How safe is EGCG?
Updated: Dec 23, 2021
A brief analysis of Epigallocatechin-3-gallate, its benefits and its role in the fight against SARS-CoV-2
Epigallocatechin-3-gallate (EGCG) is one of the main catechins in green tea. EGCG interacts directly with plasma membrane proteins and phospholipids that stimulate intracellular signaling pathways (1). In addition, EGCG is transported to intracellular compartments, the cytosol, mitochondria, lysosomes, and nuclei where it mediates additional biological actions. These various effects depend on cell type, stress conditions, and EGCG concentrations (2).
Experimental studies have shown that epigallocatechin-3-gallate (EGCG), can prevent infection by various types of viruses, including coranoviridae (3-4). In molecular coupling studies, EGCG appeared as the candidate with the greatest therapeutic potential against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (5). Double-blind, placebo-controlled clinical trials show that EGCG reduced the risk of infection by 75% in healthcare workers during an outbreak of the H1N1 influenza virus (6-7).
But, how safe is its consumption in humans?
Several studies have been carried out to toxicologically analyze extracts of green tea and purified EGCG, both in animals and humans. Toxicological evidence shows that liver damage is the most important critical event derived from the use of green tea extracts and, within them, EGCG. This damage is directly related to the dose used and the purity of the catechins used, in addition to the form and route of administration together with the fasting or feeding state of the receiving organism (8).
EGCG is rapidly absorbed by the intestinal system, distributed, metabolized in the liver and colon, and can be reabsorbed from the intestine through enterohepatic recirculation. The resulting metabolites are excreted through the bile and urinary tract. It has been observed that at a higher dose of EGCG, the plasma EGCG concentration is proportionally higher than expected, it is postulated that this is due to a saturation of the presystemic elimination of polyphenols that are administered orally (9).
In a systematic review published by Hu (8), 104 studies evaluating adverse effects in humans with the administration of green tea and purified extracts thereof, as well as EGCG, were evaluated. The doses used ranged from 29.5 to 4,000 mg of EGCG per day, with different study subjects (from healthy subjects to subjects with pathologies), all studies were carried out in adults, except one with obese children. Of the 104 studies, 66 showed no adverse effects. The rest of the studies showed gastrointestinal disturbances as the most frequent adverse effects; especially nausea (22 studies), abdominal pain or discomfort (17 studies), diarrhea (14 studies), dyspepsia / indigestion (12 studies), and elevated liver enzymes (11 studies). Less frequent was the finding of vomiting, constipation and flatulence. Adverse effects related to the caffeine content of the material were occasionally detected, which was related to nervousness, anxiety and insomnia, reported in some studies.
48 studies meet the authors criteria for evaluating hepatotoxicity. Of these, 37 showed no liver adverse effects. 11 studies showing liver adverse effects. All administered in capsules and most using Polyphenol E (a purified extract of green tea containing 800 mg of EGCG). No study, independent of the duration or purity of the material, showed liver adverse effects at doses equal to or less than 676 mg / EGCG per day on an empty stomach. Regarding the onset of hepatic adverse effects, they were observed as early as 10 days in healthy subjects who used 800 mg of fasted EGCG; in subjects using the study material with meals or in divided form, the occurrence of hepatic adverse effects appeared in those studies lasting longer than 60 days (8).
The incidence rate of adverse effects was estimated to be 4.9% based on the occurrence of events in increased liver enzymes (111 events in 2,269 people using green tea extracts in 48 studies). With a wide range of effects with the different preparations and administration forms: 0% when administered as a drink (0 events / 675 subjects), 7% when administered in capsules (111 events / 1,594 subjects); the highest incidence was in subjects using Polyphenon E (14.2%; 54 events / 380 subjects), compared to 5.2% of those using other green tea extracts and 0.8% (1 event in 133 subjects), in which they used pure EGCG (8).
Most of the hepatic adverse events, 98/111 hepatic adverse events, that occurred were mild to moderate in severity (elevation of liver enzymes less than 5 times the normal value or bilirubin less than 3 times the normal value, without other clinical symptoms ). 13 serious adverse events were reported in 5 studies, of which 9 resulted from the use of 1,315 mg of green tea extract, equivalent to 843 mg of EGCG per day and 4 subjects with the consumption of 800 mg of EGCG through Polyphenon E, in 4 studies. No severe adverse effect was observed with a purified EGCG extract. Of these 13 adverse events, 11 were mild to moderate (elevation of liver enzymes greater than 5 times the normal value or bilirubin greater than 3 times the normal value), there were no deaths.
