Drug Safety

, Volume 31, Issue 6, pp 469–484 | Cite as

Safety of Green Tea Extracts

A Systematic Review by the US Pharmacopeia
  • Dandapantula N. Sarma
  • Marilyn L. Barrett
  • Mary L. Chavez
  • Paula Gardiner
  • Richard Ko
  • Gail B. Mahady
  • Robin J. Marles
  • Linda S. Pellicore
  • Gabriel I. Giancaspro
  • Tieraona Low Dog
Review Article

Abstract

Green tea [Camellia sinensis (L.) Kuntze] is the fourth most commonly used dietary supplement in the US. Recently, regulatory agencies in France and Spain suspended market authorization of a weight-loss product containing green tea extract because of hepatotoxicity concerns. This was followed by publication of adverse event case reports involving green tea products. In response, the US Pharmacopeia (USP) Dietary Supplement Information Expert Committee (DSI EC) systematically reviewed the safety information for green tea products in order to re-evaluate the current safety class to which these products are assigned. DSI EC searched PubMed (January 1966–June 2007) and EMBASE (January 1988–June 2007) for clinical case reports and animal pharmacological or toxicological information. Reports were also obtained from a diverse range of other sources, including published reviews, the US FDA MedWatch programme, USP’s MEDMARX® adverse event reporting system, the Australian Therapeutic Goods Administration, the UK Medicines and Healthcare products Regulatory Agency, and Health Canada’s Canadian Adverse Drug Reaction Monitoring Program. Case reports pertaining to liver damage were evaluated according to the Naranjo causality algorithm scale. In addition, the Committee analysed information concerning historical use, regulatory status, and current extent of use of green tea products. A total of 216 case reports on green tea products were analysed, including 34 reports concerning liver damage. Twenty-seven reports pertaining to liver damage were categorized as possible causality and seven as probable causality. Clinical pharmacokinetic and animal toxicological information indicated that consumption of green tea concentrated extracts on an empty stomach is more likely to lead to adverse effects than consumption in the fed state. Based on this safety review, the DSI EC determined that when dietary supplement products containing green tea extracts are used and formulated appropriately the Committee is unaware of significant safety issues that would prohibit monograph development, provided a caution statement is included in the labelling section. Following this decision, USP’s DSI ECs may develop monographs for green tea extracts, and USP may offer its verification programmes related to that dietary ingredient.

