United States Pharmacopeia (USP) comprehensive review of the hepatotoxicity of green tea extracts

Hellen A Oketch-Rabah, Amy L Roe, Cynthia V Rider, Herbert L Bonkovsky, Gabriel I Giancaspro, Victor Navarro, Mary F Paine, Joseph M Betz, Robin J Marles, Steven Casper, Bill Gurley, Scott A Jordan, Kan He, Mahendra P Kapoor, Theertham P Rao, Averell H Sherker, Robert J Fontana, Simona Rossi, Raj Vuppalanchi, Leonard B Seeff, Andrew Stolz, Jawad Ahmad, Christopher Koh, Jose Serrano, Tieraona Low Dog, Richard Ko, Hellen A Oketch-Rabah, Amy L Roe, Cynthia V Rider, Herbert L Bonkovsky, Gabriel I Giancaspro, Victor Navarro, Mary F Paine, Joseph M Betz, Robin J Marles, Steven Casper, Bill Gurley, Scott A Jordan, Kan He, Mahendra P Kapoor, Theertham P Rao, Averell H Sherker, Robert J Fontana, Simona Rossi, Raj Vuppalanchi, Leonard B Seeff, Andrew Stolz, Jawad Ahmad, Christopher Koh, Jose Serrano, Tieraona Low Dog, Richard Ko

Abstract

As part of the United States Pharmacopeia's ongoing review of dietary supplement safety data, a new comprehensive systematic review on green tea extracts (GTE) has been completed. GTEs may contain hepatotoxic solvent residues, pesticide residues, pyrrolizidine alkaloids and elemental impurities, but no evidence of their involvement in GTE-induced liver injury was found during this review. GTE catechin profiles vary significantly with manufacturing processes. Animal and human data indicate that repeated oral administration of bolus doses of GTE during fasting significantly increases bioavailability of catechins, specifically EGCG, possibly involving saturation of first-pass elimination mechanisms. Toxicological studies show a hepatocellular pattern of liver injury. Published adverse event case reports associate hepatotoxicity with EGCG intake amounts from 140 mg to ∼1000 mg/day and substantial inter-individual variability in susceptibility, possibly due to genetic factors. Based on these findings, USP included a cautionary labeling requirement in its Powdered Decaffeinated Green Tea Extract monograph that reads as follows: "Do not take on an empty stomach. Take with food. Do not use if you have a liver problem and discontinue use and consult a healthcare practitioner if you develop symptoms of liver trouble, such as abdominal pain, dark urine, or jaundice (yellowing of the skin or eyes)."

Keywords: ADME, Absorption, distribution, metabolism, and excretion; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUC, area under the curve; Bw, body weight; C, Catechin; CAM, causality assessment method; CG, (+)‐catechin‐3‐gallate; CIH, Concanavalin A-induced hepatitis; CMC, chemistry, manufacturing, and controls; COMT, catechol‐O‐methyltransferase; Camellia sinensis; ConA, Concanavalin A; DILI, drug‐induced liver injury; DILIN, Drug‐Induced Liver Injury Network; DO, Diversity Outbred; DS, Dietary Supplement; DSAE, JS3 USP Dietary Supplements Admission Evaluations Joint Standard-Setting Subcommittee; Dietary supplements; EC, (–)‐epicatechin; ECG, (‐)‐epicatechin‐3‐gallate; EFSA, European Food Safety Authority; EGC, (–)‐epigallocatechin; EGCG, (–)‐epigallocatechin‐3‐gallate; FDA, United States Food and Drug Administration; GC, (+)‐gallocatechin; GCG, (–)‐gallocatechin‐3‐gallate; GT(E), green tea or green tea extract; GT, green tea; GTE, green tea extract; GTEH, EP Green Tea Extract Hepatotoxicity Expert Panel; Green tea; Green tea extract; HDS, herbal dietary supplement; HPMC, Hydroxypropyl methylcellulose; Hepatotoxicity; LD50, lethal dose, median; LFT(s), liver function test(s); LT(s), Liver test(s); Liver injury; MGTT, Minnesota Green Tea Trial; MIDS, multi-ingredient dietary supplement; MRL, maximum residue limit; NAA, N-acetyl aspartate; NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases; NIH, National Institutes of Health; NOAEL, no observed adverse effect level; NTP, National Toxicology Program; OSM, online supplementary material; PAs, Pyrrolizidine Alkaloids; PD-1, Programmed death domain-1; PDGTE, powdered decaffeinated green tea extract; PK/PD, pharmacokinetics and pharmacodynamics; RUCAM, Roussel Uclaf Causality Assessment Method; SIDS, single-ingredient dietary supplement; TGF-beta, Transforming growth factor beta; USP, United States Pharmacopeia; γ-GT, Gamma-glutamyl transferase.

Conflict of interest statement

The authors have declared the following: HAO-R and GIG are employed by USP. The below listed authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper: Hellen A Oketch-Rabah, Gabriel I. Giancaspro, Jawad Ahmad, Steven Casper, Bill Gurley, Cynthia V. Rider, Leonard B Seef, Jose Serrano, Joseph M. Betz, Christopher Koh, Kan He, Mary F. Paine, Raj Vuppalanchi, Robin J. Marles, Averell H. Sherker, Simona Rossi, Scott Jordan, Victor J. Navarro, Andrew Stolz. The below listed authors declare the described financial interests/personal relationships which may be considered as potential competing interests: Tieraona Low Dog is a Consultant at MegaFoods; Herbert L. Bonkovsky has been and continues to be an investigator in the NIH-sponsored US Drug-Induced Liver Injury Network since 2003 and is supported by a cooperative agreement between NIDDK and UNC & Wake Forest University, U01 DK 065201; Amy L. Roe works for a company that manufactures and distributes dietary supplements; including some that may contain green tea extract; Richard Ko is the founder and owner of Herbal Synergy, a company that consults for the dietary supplement, food, and pharmaceutical companies; Kan He is employed by Herbalife, a company that manufactures and distributes dietary supplement that may contain green tea or green tea extracts; Robert J. Fontana receives research support from Gilead, Abbvie, and BristolMyerSquibb, and also provides consulting for Alynam and AstraZeneca; Mahendra P. Kapoor is an employee of Taiyo Kagaku Co Ltd, a company that manufactures several nutraceutical ingredients including green tea extracts; Theertham Pradyumna Rao is an employee of Taiyo Kagaku Co Ltd, a company that manufactures several nutraceutical ingredients including green tea extracts.

© 2020 Published by Elsevier B.V.

Figures

Fig. 1
Fig. 1
A summary of literature search results and categorization of retrieved articles. * Databases searched include: PubMed, Google Scholar, NLM, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Register of Controlled Trials [CENTRAL], Agricultural Online Access [AGRICOLA], Allied and Complimentary Medicine [AMED], Computer Access to Research on Dietary Supplements [CARDS], Cumulative Index to Nursing and Allied Health Literature [CINAHL] EBSCO Health, Database of Abstracts of Reviews of Effects [DARE] PubMed Health; Embase; International Pharmaceutical Abstracts; National Technological Information Service [NTIS. ** Search strategy used a combination of [Green Tea Extract or Tea Polyphenols or EGCG] and [clinical trials or adverse reactions or adverse effects or case reports or hepatotoxicity or pharmacokinetics or liver or animals].

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