Only in 3 of the 5 studies that showed severe adverse effects referred to resolution. Lovera reports that the levels of enzymes and bilirubin returned to normal levels after stopping the intervention (10); García reported that the levels returned to normal with the suspension of the administration of Polyphenon E (11). Dostal reported that of the 55 people who presented adverse effects, all returned to normal, except one in which no follow-up was performed (12).
Hepatotoxicity appears to be related to internal exposure to EGCG in the body. Catechins are eliminated from the body after phase II transformation, through the formation of glucuronide sulfate and methylated conjugates, which are less toxic than their native forms (8). Lambert (13), postulates that the liver damage caused by EGCG is, in part, due to an injury by oxidative stress, related to a high plasma concentration of free catechins, which could increase liver lipid peroxidation.
Some polymorphisms may have a role in the pathogenesis of liver damage. For example, subjects with low activity in catechol-O-methyl transferase (COMT), an enzyme involved in methylation of catechins, could be more prone to hepatotoxicity events (13-15). However, this has not been tested in humans (16,17).
There is some evidence in vitro tests that the administration of EGCG to hepatocytes with mitochondria that have membrane damage could produce a greater alteration, which does not occur when the mitochondrial membranes are undamaged (18,19), which suggests, if proven in vivo, that mitochondrial diseases could have a role as a predisposition to liver damage.
Other toxic effects related to EGCG
There is no evidence of thyroid damage. Neither is olfactory toxicity and damage to the nasal epithelium. Current evidence shows that damage to the heart, kidney, pancreas, spleen, bone marrow and reproductive organs that have been reported in animal models is secondary to severe gastrointestinal and liver adverse effects. In fact, they are not observed if they are not associated with severe gastrointestinal or hepatic adverse effects. There is no evidence of a carcinogenic role. A role of green tea extracts and EGCG has not been shown to be mutagenic or genotoxic (8).
An ECG role in weight loss has been demonstrated, demonstrated in animals and humans. Apparently due to the role of green tea catechins in increasing lipogenesis (20).
EGCG has a favorable safety profile for human consumption, it has a high tolerance for this catechin food in humans. In multiple placebo-controlled clinical trials in which EGCG has been tested for different therapeutic purposes in adults, EGCG has been well-tolerated and no significantly different adverse or side effects than placebo have been observed. Two randomized double-blind clinical trials in pregnant women at doses of 500 mg/day in their third trimester of pregnancy confirmed that EGCG was well tolerated and safe for both mother and offspring (21,22). Since 2016, after the results of the TESDAD trial came to light, EGCG has been used successfully as a nutritional supplement in the treatment of cognitive deficit in patients with Down syndrome (23). The main precaution to consider is possible liver toxicity in some people exposed to high doses. Although the frequency of liver damage associated with the use of EGCG has been somewhat exceptional in most clinical trials conducted so far, it is recommended to follow patients with routine liver tests to adjust the dose or discontinue treatment if necessary.
1. Singh BN, Shankar S, Srivastava RK. Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications. Biochem Pharmacol. 2011 Dec 15;82(12):1807–21.
2. Kim H-S, Quon MJ, Kim J-A. New insights into the mechanisms of polyphenols beyond antioxidant properties; lessons from the green tea
3. MATSUMOTO M. Inhibitory effects of epigallocatechin gallate on the propagation of bovine coronavirus in Madin-Darby bovine kidney cells. Animal Science Journal. 2005 Sep 11;76:507–12.
4. Roh C. A facile inhibitor screening of SARS coronavirus N protein using nanoparticle-based RNA oligonucleotide. Int J Nanomedicine. 2012 May;:2173–7.
5. Khan MF, Khan MA, Khan ZA, Ahamad T, Ansari WA. Identification of Dietary Molecules as Therapeutic Agents to Combat COVID-19 Using Molecular Docking Studies. 2020 Mar 27.
6. Matsumoto K, Yamada H, Takuma N, Niino H, Sagesaka YM. Effects of Green Tea Catechins and Theanine on Preventing Influenza Infection among Healthcare Workers: A Randomized Controlled Trial. BMC Complementary and Alternative Medicine. 2011;11(1):15.
7. Furushima D, Nishimura T, Takuma N, Iketani R, Mizuno T, Matsui Y, et al. Prevention of Acute Upper Respiratory Infections by Consumption of Catechins in Healthcare Workers: A Randomized, Placebo-Controlled Trial. Nutrients. 2020 Jan;12(1):4–12.
