- Email: [email protected]
The nutraceutical benefit, part I: green tea
NUTRITIONAL PHARMACEUTICALS
Editors: Gil Hardy, PhD Eric Newsholme, PhD, DSc
The Nutraceutical Benefit, Part I: Green Tea Tomoi Sato, MD, and Go Miyata, MD, PhD From the Surgical Metabolism and Nutrition Laboratory, Department of Surgery, State University of New York Health Science Center, University Hospital, Syracuse, New York, USA reen tea has been consumed as a beverage for thousands of years in China and in Japan; it also has been used for its medicinal purposes. Because of the lack of specific scientific methods, scientists have dismissed the notion of green tea for its healing properties. However, in recent years, much attention has focused on the role of green tea for its antimicrobial, immunostimulatory, anticarcinogenic, and antiinflammatory capacities and for its protective effect against cardiovascular diseases. Green tea comes from the plant Camilla sinesis, which contains polyphenols such as epigallocatechin gallate (EGCG), epicatechin gallate, epigallocatechin, and epicatechin, which have antioxidant properties.1–3 The antimicrobial capacity of green tea is effective against various bacteria that cause diarrhea (e.g., Staphylococcus aureus, Staphylococcus epidermidis, Vibrio cholerae O1)4 and dental caries (e.g., Escherichia coli, Streptococcus salivarius, Streptococcus mutans).5 The mechanism proposed for these antimicrobial activities is that bactericidal catechins primarily act on and damage bacterial membranes.6 Also, as shown in Figure 1, the immunostimulatory capacity has been shown in studies that have documented EGCG stimulating the immune system to produce splenic B lymphocytes in mice7 and T lymphocyte and natural killer cell activity in tumor-bearing mice.8 The possible way in which these polyphenols function has been demonstrated by an animal study.9 As shown in Figure 2, oral or intravenous nutrients including immunomodulating nutraceuticals are sensed by nutrientspecific receptors or sensors in the portohepatic area which, through afferent vagal fibers, project onto the dorsomotor nucleus and interact with the hypothalamus. Changes in vagal afferent firing rate occur. An increase in vagal thymic and vagal lymph node efferent activity occurs, stimulating the increased release of T cells. Simultaneously, decrease in splenic efferents occurs, inhibiting the uptake of lymphocytes. The net effect is an increase in circulating cellular and humoral immunity.
G
Correspondence to: Tomoi Sato, MD, Department of Surgery, SUNY Health Science Center, University Hospital, 750 East Adams Street, Syracuse, NY 13210, USA. E-mail: [email protected]
Evidence of the anticarcinogenic capacity of green tea is based on accumulated epidemiologic human studies10 –12 and numerous animal models.13–16 In a prospective study in a Japanese population, a negative correlation was observed between green-tea consumption and the onset age of cancer. Among women, consumption of more than 10 cups (1800 mL; approximately 300 – 400 mg of EGCG) per day was associated with a significant decrease in cancer incidence with age.10 In a Chinese-population-based case-control study, newly diagnosed cancer patients (931 colon, 884 rectum, and 451 pancreas) and 1552 cancer-free individuals as a control showed an inverse correlation between daily consumption of green tea and risk of rectal and pancreatic cancers.11 The consumption of the brew from green-tea leaves (⬎300 g/mo in men and 200 g/mo in women) was associated with a significant reduction in these cancers. In another epidemiologic study, stage-I and -II breast cancer patients in Japan who consumed more than 5 cups (about 750 mL) per day had a significantly lower recurrence rate (16.7%) and longer disease-free years (3.6 y) than did patients who consumed fewer than 4 cups per day (24.3% and 2.8 y, respectively).12 The anticarcinogenic capacity of green tea has also been reported in experimental animal studies: in tobacco-specific nitrosamine-induced lung tumorigenesis in A/J mice,13 in N-nitrosomethylbenzylamineinduced esophageal tumors in rats,14 in ultraviolet-induced skin tumors in hairless mice,15 and in N-butyl-N-(4-hydroxybutyl)nitrosamine induced urinary tumors in rats.16 It is likely that green tea acts on various kinds of cancers in different organs. Possible mechanisms for the anticancer properties of green tea have been proposed from several laboratories. Parshad et al.17 reported the protective action of polyphenols. Green tea polyphenols significantly decreased fluorescent light-induced chromatid breaks in human fibroblasts GM5757 cells (19.3 versus 34.0 chromatid breaks/ 100 metaphase cells).17 Using computer modeling with the urokinase active site serving as a template EGCG, Jankun et al.18 reported the inhibitory effect of EGCG on urokinase, a proteolytic enzyme necessary for invading tissue and/or metastasizing neoplastic cells, resulting in prevention of tumor growth and metastasis.18 Another
Nutrition 16:315–317, 2000 ©Elsevier Science Inc., 2000. Printed in the United States. All rights reserved.