References

  1. 1.
    Bhattacharyya L, Cecil T, Dabbah R, et al. The value of USP public standards for therapeutic products. Pharm Res 2004; 21(10): 1725–31PubMedCrossRefGoogle Scholar
  2. 2.
    Schiff Jr PL, Srinivasan VS, Giancaspro GI, et al. The development of USP botanical dietary supplement monographs, 1995–2005. J Nat Prod 2006; 69(3): 464–72PubMedCrossRefGoogle Scholar
  3. 3.
    Atwater J, Salguero JM, Roll DB. The USP Dietary Supplement Verification Program: Helping Pharmacists and Consumers Select Dietary Supplements. US Pharm 2005; 30: 61–4Google Scholar
  4. 4.
    McGuffin M, Kartesz JT, Leung AY, et al., editors. In: Herbs of Commerce. 2nd ed. Silver Spring (MD): American Herbal Products Association, 2000Google Scholar
  5. 5.
    Nutrition Business Journal. Top US herbal supplements 2006. Boulder (CO): Nutrition Business Journal, 2006Google Scholar
  6. 6.
    Bun SS, Bun H, Guedon D, et al. Effect of green tea extracts on liver functions in Wistar rats. Food Chem Toxicol 2006; 44(7): 1108–13PubMedCrossRefGoogle Scholar
  7. 7.
    Barrett ML. The handbook of clinically tested herbal remedies. Vol 2. New York: The Haworth Herbal Press, 2004Google Scholar
  8. 8.
    Graham HN. Green tea composition, consumption, and polyphenol chemistry. Prev Med 1992; 21(3): 334–50PubMedCrossRefGoogle Scholar
  9. 9.
    FDA. Veregen [online]. Available from URL: http://www.fda.gov/cder/foi/label/2006/021902lbl.pdf [Accessed 2007 Oct 23]
  10. 10.
    Kantelip JP, Laroche D. Green tea and liver disorders. National Drug Surveillance survey submitted to the Technical Committee. Besancon: Besancon regional drug surveillance centre; 2003 Feb 11Google Scholar
  11. 11.
    Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30(2): 239–45PubMedCrossRefGoogle Scholar
  12. 12.
    Busto U, Naranjo CA, Sellers EM. Comparison of two recently published algorithms for assessing the probability of adverse drug reactions. Br J Clin Pharmacol 1982; 13(2): 223–7PubMedCrossRefGoogle Scholar
  13. 13.
    Michel DJ, Knodel LC. Comparison of three algorithms used to evaluate adverse drug reactions. Am J Hosp Pharm 1986; 43(7): 1709–14PubMedGoogle Scholar
  14. 14.
    Jones JK. Adverse drug reactions in the community health setting: approaches to recognizing, counseling, and reporting. Fam Community Health 1982; 5(2): 58–67PubMedGoogle Scholar
  15. 15.
    Kramer MS, Leventhal JM, Hutchinson TA, et al. An algorithm for the operational assessment of adverse drug reactions: I. Background, description, and instructions for use. JAMA 1979; 242(7): 623–32PubMedCrossRefGoogle Scholar
  16. 16.
    WHO. WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems. Geneva: WHO, 2004Google Scholar
  17. 17.
    Danan G, Benichou C. Causality assessment of adverse reactions to drugs: I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol 1993; 46(11): 1323–30PubMedCrossRefGoogle Scholar
  18. 18.
    Andrade RJ, Robles M, Fernandez-Castaner A, et al. Assessment of drug-induced hepatotoxicity in clinical practice: a challenge for gastroenterologists. World J Gastroenterol 2007; 13(3): 329–40PubMedGoogle Scholar
  19. 19.
    Davern T. Can we replace opinion consensus with a Bayesian process? [online]. Available from URL: http://www.fda.gov/cder/livertox/presentations2006/Davern.pdf[Accessed 2007 Oct 23]
  20. 20.
    Seeff LB. Causality assessment for drug-induced liver injury [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/06/slides/2006-4266s1-01-08-FDA-Seeff_files/frame.htm [Accessed 2007 Oct 23]
  21. 21.
    Gloro R, Hourmand-Ollivier I, Mosquet B, et al. Fulminant hepatitis during self-medication with hydroalcoholic extract of green tea. Eur J Gastroenterol Hepatol 2005; 17(10): 1135–7PubMedCrossRefGoogle Scholar
  22. 22.
    Seddik M, Lucidarme D, Creusy C, et al. Is Exolise hepatotoxic? [in French]. Gastroenterol Clin Biol 2001; 25(8-9): 834–5PubMedGoogle Scholar
  23. 23.
    Vial T, Bernard G, Lewden B, et al. Acute hepatitis due to Exolise, a Camellia sinensis-derived drug [in French]. Gastroenterol Clin Biol 2003; 27(12): 1166–7PubMedGoogle Scholar
  24. 24.
