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

The predominant catechin in green tea, epigallocatechin gallate (EGCG), may be hepatotoxic in high doses. Our objective was to investigate the influence of catechol-O-methyltransferase (COMT) and uridine 5’-diphospho-glucuronosyltransferase 1A4 (UGT1A4) 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 (N = 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 COMT and UGT1A4 genotypes. Mean age and BMI within the GTE group (n = 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 COMT (rs4680) A/G genotype versus −4.8% in the A/A genotype (p = 0.03). From baseline to months 6 and 9, respectively, mean ALT change was +78.1% and +82.1% in the UGT1A4 (rs6755571) A/C genotype versus +28.0% and +30.1% in the C/C genotype (p < 0.001 and p = 0.004, respectively). The UGT1A4 (rs6755571) A/C 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.

绿茶中主要的儿茶素为表没食子儿茶素没食子酸酯（epigallocatechin gallate, EGCG），高剂量摄入时可能具有肝毒性。本研究旨在探讨儿茶酚-O-甲基转移酶（catechol-O-methyltransferase, COMT）与尿苷5'-二磷酸葡萄糖醛酸转移酶1A4（uridine 5’-diphospho-glucuronosyltransferase 1A4, UGT1A4）的基因型，对绝经后女性长期高剂量补充绿茶提取物（green tea extract, GTE）后肝损伤生物标志物变化的影响。本研究利用明尼苏达绿茶试验（Minnesota Green Tea Trial, N=1075）的数据进行二次分析，该试验将受试者随机分为两组，分别服用高剂量GTE（每日843mg EGCG）或安慰剂胶囊，干预时长为12个月。本研究采用协方差分析，校正潜在混杂因素后，考察了不同COMT及UGT1A4基因型受试者的天冬氨酸氨基转移酶（aspartate aminotransferase, AST）、丙氨酸氨基转移酶（alanine aminotransferase, ALT）、AST:ALT比值以及碱性磷酸酶从基线至第3、6、9、12个月的变化情况。GTE组（n=400）受试者的平均年龄为59.8岁，平均体质量指数（body mass index, BMI）为25.1kg/m²，其中98%为白人受试者。在基线至第3个月时，COMT（rs4680）A/G基因型受试者的AST:ALT比值平均变化为+1.0%，而A/A基因型受试者的该比值平均变化为-4.8%（p=0.03）。在基线至第6、9个月时，UGT1A4（rs6755571）A/C基因型受试者的ALT平均变化分别为+78.1%和+82.1%，而C/C基因型受试者的ALT平均变化分别为+28.0%和+30.1%（分别为p<0.001与p=0.004）。UGT1A4（rs6755571）A/C基因型可能是绝经后女性经6~9个月高剂量GTE补充后，出现临床相关血清转氨酶升高的重要危险因素。阐明GTE相关肝毒性的遗传机制，有望为GTE的临床治疗应用提供基于遗传学的精准范式。