Hepatotoxicity with High-Dose Green Tea Extract: Effect of <i>Catechol-O-Methyltransferase and Uridine 5’-Diphospho-glucuronosyltransferase 1A4</i> Genotypes

The predominant catechin in green tea, epigallocatechin gallate (EGCG), may be hepatotoxic in high doses. Our objective was to investigate the influence of <i>catechol-O-methyltransferase</i> (<i>COMT</i>) and <i>uridine 5’-diphospho-glucuronosyltransferase 1A4</i> (<i>UGT1A4</i>) genotypes on changes in liver injury biomarkers in response to long-term, high-dose green tea extract (GTE) supplementation among postmenopausal women. A secondary analysis was conducted using data from the Minnesota Green Tea Trial (<i>N</i> = 1,075), in which participants were randomized to consume high-dose GTE (843 mg/day EGCG) or placebo capsules for 12 months. Analysis of covariance adjusting for potential confounders was performed to examine changes in aspartate aminotransferase (AST), alanine aminotransferase (ALT), AST: ALT ratio, and alkaline phosphatase from baseline to months 3, 6, 9, and 12 across <i>COMT</i> and <i>UGT1A4</i> genotypes. Mean age and BMI within the GTE group (<i>n</i> = 400) were 59.8 yrs and 25.1 kg/m², respectively, and 98% of subjects were white. From baseline to month 3, mean AST: ALT ratio change was +1.0% in the <i>COMT</i> (rs4680) <i>A/G</i> genotype versus −4.8% in the <i>A/A</i> genotype (<i>p</i> = 0.03). From baseline to months 6 and 9, respectively, mean ALT change was +78.1% and +82.1% in the <i>UGT1A4</i> (rs6755571) <i>A/C</i> genotype versus +28.0% and +30.1% in the <i>C/C</i> genotype (<i>p</i> &lt; 0.001 and <i>p</i> = 0.004, respectively). The <i>UGT1A4</i> (rs6755571) <i>A/C</i> genotype may be an important risk factor for clinically-relevant serum transaminase elevations with 6-9 months of high-dose GTE supplementation among postmenopausal women. Understanding the genetic underpinnings of GTE-related hepatotoxicity may allow for a genetically-informed paradigm for therapeutic use of GTE.