    Pedros C, Cereza G, Garcia N, et al. Liver toxicity of Camellia sinensis dried etanolic extract [in Spanish]. Med Clin (Barc) 2003; 121(15): 598–9CrossRefGoogle Scholar
  25. 25.
    Jimenez-Saenz M, Martinez-Sanchez M del C. Acute hepatitis associated with the use of green tea infusions. J Hepatol 2006; 44(3): 616–7PubMedCrossRefGoogle Scholar
  26. 26.
    Stevens T, Qadri A, Zein NN. Two patients with acute liver injury associated with use of the herbal weight-loss supplement Hydroxycut. Ann Intern Med 2005; 142(6): 477–8PubMedGoogle Scholar
  27. 27.
    Porcel JM. Hepatotoxicity associated with green tea extracts [online]. Available from URL: http://www.annals.org/cgi/elet-ters/142/6/477#1445 [Accessed 2007 Oct 23]
  28. 28.
    Javaid A, Bonkovsky HL. Hepatotoxicity due to extracts of Chinese green tea (Camellia sinensis): a growing concern. J Hepatol 2006; 45(2): 334–5PubMedCrossRefGoogle Scholar
  29. 29.
    Molinari M, Watt KD, Kruszyna T, et al. Acute liver failure induced by green tea extracts: case report and review of the literature. Liver Transpl 2006; 12(12): 1892–5PubMedCrossRefGoogle Scholar
  30. 30.
    Bonkovsky HL. Hepatotoxicity associated with supplements containing Chinese green tea (Camellia sinensis). Ann Intern Med 2006; 144(1): 68–71PubMedGoogle Scholar
  31. 31.
    Gregory PJ. Chromium polynicotinate linked to hepatotoxicity [online]. Available from URL: http://www.annals.org/cgi/elet-ters/142/6/477#1445 [Accessed 2007 Oct 23]
  32. 32.
    Lanca S, Alves A, Vieira AI, et al. Chromium-induced toxic hepatitis. Eur J Intern Med 2002; 13(8): 518–20PubMedCrossRefGoogle Scholar
  33. 33.
    Woolf AD, Watson WA, Smolinske S, et al. The severity of toxic reactions to ephedra: comparisons to other botanical products and national trends from 1993–2002. Clin Toxicol (Phila) 2005; 43(5): 347–55CrossRefGoogle Scholar
  34. 34.
    Nadir A, Reddy D, Van Thiel DH. Cascara sagrada-induced intrahepatic cholestasis causing portal hypertension: case report and review of herbal hepatotoxicity. Am J Gastroenterol 2000; 95(12): 3634–7PubMedCrossRefGoogle Scholar
  35. 35.
    Anonymous. Medroxyprogesterone acetate injectable suspension product monograph [online]. Available from URL: http://www.fda.gov/medwatch/safety/2004/DepoProvera_Label.pdf [Accessed 2007 Oct 23] 484
  36. 36.
    Pisters KM, Newman RA, Coldman B, et al. Phase I trial of oral green tea extract in adult patients with solid tumors. J Clin Oncol 2001; 19(6): 1830–8PubMedGoogle Scholar
  37. 37.
    Yang CS, Chen L, Lee MJ, et al. Blood and urine levels of tea catechins after ingestion of different amounts of green tea by human volunteers. Cancer Epidemiol Biomarkers Prev 1998; 7(4): 351–4PubMedGoogle Scholar
  38. 38.
    Chow HH, Cai Y, Alberts DS, et al. Phase I pharmacokinetic study of tea polyphenols following single-dose administration of epigallocatechin gallate and polyphenon E. Cancer Epidemiol Biomarkers Prev 2001; 10(1): 53–8PubMedGoogle Scholar
  39. 39.
    Chow HH, Cai Y, Hakim IA, et al. Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of epigallocatechin gallate and polyphenon E in healthy individuals. Clin Cancer Res 2003; 9(9): 3312–9PubMedGoogle Scholar
  40. 40.
    Chow HH, Hakim IA, Vining DR, et al. Effect of dosing condition on the oral bioavailability of green tea catechins after single-dose administration of Polyphenon E in healthy individuals [online]. Available from URL: http://www.aacr.org/PDF_files/2004Prevention/Program/2004_Prevention_Abstracts.pdf [Accessed 2008 Apr 22]
  41. 41.
    Chow HH, Hakim IA, Vining DR, et al. Effects of dosing condition on the oral bioavailability of green tea catechins after single-dose administration of Polyphenon E in healthy individuals. Clin Cancer Res 2005; 11(12): 4627–33PubMedCrossRefGoogle Scholar
  42. 42.
    Ullmann U, Haller J, Decourt JP, et al. A single ascending dose study of epigallocatechin gallate in healthy volunteers. J Int Med Res 2003; 31(2): 88–101PubMedGoogle Scholar
  43. 43.
    Ullmann U, Haller J, Decourt JD, et al. Plasma-kinetic characteristics of purified and isolated green tea catechin epigallocatechin gallate (EGCG) after 10 days repeated dosing in healthy volunteers. Int J Vitam Nutr Res 2004; 74(4): 269–78PubMedCrossRefGoogle Scholar
