title: Green tea polyphenol (-)-epigallocatechin-3-gallate triggered hepatotoxicity in mice: responses of major antioxidant enzymes and the Nrf2 rescue pathway.
abstract: (-)-Epigallocatechin-3-gallate (EGCG), a constituent of green tea, has been suggested to have numerous health-promoting effects. On the other hand, high-dose EGCG is able to evoke hepatotoxicity. In the present study, we elucidated the responses of hepatic major antioxidant enzymes and nuclear factor erythroid 2-related factor 2 (Nrf2) rescue pathway to high-dose levels of EGCG in Kunming mice. At a non-lethal toxic dose (75mg/kg, i.p.), repeated EGCG treatments markedly decreased the levels of superoxide dismutase, catalase, and glutathione peroxidase. As a rescue response, the nuclear distribution of Nrf2 was significantly increased; a battery of Nrf2-target genes, including heme oxygenase 1 (HO1), NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferase (GST), and those involved in glutathione and thioredoxin systems, were all up-regulated. At the maximum tolerated dose (45mg/kg, i.p.), repeated EGCG treatments did not disturb the major antioxidant defense. Among the above-mentioned genes, only HO1, NQO1, and GST genes were significantly but modestly up-regulated, suggesting a comprehensive and extensive activation of Nrf2-target genes principally occurs at toxic levels of EGCG. At a lethal dose (200mg/kg, i.p.), a single EGCG treatment dramatically decreased not only the major antioxidant defense but also the Nrf2-target genes, demonstrating that toxic levels of EGCG are able to cause a biphasic response of Nrf2. Overall, the mechanism of EGCG-triggered hepatotoxicity involves suppression of major antioxidant enzymes, and the Nrf2 rescue pathway plays a vital role for counteracting EGCG toxicity.
authors.affiliation: Key Laboratory of Tea Biochemistry & Biotechnology, School of Tea & Food Science, Anhui Agricultural University, Hefei, Anhui 230036, PR China.
authors.forename: Dongxu
authors.initials: D
authors.lastname: Wang
authors.affiliation: Key Laboratory of Tea Biochemistry & Biotechnology, School of Tea & Food Science, Anhui Agricultural University, Hefei, Anhui 230036, PR China.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Tea Biochemistry & Biotechnology, School of Tea & Food Science, Anhui Agricultural University, Hefei, Anhui 230036, PR China.
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Wan
authors.affiliation: Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Chung S
authors.initials: CS
authors.lastname: Yang
authors.affiliation: Key Laboratory of Tea Biochemistry & Biotechnology, School of Tea & Food Science, Anhui Agricultural University, Hefei, Anhui 230036, PR China. Electronic address: zjs@ahau.edu.cn.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000447:Aldehydes / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002374:Catalase / Q000378:metabolism; D002392:Catechin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism*; D005979:Glutathione Peroxidase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D013662:Tea / Q000737:chemistry; D054481:Thioredoxin Reductase 1 / Q000235:genetics / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism
chemical_list: D000447:Aldehydes; D006657:Histones; D015850:Interleukin-6; D051267:NF-E2-Related Factor 2; D013662:Tea; C515559:Txn1 protein, mouse; C475961:gamma-H2AX protein, mouse; D013879:Thioredoxins; D002392:Catechin; C045651:epigallocatechin gallate; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D054481:Thioredoxin Reductase 1; C516125:Txnrd1 protein, mouse; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C027576:4-hydroxy-2-nonenal
keywords: (−)-Epigallocatechin-3-gallate; Antioxidant enzymes; Dose response; Hepatotoxicity; Nrf2; Selenoprotein