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http://dx.doi.org/10.5808/GI.2009.7.2.097

High-concentration Epigallocatechin Gallate Treatment Causes Endoplasmic Reticulum Stress-mediated Cell Death in HepG2 Cells  

Ahn, Joon-Ik (Molecular Pharmacology Division, Pharmacological Research Department, National Institute of Toxicological Research)
Jeong, Kyoung-Ji (Molecular Pharmacology Division, Pharmacological Research Department, National Institute of Toxicological Research)
Ko, Moon-Jeong (Molecular Pharmacology Division, Pharmacological Research Department, National Institute of Toxicological Research)
Shin, Hee-Jung (Molecular Pharmacology Division, Pharmacological Research Department, National Institute of Toxicological Research)
Chung, Hye-Joo (Molecular Pharmacology Division, Pharmacological Research Department, National Institute of Toxicological Research)
Jeong, Ho-Sang (Molecular Pharmacology Division, Pharmacological Research Department, National Institute of Toxicological Research)
Publication Information
Genomics & Informatics / v.7, no.2, 2009 , pp. 97-106 More about this Journal
Abstract
Epigallocatechin gallate (EGCG), a well-known antioxidant molecule, has been reported to cause hepatotoxicity when used in excess. However, the mechanism underlying EGCG-induced hepatotoxicity is still unclear. To better understand the mode of action of EGCG-induced hepatotoxicity, we examined the effect of EGCG on human hepatic gene expression in HepG2 cells using microarrays. Analyses of microarray data revealed more than 1300 differentially expressed genes with a variety of biological processes. Upregulated genes showed a primary involvement with protein-related biological processes, such as protein synthesis, protein modification, and protein trafficking, while downregulated genes demonstrated a strong association with lipid transport. Genes involved in cellular stress responses were highly upregulated by EGCG treatment, in particular genes involved in endoplasmic reticulum (ER) stress, such as GADD153, GADD34, and ATF3. In addition, changes in genes responsible for cholesterol synthesis and lipid transport were also observed, which explains the high accumulation of EGCG-induced lipids. We also identified other regulatory genes that might aid in clarifying the molecular mechanism underlying EGCG-induced hepatotoxicity.
Keywords
endoplasmic reticulum stress; epigallocatechin gallate; hepatotoxicity; microarray;
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1 Burton, T.R., and Gibson, S.B. (2009). The role of Bcl-2 family member BNIP3 in cell death and disease: NIPping at the heels of cell death. Cell Death Differ. 16, 515-523   DOI   ScienceOn
2 Ermakova, S.P., Kang, B.S., Choi, B.Y., Choi, H.S., Schuster, T.F., Ma, W.Y., Bode, A.M., and Dong, Z. (2006). (-)-Epigallocatechin gallate overcomes resistance to etoposide-induced cell death by targeting the molecular chaperone glucose-regulated protein 78. Cancer Res. 66, 9260-9269   DOI   ScienceOn
3 Ji, C., and Kaplowitz, N. (2006). ER stress: can the liver cope? J. Hepatol. 45, 321-333   DOI   ScienceOn
4 Lai, E., Teodoro, T., and Volchuk, A. (2007). Endoplasmic reticulum stress: signaling the unfolded protein response. Physiology 22, 193-201   DOI   ScienceOn
5 Sieber, M., Hoffmann, D., Adler, M., Vaidya, V.S., Clement, M., Bonventre, J.V., Zidek, N., Rached, E., Amberg, A., Callanan, J.J., Dekant, W., and Mally, A. (2009). Comparative analysis of novel noninvasive renal biomarkers and metabonomic changes in a rat model of gentamicin nephrotoxicity. Toxicol. Sci. 109, 336-349   DOI   ScienceOn
