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. 2010 Jan;48(1):409-16.
doi: 10.1016/j.fct.2009.10.030. Epub 2009 Oct 31.

Hepatotoxicity of high oral dose (-)-epigallocatechin-3-gallate in mice

Joshua D Lambert  1 , Mary J Kennett, Shengmin Sang, Kenneth R Reuhl, Jihyeung Ju, Chung S Yang
Affiliations

Hepatotoxicity of high oral dose (-)-epigallocatechin-3-gallate in mice

Joshua D Lambert et al. Food Chem Toxicol. 2010 Jan.

Abstract

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.

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Figures

Figure 1
Figure 1
Effect of oral EGCG on the survival of male CF-1 mice. Oral EGCG caused a time and dose-dependent decrease in survival when give as either a (a) single bolus dose (750 – 1500 mg/kg, i.g.) or as (b) multiple once-daily bolus doses(0 – 750 mg/kg, i.g.). N = 10 – 12 per group. formula image = p < 0.05 by χ2 test
Figure 2
Figure 2
Biochemical and histopathological analysis of EGCG-mediated hepatotoxicity in male, CF-1 mice. Plasma ALT levels were determined spectrophotometrically following (a) single dose (750 – 1500 mg/kg, i.g.) or (b) multiple once-daily dose (750 mg/kg, i.g.) treatment with EGCG. For mice treated with multiple once-daily doses of EGCG, the plasma was collected 24 h after the last dose. Each bar represents the mean of n = 3 – 8. Error bars represent the SEM. formula image = p < 0.05 vs other treatment groups and times by one-way ANOVA with Tukey's post-test. Histological analysis of EGCG hepatotoxicity was performed 24 and 48 h after a single dose of 1500 mg/kg, i.g. EGCG. White arrows indicate apoptotic bodies. Micrographs are shown at 100X and 400X magnification.
Figure 3
Figure 3
Induction of hepatocyte apoptosis in mice by treatment with high dose oral bolus EGCG. (a) Histopathological analysis revealed an increased number of apoptotic bodies in the livers of CF-1 mice after treatment with two once-daily doses of 750 mg/kg, i.g. EGCG. Bars represent the mean of n = 4 – 5. Error bars represent the SEM. formula image = p < 0.01 compared to control. (b) Western blot analysis of liver homogenate showed an increase in the levels of cleaved caspase 3 in EGCG-treated mice, but not in vehicle-treated controls.
Figure 4
Figure 4
EGCG-induced lipid peroxidation in male CF-1 mice. (a) Hepatic malonyldialdehyde and (b) plasma 8-isoprostane levels were increased in CF-1 mice after treatment with two once-daily doses of 750 mg/kg, i.g. EGCG. Bars represent the mean of n = 3 – 4. Error bars represent the SEM. formula image = p < 0.01 compared to control. (c) IHC analysis showed that treatment with a single dose of 1500 mg/kg, i.g. EGCG or two once-daily doses of 750 mg/kg, i.g. EGCG increased staining for 4-HNE. Micrographs are representative of control and EGCG-intoxicated mice, and are at 200X magnification.
Figure 5
Figure 5
EGCG-induced oxidative stress in male CF-1 mice. Hepatic metallothionein I/II protein levels in CF-1 mice were increased by a single dose of 1500 mg/kg, i.g. or two once-daily doses of 750 mg/kg, i.g. EGCG. Hepatic γ-H2AX protein levels in CF-1 mice were increased by two once-daily doses of 750 mg/kg, i.g.
Figure 6
Figure 6
Formation of EGCG-cysteine conjugates in vivo. (a) LC-ESI/MS analysis of the urine from CF-1 mice (pooled from n = 5) treated with 1500 mg/kg, i.g. EGCG revealed the presence of two EGCG cysteine metabolites. MS2 analysis revealed fragmentation patterns consistent with (b) EGCG-2’-cys and (c) EGCG-2”-cys. MS analysis was conducted in the negative mode and structural determination was based on comparison with authentic standards.
Figure 7
Figure 7
EGCG-induced hepatotoxicity is associated with increased plasma levels of IL-6 and MCP-1. CF-1 mice were sacrificed (a, b) 24 h after 2 once-daily doses of 750 mg/kg, i.g. EGCG or (c, d) 48 h after a single dose of EGCG (750 – 1500 mg/kg,i.g.). Each bar represents the mean of n = 4 – 8. Error bars represent SEM. formula image = p < 0.01 compared to the control by Student's t test. formula image = p < 0.05 vs all other treatment groups by one-way ANOVA with Tukey's post-test.
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