Epigallocatechin gallate induces a hepatospecific decrease in the CYP3A expression level by altering intestinal flora

Area of Science:

• Pharmacology
• Hepatology
• Microbiome Research

Background:

• High-dose green tea polyphenol (GP) intake reduces hepatic drug-metabolizing enzyme cytochrome P450 3A (CYP3A) expression and activity.
• Epigallocatechin gallate (EGCG) is the primary active component of GP.

Purpose of the Study:

• To investigate if EGCG is responsible for the GP-induced decrease in hepatic CYP3A expression.
• To elucidate the underlying mechanism involving intestinal bacteria, lithocholic acid (LCA), and pregnane X receptor (PXR) signaling.

Main Methods:

• Mice were administered a diet containing 1.5% EGCG.
• Hepatic CYP3A expression, PXR nuclear translocation, fecal LCA concentration, and intestinal Clostridium spp. levels were measured.

Main Results:

• EGCG administration led to a significant decrease in hepatic CYP3A expression starting on day two.
• Reduced nuclear translocation of PXR was observed in the EGCG-treated group.
• Fecal LCA levels and the abundance of intestinal Clostridium spp. were significantly decreased by EGCG treatment.

Conclusions:

• EGCG is the causative agent for the hepatospecific decrease in CYP3A expression induced by high-dose GP intake.
• EGCG, acting within the intestine, reduces LCA-producing bacteria, leading to lower hepatic LCA levels.
• This reduction in LCA diminishes PXR nuclear translocation, consequently decreasing CYP3A expression.