possible mechanism proposed by Ahmad et al. was an induction of apoptosis and cellcycle arrest by EGCG.19 In that study, human epidermoid carcinoma A431 cells treated with 160 g/mL EGCG resulted in increased apoptosis to 80.9% versus 1.5% in vehicle-treated cells as analyzed by flow cytometry. Further, 80 g/mL EGCGtreated cells contained 74% of G0 and G1 cycle cells versus 41% in vehicle-treated cells. Green tea also has a known antiinflammatory effect. Because tumor necrosis factor-␣ (TNF-␣) among numerous kinds of cytokines plays a major role in inflammatory response, Yang et al.20 reported the effect of EGCG on lipopolysaccharideinduced TNF-␣ gene expression in the macrophage cell line, RAQ264.7, and the activity of nuclear factor-B, an oxidative stresssensitive transcription factor that controls the expression of different kinds of genes active in inflammation including cytokines.20 Pretreatment with 100 mmol/L EGCG decreased lipopolysaccharideinduced TNF-␣ mRNA expression to 50%, its production to 45%, and nuclear factorB-binding activity by 30% as compared with non-pretreatment control. This mechanism of the antiinflammatory effect of EGCG is the same as that of other known antiinflammatory agents (e.g., sodium salicylate, dexamethasone), suggesting that green tea could be effective for various kinds of inflammatory diseases, including Crohn’s disease.21 The protective effect of green tea against cardiovascular diseases was reported in a Japanese epidemiologic study.22 In that study, in Japanese men older than 40 y (n ⫽ 1371), increased consumption of green tea, especially more than 10 cups (about 1500 mL) per day, was associated with a decreased concentration of serum total cholesterol and low-density lipoprotein and with an increased concentration of high-density lipoprotein, and thus with a decreased atherogenic index (ratio of low-density to high-density lipoprotein). In mice fed an atherogenic diet, green-tea extract prevented an increase of serum lipid peroxides in a dose-dependent manner.23 Moreover, green-tea extract at 0.5 mol/L concentration increased the lag time of low-density lipoprotein oxidation to 211 min from baseline (79 min) in an in vitro low-density 0899-9007/00/$20.00 PII S0889-9007(99)00301-9
316
THE NUTRACEUTICAL BENEFIT, PART I
FIG. 1. Schematic representation of the site of action of green tea to enhance the cell-mediated and humoral immune system.
FIG. 2. Schema of the postulated effect of nutraceuticals on immune activity. The liver, brain, thymus, spleen, and a representative lymph node are shown. (Reproduced with permission from reference 9.)
THE NUTRACEUTICAL BENEFIT, PART I lipoprotein oxidation method.24 Based on these data, the antioxidant effect of green tea seems to decrease lipid oxidation, resulting in the prevention of atherosclerosis and cardiovascular diseases. Because green tea is safe (it is sterilized with boiling) and relatively cheap, drinking green tea can be recommended without risk for people suffering from carcinogenic, inflammatory, and cardiovascular diseases.
317
7.
8.
9.
10.
REFERENCES 11. 1. Cotelle N, Bernier JL, He´nichart JP, et al. Scavenger and antioxidant properties of ten synthetic flavones. Free Rad Bio Med 1992;13:211 2. Guo Q, Zhao B, Li M, Shen S, Xin W. Studies on protective mechanisms of four components of green tea polyphenols against lipid peroxidation in synaptosomes. Biochim Biophys Acta 1996;1304:210 3. Dreosti IE. Bioactive ingredients: antioxidants and polyphenols in tea. Nutr Rev 1996;54:S51 4. Toda M, Okubo S, Ohnishi R, Shimamura T. Antibacterial and bactericidal activities of Japanese green tea. Jpn J Bacteriol 1989;44:669 5. Rasheed A, Haider M. Antibacterial activity of Camellia sinensis extracts against dental caries. Arch Pharm Res 1998;21:348 6. Ikigai H, Nakae T, Hara Y, Shimamura T. Bacteri-
12.
