Hepatotoxicity of high oral dose (-)-epigallocatechin-3-gallate in mice.
The tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) has been studied for chronic disease preventive effects, and is marketed as part of many dietary supplements. However, case-reports have associated the use of green tea-based supplements with liver toxicity. We studied the hepatotoxic effects of high dose EGCG in male CF-1 mice. A single dose of EGCG (1500 mg/kg, i.g.) increased plasma alanine aminotransferase (ALT) by 138-fold and reduced survival by 85%. Once-daily dosing with EGCG increased hepatotoxic response. Plasma ALT levels were increased 184-fold following two once-daily doses of 750 mg/kg, i.g. EGCG. Moderate to severe hepatic necrosis was observed following treatment with EGCG. EGCG hepatotoxicity was associated with oxidative stress including increased hepatic lipid peroxidation (5-fold increase), plasma 8-isoprostane (9.5-fold increase) and increased hepatic metallothionein and gamma-histone 2AX protein expression. EGCG also increased plasma interleukin-6 and monocyte chemoattractant protein-1. Our results indicate that higher bolus doses of EGCG are hepatotoxic to mice. Further studies on the dose-dependent hepatotoxic effects of EGCG and the underlying mechanisms are important given the increasing use of green tea dietary supplements, which may deliver much higher plasma and tissue concentrations of EGCG than tea beverages.
Lambert
Joshua D
JD
Department of Food Science, The Pennsylvania State University, 332 Food Science Building, University Park, PA 16802, USA. jdl134@psu.edu
Kennett
Mary J
MJ
Sang
Shengmin
S
Reuhl
Kenneth R
KR
Ju
Jihyeung
J
Yang
Chung S
CS
D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000493:pharmacokinetics / Q000633:toxicity*; D015415:Biomarkers; D002392:Catechin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000652:urine; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007150:Immunohistochemistry; D015227:Lipid Peroxidation / Q000187:drug effects; D008111:Liver Function Tests; D008297:Male; D008668:Metallothionein / Q000378:metabolism; D051379:Mice; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D021241:Spectrometry, Mass, Electrospray Ionization; D016019:Survival Analysis
D000447:Aldehydes; D000975:Antioxidants; D015415:Biomarkers; D016207:Cytokines; D016877:Oxidants; D002392:Catechin; D008668:Metallothionein; C045651:epigallocatechin gallate; C027576:4-hydroxy-2-nonenal; D003545:Cysteine