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

doi:10.1016/j.toxrep.2020.02.008

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

Toxicol Rep. 2020 Feb 15:7:386-402. doi: 10.1016/j.toxrep.2020.02.008. eCollection 2020.

Authors

Hellen A Oketch-Rabah^{1

2}, Amy L Roe^{2

3}, Cynthia V Rider², Herbert L Bonkovsky^{4

5}, Gabriel I Giancaspro^{1

2}, Victor Navarro^{2

6}, Mary F Paine^{2

7}, Joseph M Betz², Robin J Marles², Steven Casper⁴, Bill Gurley², Scott A Jordan², Kan He², Mahendra P Kapoor², Theertham P Rao², Averell H Sherker^{6

8}, Robert J Fontana^{6

9}, Simona Rossi⁶, Raj Vuppalanchi⁴, Leonard B Seeff⁶, Andrew Stolz⁶, Jawad Ahmad⁶, Christopher Koh^{6

10}, Jose Serrano^{6

8}, Tieraona Low Dog², Richard Ko^{2

11}

Affiliations

¹ U.S. Pharmacopeial Convention, Rockville, MD, USA.
² United States Pharmacopeia Green Tea Hepatotoxicity Expert Panel (USP GTEH EP, 2015-2020 cycle), Rockville, MD, USA.
³ Vice Chair, (USP GTEH EP, 2015-2020 cycle).
⁴ U.S. FDA Liaison to the USP GTEH EP (2015-2020 cycle).
⁵ Section on Gastroenterology & Hepatology, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA.
⁶ Expert Members of the Drug Induced Liver Injury Network (DILIN), USA.
⁷ Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA.
⁸ Liver Diseases Research Branch National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 6707 Democracy Blvd., Bethesda, MD, USA.
⁹ Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
¹⁰ Liver Diseases Branch, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, 10 Center Drive, Building 10, Rm 9B-16, Bethesda, MD, 20892,USA.
¹¹ Chair (USP GTEH EP, 2015-2020 cycle).

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.

Publication types

Review