8. Hu J, Webster D, Cao J, Shao A. The safety of green tea and green tea extracts consumption in adults – Results of a systematic review. Regulatory Toxicology and Pharmacology. Elsevier Inc; 2018 Mar 23;:1–72.
9. Lee MJ, Wang ZY, Li H, Chen L, Sun Y, Gobbo S, et al. Analysis of plasma and urinary tea polyphenols in human subjects. Cancer Epidemiol Biomarkers Prev. 1995 Jun;4(4):393–9.
10. Lovera J, Ramos A, Devier D, Garrison V, Kovner B, Reza T, et al. Polyphenon E, non-futile at neuroprotection in multiple sclerosis but unpredictably hepatotoxic: Phase I single group and phase II randomized placebo-controlled studies. Journal of the Neurological Sciences. 2015 Nov;358(1-2):46–52.
11. Garcia FAR, Cornelison T, Nuño T, Greenspan DL, Byron JW, Hsu C-H, et al. Results of a phase II randomized, double-blind, placebo-controlled trial of Polyphenon E in women with persistent high-risk HPV infection and low-grade cervical intraepithelial neoplasia. Gynecologic Oncology. 2014 Feb;132(2):377–82.
12. Dostal AM, Samavat H, Bedell S, Torkelson C, Wang R, Swenson K, et al. The safety of green tea extract supplementation in postmenopausal women at risk for breast cancer: results of the Minnesota Green Tea Trial. Food and Chemical Toxicology. 2015 Sep;83:26–35.
13. Lambert JD, Sang S, Yang CS. Biotransformation of Green Tea Polyphenols and the Biological Activities of Those Metabolites. Mol Pharmaceutics. 2007 Sep 18;4(6):819–25.
14. Forester SC, Lambert JD. The catechol-O-methyltransferase inhibitor, tolcapone, increases the bioavailability of unmethylated (-)-epigallocatechin-3-gallate in mice. Journal of Functional Foods. 2015 Aug;17:183–8.
15. Wu AH, Tseng C-C, Van Den Berg D, Yu MC. Tea Intake, COMT Genotype, and Breast Cancer in Asian-American Women. Cancer Res. American Association for Cancer Research; 2003 Nov 1;63(21):7526–9.
16. Miller RJ, Jackson KG, Dadd T, Nicol B, Dick JL, Mayes AE, et al. A preliminary investigation of the impact of catechol-O-methyltransferase genotype on the absorption and metabolism of green tea catechins. Eur J Nutr. 2011 Mar 29;51(1):47–55.
17. Perry AH. Influence of COMT genotype polymorphism on plasma and urine green tea catechin levels in postmenopausal women. 2014 Sep 1.
18. Kucera O, Mezera V, Moravcova A, Endlicher R, Lotkova H, Drahota Z, et al. In VitroToxicity of Epigallocatechin Gallate in Rat Liver Mitochondria and Hepatocytes. Oxidative Medicine and Cellular Longevity. 2015;2015(14):1–10.
19. Weng Z, Zhou P, Salminen WF, Yang X, Harrill AH, Cao Z, et al. Green tea epigallocatechin gallate binds to and inhibits respiratory complexes in swelling but not normal rat hepatic mitochondria. Biochem Biophys Res Commun. Elsevier Inc; 2014 Jan 17;443(3):1097–104.
20. Hursel R, Westerterp-Plantenga MS. Catechin- and caffeine-rich teas for control of body weight in humans. Am J Clin Nutr. 2013 Oct 30;98(6):1682S–1693S.
21. Shi DD, Guo JJ, Zhou L, Wang N. Epigallocatechin gallate enhances treatment efficacy of oral nifedipine against pregnancy-induced severe pre-eclampsia: A double-blind, randomized and placebo-controlled clinical study. J Clin Pharm Ther. 2017 Jul 20;43(1):21–5.
22. Zhang H, Su S, Yu X, Li Y. Dietary epigallocatechin 3-gallate supplement improves maternal and neonatal treatment outcome of gestational diabetes mellitus: a double-blind randomised controlled trial. J Hum Nutr Diet. 2017 Mar 6;30(6):753–8.
23. la Torre PharmD de R, de Sola PhD S, MD GH, MD MF, MD JP, MSc JR, et al. Articles Safety and efficacy of cognitive training plus epigallocatechin-3-gallate in young adults with Down’s syndrome (TESDAD): a double-blind, randomised, placebo-controlled, phase 2 trial. The Lancet Neurology. Elsevier Ltd; 2016 Jun 2;15(8):801–10.