. Mitochondrial dysfunction and biotransformation of $\beta$-carboline alkaloids, harmine and harmaline, on isolated rat hepatocytes. Chem Biol Interact. 2010. 188: 393-403. https://doi.org/10.1016/j.cbi.2010.09.004
  17. Park CM, Jin KS, Lee YW, Song YS. Luteolin and chicoric acid synergistically inhibited inflammatory responses via inactivation of PI3K-Akt pathway and impairment of NFkappaB translocation in LPS stimulated RAW 264.7 cells. Eur J Pharmacol. 2011. 660: 454-459. https://doi.org/10.1016/j.ejphar.2011.04.007
  18. Rebrin I, Forster MJ, Sohal RS. Association between life-span extension by caloric restriction and thiol redox state in two different strains of mice. Free Radic Biol Med. 2011. 51: 225-233. https://doi.org/10.1016/j.freeradbiomed.2011.04.006
  19. 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. 2013. 65C: 70-75.
  20. Thannickal VJ, Fanburg BL. Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol. 2000. 279: L1005-1028.
  21. Tietze F. Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues. Anal Biochem. 1969. 27: 502-522. https://doi.org/10.1016/0003-2697(69)90064-5
  22. Vitaglione P, Morisco F, Caporaso N, Fogliano V. Dietary antioxidant compounds and liver health. Crit Rev Food Sci Nutr. 2004. 44: 575-586.