In VitroToxicity of Epigallocatechin Gallate in Rat Liver Mitochondria and Hepatocytes

Abstract

Epigallocatechin-3-gallate (EGCG) is the main compound of green tea with well-described antioxidant, anti-inflammatory, and tumor-suppressing properties. However, EGCG at high doses was reported to cause liver injury. In this study, we evaluated the effect of EGCG on primary culture of rat hepatocytes and on rat liver mitochondria in permeabilized hepatocytes. The 24-hour incubation with EGCG in concentrations of 10 μmol/L and higher led to signs of cellular injury and to a decrease in hepatocyte functions. The effect of EGCG on the formation of reactive oxygen species (ROS) was biphasic. While low doses of EGCG decreased ROS production, the highest tested dose induced a significant increase in ROS formation. Furthermore, we observed a decline in mitochondrial membrane potential in cells exposed to EGCG when compared to control cells. In permeabilized hepatocytes, EGCG caused damage of the outer mitochondrial membrane and an uncoupling of oxidative phosphorylation. EGCG in concentrations lower than 10 μmol/L was recognized as safe for hepatocytes in vitro.

Effects of Epigallocatechin Gallate on Tert-Butyl Hydroperoxide-Induced Mitochondrial Dysfunction in Rat Liver Mitochondria and Hepatocytes

“…Second, EGCG is able to activate the stress-responding transcription factor Nrf2 [2, 7]. Third, EGCG can have uncoupling effects, [8] and mild uncoupling is able to attenuate production of mitochondrial reactive oxygen species (ROS) [9, 10]. …”

“…In contrast, high doses of EGCG were found to be hepatotoxic [8, 11–13]. Similarly, EGCG displayed toxicity on mitochondria in permeabilized hepatocytes [8] and on mitochondria in a hepatoma cell line [14].…”

Therapeutic effects of EGCG: a patent review

“…EGCG in a Expert Opinion on Therapeutic Patents concentration of 10 μmol/L displayed in vitro toxicity to primary rat hepatocytes and at high doses led to the damage to the outer mitochondrial membrane [61].…”

“…Certain limitations related to efficacy, bioavailability and high dose toxicity need to be addressed before it can be used as approved therapeutic moiety [61]. To improve the stability of the native compound, EGCG derivatives and alterations have been carried out and protected by patents.…”

Inferring the Efficacy and Safety of Green Tea Water Extractafter Prolonged Consumption Against Epirubicin-Induced Hepatotoxicity in Mice: A Histological Study.

“…This protection property is attributed to green tea catechins (GTC), the main metabolites in GT (Quiles et al, 2002).Theypossess outstanding antioxidant and free radical scavenging properties (Scott et al, 1993;Toda, 2011) and include (-)-epigallocatechin-3-gallate (EGCG) which composes more than 50% of the mass of all GTCs (Nagle et al, 2006). Furthermore, EGCG has been implicated with chemoprevention and anticancer properties (Azam et al, 2004) alas, high dosage of EGCG was reported to cause toxicity of rat liver mitochondria and hepatocytes (Kucera et al, 2015) as well as severe hepatic necrosis due to increased oxidative stress and lipid peroxidation in mice ).…”