Seminar - Effect of Dose Level and Obesity on the Metabolism of Green Tea Polyphenol (-)-epigallocatechin-3-gallate in Mice

Green tea (Camellia sinensis, Theaceae) is one of the most widely consumed beverages worldwide and has a long history of safe consumption. Epigallocatechin-3-gallate (EGCG), the most abundant catechin in green tea, has been reported to have various health benefits, including antioxidant, anti-inflammatory, and obesity-preventive properties. With the rising global prevalence of obesity, green tea-based dietary supplements, which can deliver much higher doses of EGCG than traditional tea infusions, have gained increasing popularity. However, emerging evidence has raised concerns about hepatotoxicity associated with high oral bolus doses of EGCG. Previous studies suggest that the formation of bioactivated or incompletely detoxified metabolites at high doses may contribute to EGCG-induced toxicity, yet EGCG metabolism at toxic doses, especially in susceptible populations, remains understudied. This dissertation aims to address this gap by investigating how EGCG metabolism is influenced by dose and obesity, and how these factors modulate the expression of the main EGCG-metabolizing enzymes. In study 1, we characterized dose-dependent EGCG metabolism in lean mice after a single intragastric administration of EGCG at non-toxic (100 mg/kg) or toxic (750 mg/kg) doses. The results suggested that glucuronidation and sulfation may be more important at higher doses compared to methylation, and that EGCG oxidation products increase at toxic doses. Study 2 examined how high-fat diet-induced obesity alters dose-dependent EGCG metabolism. The results indicated that obesity causes a shift in the dominant biotransformation pathway of EGCG and enhances the formation of oxidative metabolites at higher EGCG doses. Obese mice exhibited reduced mRNA expression of key enzymes involved in glucuronidation and sulfation compared to lean mice, while EGCG at the toxic dose downregulated enzymes involved in methylation and sulfation. However, no corresponding differences in protein levels were observed. Study 3 explored time-dependent changes in hepatic expression of EGCG-metabolizing enzymes in lean and obese mice following a single intragastric dose of EGCG. A significant diet × dose × time interaction was observed at the mRNA level. However, mRNA changes did not consistently translate into protein-level changes, suggesting potential post-translational regulation. Taken together, this dissertation demonstrated that EGCG metabolism is modulated by both dose and body condition. The findings suggest that enhanced formation of oxidation metabolites may contribute to EGCG-induced hepatotoxicity at high doses, with obesity potentially increasing physiological susceptibility to adverse effects.

Join this virtual seminar on Zoom