  44. 44.
    Swezey RR, Aldridge DE, LeValley SE, et al. Absorption, tissue distribution and elimination of 4-[3H]-epigallocatechin gallate in beagle dogs. Int J Toxicol 2003; 22(3): 187–93PubMedCrossRefGoogle Scholar
  45. 45.
    Chen L, Lee MJ, Li H, et al. Absorption, distribution, elimination of tea polyphenols in rats. Drug Metab Dispos 1997; 25(9): 1045–50PubMedGoogle Scholar
  46. 46.
    Zhu BT, Patel UK, Cai MX, et al. Rapid conversion of tea catechins to monomethylated products by rat liver cytosolic catechol-O-methyltransferase. Xenobiotica 2001; 31(12): 879–90PubMedCrossRefGoogle Scholar
  47. 47.
    Zhu M, Chen Y, Li RC. Oral absorption and bioavailability of tea catechins. Planta Med 2000; 66(5): 444–7PubMedCrossRefGoogle Scholar
  48. 48.
    Suganuma M, Okabe S, Oniyama M, et al. Wide distribution of [3H](−)-epigallocatechin gallate, a cancer preventive tea polyphenol, in mouse tissue. Carcinogenesis 1998; 19(10): 1771–6PubMedCrossRefGoogle Scholar
  49. 49.
    Lambert JD, Lee MJ, Lu H, et al. Epigallocatechin-3-gallate is absorbed but extensively glucuronidated following oral administration to mice. J Nutr 2003; 133(12): 4172–7PubMedGoogle Scholar
  50. 50.
    Galati G, Lin A, Sultan AM, et al. Cellular and in vivo hepato-toxicity caused by green tea phenolic acids and catechins. Free Radic Biol Med 2006; 40(4): 570–80PubMedCrossRefGoogle Scholar
  51. 51.
    Isbrucker RA, Edwards JA, Wolz E, et al. Safety studies on epigallocatechin gallate (EGCG) preparations. Part 2: dermal, acute, and short-term toxicity studies. Food Chem Toxicol 2006; 44(5): 636–50PubMedCrossRefGoogle Scholar
  52. 52.
    Chen JH, Tipoe GL, Liong EC, et al. Green tea polyphenols prevent toxin-induced hepatotoxicity in mice by down-regulating inducible nitric oxide-derived prooxidants. Am J Clin Nutr 2004; 80(3): 742–51PubMedGoogle Scholar
  53. 53.
    Zhang XG, Xu P, Liu Q, et al. Effect of tea polyphenol on cytokine gene expression in rats with alcoholic liver disease. Hepatobiliary Pancreat Dis Int 2006; 5(2): 268–72PubMedGoogle Scholar
  54. 54.
    Dobrzynska I, Sniecinska A, Skrzydlewska E, et al. Green tea modulation of the biochemical and electric properties of rat liver cells that were affected by ethanol and aging. Cell Mol Biol Lett 2004; 9(4A): 709–21PubMedGoogle Scholar
  55. 55.
    Nishikawa T, Nakajima T, Moriguchi M, et al. A green tea polyphenol, epigalocatechin-3-gallate, induces apoptosis of human hepatocellular carcinoma, possibly through inhibition of Bcl-2 family proteins. J Hepatol 2006; 44(6): 1074–82PubMedCrossRefGoogle Scholar
  56. 56.
    Fiorini RN, Donovan JL, Rodwell D, et al. Short-term administration of (−)-epigallocatechin gallate reduces hepatic steatosis and protects against warm hepatic ischemia/reperfusion injury in steatotic mice. Liver Transpl 2005; 11(3): 298–308PubMedCrossRefGoogle Scholar
  57. 57.
    Schmidt M, Schmitz HJ, Baumgart A, et al. Toxicity of green tea extracts and their constituents in rat hepatocytes in primary culture. Food Chem Toxicol 2005; 43(2): 307–14PubMedCrossRefGoogle Scholar
  58. 58.
    Imai K, Suga K, Nakachi K. Cancer-preventive effects of drinking green tea among a Japanese population. Prev Med 1997; 26(6): 769–75PubMedCrossRefGoogle Scholar
  59. 59.
    Woo JJ. Adverse event monitoring and multivitamin-mul-timineral dietary supplements. Am J Clin Nutr 2007; 85(1): 323S–4SPubMedGoogle Scholar
  60. 60.
    USP. USP-NF development process [online]. Available from URL: http://www.usp.org/USPNF/devProcess/ [Accessed 2007 Oct 23]

Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  • Dandapantula N. Sarma
    • 1
  • Marilyn L. Barrett
    • 2
  • Mary L. Chavez
    • 2
  • Paula Gardiner
    • 2
  • Richard Ko
    • 2
  • Gail B. Mahady
    • 2
  • Robin J. Marles
    • 2
  • Linda S. Pellicore
    • 2
  • Gabriel I. Giancaspro
    • 1
  • Tieraona Low Dog
    • 2
  1. 1.US PharmacopeiaRockvilleUSA
  2. 2.US Pharmacopeia Dietary Supplements Information Expert CommitteeRockvilleUSA
  3. 3.US PharmacopeiaRockvilleUSA

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