6 Vittal, R., Selvanayagam, Z.E., Sun, Y., Hong, J., Liu, F., Chin, K.V., and Yang, C.S. (2004). Gene expression changes induced by green tea polyphenol (-)-epigallocatechin-3-gallate in human bronchial epithelial 21BES cells analyzed by DNA microarray. Mol. Cancer Ther. 3, 1091-1099   PUBMED
7 Galati, G., Lin, A., Sultan, A.M., and O'Brien, P.J. (2006). Cellular and in vivo hepatotoxicity caused by green tea phenolic acids and catechins. Free Radic. Biol. Med. 40, 570-580   DOI   ScienceOn
8 Wang, X.Z., Lawson, B., Brewer, J.W., Zinszner, H., Sanjay, A., Mi, L.J., Boorstein, R., Kreibich, G., Hendershot, L.M., and Ron, D. (1996). Signals from the stressed endoplasmic reticulum induce C/EBP-homologous protein (CHOP/GADD153). Mol. Cell. Biol. 16, 4273-4280   DOI   PUBMED
9 Jiang, H.Y., Wek, S.A., McGrath, B.C., Lu, D., Hai, T., Harding, H.P., Wang, X., Ron, D., Cavener, D.R., and Wek, R.C. (2004). Activating transcription factor 3 is integral to the eukaryotic initiation factor 2 kinase stress response. Mol. Cell. Biol. 24, 1365-1377   DOI   ScienceOn
10 Goodin, M.G., and Rosengren, R.J. (2003). Epigallocatechin gallate modulates CYP450 isoforms in the female Swiss-Webster mouse. Toxicol. Sci. 76, 262-270   DOI   ScienceOn
11 Dodo, K., Minato, T., Noguchi-Yachide, T., Suganuma, M., and Hashimoto, Y. (2008). Antiproliferative and apoptosis-inducing activities of alkyl gallate and gallamide derivatives related to (-)-epigallocatechin gallate. Bioorg. Med. Chem. 16, 7975-7982   DOI   ScienceOn
12 Nichols, K.D., and Kirby, G.M. (2008). Microarray analysis of hepatic gene expression in pyrazole-mediated hepatotoxicity: identification of potential stimuli of Cyp2a5 induction. Biochem. Pharmacol. 75, 538-551   DOI   ScienceOn
13 Shannan, B., Seifert, M., Leskov, K., Willis, J., Boothman, D., Tilgen, W., and Reichrath, J. (2006). Challenge and promise: roles for clusterin in pathogenesis, progression and therapy of cancer. Cell Death Differ. 13, 12-19   DOI   ScienceOn
14 Kuzuhara, T., Sei, Y., Yamaguchi, K., Suganuma, M., and Fujiki, H. (2006). DNA and RNA as new binding targets of green tea catechins. J. Biol. Chem. 281, 17446-17456   DOI   ScienceOn
15 Pacheco, C.D., and Lieberman, A.P. (2008). The pathogenesis of Niemann-Pick type C disease: a role for autophagy? Expert Rev. Mol. Med. 10, e26   DOI   PUBMED   ScienceOn
16 Komissarova, E.V., Li, P., Uddin, A.N., Chen, X., Nadas, A., and Rossman, T.G. (2008). Gene expression levels in normal human lymphoblasts with variable sensitivities to arsenite: identification of GGT1 and NFKBIE expression levels as possible biomarkers of susceptibility. Toxicol. Appl. Pharmacol. 226, 199-205   DOI   ScienceOn
17 Outinen, P.A., Sood, S.K., Pfeifer, S.I., Pamidi, S., Podor, T.J., Li, J., Weitz, J.I., and Austin, R.C. (1999). Homocysteine-induced endoplasmic reticulum stress and growth arrest leads to specific changes in gene expression in human vascular endothelial cells. Blood 94, 959-967   PUBMED
18 Schmidt, M., Schmitz, H.J., Baumgart, A., Guedon, D., Netsch, M.I., Kreuter, M.H., Schmidlin, C.B., and Schrenk, D. (2005). Toxicity of green tea extracts and their constituents in rat hepatocytes in primary culture. Food Chem. Toxicol. 43, 307-314.   DOI   ScienceOn
19 Lambert, J.D., Sang, S., and Yang, C.S. (2007). Possible controversy over dietary polyphenols: benefits vs risks. Chem. Res. Toxicol. 20, 583-585   DOI   ScienceOn
20 Marciniak, S.J., Yun, C.Y., Oyadomari, S., Novoa, I., Zhang, Y., Jungreis, R., Nagata, K., Harding, H.P., and Ron, D. (2004). CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev. 18, 3066-3077   DOI   ScienceOn
21 Isbrucker R.A., Edwards, J.A., Wolz, E., Davidovich, A., and Bausch, J. (2006). Safety studies on epigallocatechin gallate (EGCG) preparations. Part 3: teratogenicity and reproductive toxicity studies in rats. Food Chem. Toxicol. 44, 651-661   DOI   ScienceOn