ABSTRACT
Green tea and (-)-epigallocatechin-3-gallate (EGCG) have been studied for their obesity-related health effects. Many green tea extract (GTE)-based dietary supplements are commercially-available. Although green tea beverage has a long history of safe use, a growing number of case-reports have linked GTE-based supplements to incidents of hepatotoxicity. Animal studies support the hepatotoxic potential of GTE and EGCG, but the mechanisms remain unclear. Here, we examined the hepatotoxic effects of EGCG in C57BL/6J mice and evaluated changes in hepatic antioxidant response and mitochondria structure and function. Intragastric dosing with EGCG (500 - 750 mg/kg) once daily for 3 d caused hepatic inflammation, necrosis, and hemorrhage. Hepatotoxicity was associated with increased oxidative stress and decreased superoxide dismutase and glutathione peroxidase levels. Real-time PCR and transmission electron microscopy showed decreased hepatic mitochondria copy number in EGCG-treated mice. The mRNA levels of marker genes of respiratory complex I and III, sirtuin 3, forkhead box O3a, and peroxisome-EGCG-treated mice. Sirtuin 3 protein levels were also decreased by EGCG. Our data indicate the mitochondria may be a target for EGCG, and that inhibition of mitochondria function/antioxidant response may be important for the hepatotoxicity of bolus EGCG.
Subject(s)
Catechin/analogs & derivatives , Chemical and Drug Induced Liver Injury/metabolism , Mitochondria, Liver/drug effects , Oxidative Stress/drug effects , Tea/chemistry , Animals , Antioxidants/metabolism , Biomarkers , Catechin/pharmacology , DNA Damage/drug effects , Electron Transport Chain Complex Proteins/genetics , Electron Transport Chain Complex Proteins/metabolism , Gene Expression Regulation/drug effects , Glutathione/metabolism , Lipid Peroxidation/drug effects , Liver/enzymology , Male , Mice , Mice, Inbred C57BL , Mitochondria, Liver/metabolismABSTRACT
Human case-studies have reported an association between green tea-based dietary supplements and hepatotoxicity. Studies have demonstrated the hepatotoxicity of high-dose oral bolus dosing with the tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) in mice and dogs. We examined the effect of pretreatment with dietary EGCG on the hepatotoxicity and bioavailability of acute oral bolus dosing with EGCG in CF-1 mice. EGCG (750 mg/kg, i.g., once daily for 3 days) increased plasma alanine aminotransferase by 80-fold, decreased both reduced (by 59%) and total (by 33%) hepatic glutathione, and increased hepatic levels of phosphorylated histone 2AX. Pretreatment with dietary EGCG (3.2 mg/g diet) for 2 weeks mitigated hepatotoxicity. Acute oral EGCG also decreased mRNA expression of glutathione reductase. Dietary pretreatment prevented these decreased and increased glutathione peroxidase (Gpx)2, Gpx3, Gpx5, and Gpx7 expression. We found that dietary EGCG reduced the plasma (57% reduction) and hepatic (71% reduction) EGCG exposure following oral bolus dosing compared to mice that were not pre-treated. Overall, it appears that EGCG can modulate its own bioavailability and that dietary treatment may reduce the toxic potential of acute high oral bolus doses of EGCG. These data may partly explain the observed variation in hepatotoxic response to green tea-containing dietary supplements.