13.
14.
15.
cidal catechins damage the lipid bilayer. Biochim Biophys Acta 1993;1147:132 Hu ZQ, Toda M, Okubo S, Hara Y, Shimamura T. Mitogenic activity of (⫺)epigallocatechin gallate on B-cells and investigation of its structure-function relationship. Int J Immunopharmacol 1992;14:1399 Yan YS. Effect of Chinese tea extract on the immune function of mice bearing tumor and their antitumor activity. Chin J Prev Med 1992;26:5 Niijima A, Meguid MM. Influence of systemic arginine-lysine on immune organ function: an electrophysiological study. Brain Res Bull 1998;45:437 Imai K, Suga K, Nakachi K. Cancer-preventive effects of drinking green tea among a Japanese population. Prev Med 1997;26:769 Ji BT, Chow WH, Hsing AW, et al. Green tea consumption and the risk of pancreatic and colorectal cancers. Int J Cancer 1997;70:255 Nakachi K, Suemasu K, Suga K, et al. Influence of drinking green tea on breast cancer malignancy among Japanese patients. Jpn J Cancer Res 1998; 89:254 Xu Y, Ho CT, Amin SG, Han C, Chung FL. Inhibition of tobacco-specific nitrosamine-induced lung tumorigenesis in A/J mice by green tea and its major polyphenol as antioxidants. Cancer Res 1992;52: 3875 Chen J. The effects of Chinese tea on the occurrence of esophageal tumors induced by N-nitrosomethylbenzylamine in rats. Prev Med 1992;21:385 Record IR, Dreosti IE. Protection by tea against
16.
17.
18.
19.
20.
21. 22.
23.
24.
UV-A ⫹ B-induced skin cancers in hairless mice. Nutr Cancer 1998;32:71 Sato D. Inhibition of urinary bladder tumors induced by N-butyl-N-(4-hydroxybutyl)-nitrosamine in rats by green tea. Int J Urol 1999;6:93 Parshad R, Sanford KK, Price FM, et al. Protective action of plant polyphenols on radiation-induced chromatid breaks in cultured human cells. Anticancer Res 1998;18:3263 Jankun J, Selman SH, Swiercz R, SkrzypczakJankun E. Why drinking green tea could prevent cancer. Nature 1997;387:561 Ahmad N, Feyes DK, Nieminen AL, Agarwal R, Mukhtar H. Green tea constituent epigallocatechin3-gallate and induction of apoptosis and cell cycle arrest in human carcinoma cells. J Natl Cancer Inst 1997;89:1881 Yang F, de Villiers WJ, McClain CJ, Varilek GW. Green tea polyphenols block endotoxin-induced tumor necrosis factor-production and lethality in a murine model. J Nutr 1998;128:2334 Alic M. Green tea for remission maintenance in Crohn’s disease? Am J Gastroenterol 1999;94:1710 Imai K, Nakachi K. Cross sectional study of effects of drinking green tea on cardiovascular and liver diseases. Br Med J 1995;310:693 Yamaguchi Y, Hayashi M, Yamazoe H, Kunitomo M. Preventive effects of green tea extract on lipid abnormalities in serum, liver and aorta of mice fed a atherogenic diet. Folia Pharmacol Japon 1991; 97:329 Luo M, Kanner K, Wahlqvist ML, O’Brien RC. Inhibition of LDL oxidation by green tea extract. Lancet 1997;349:360
Editors: Gil Hardy, PhD Eric Newsholme, PhD, DSc
The Nutraceutical Benefit, Part I: Green Tea Tomoi Sato, MD, and Go Miyata, MD, PhD From the Surgical Metabolism and Nutrition Laboratory, Department of Surgery, State University of New York Health Science Center, University Hospital, Syracuse, New York, USA reen tea has been consumed as a beverage for thousands of years in China and in Japan; it also has been used for its medicinal purposes. Because of the lack of specific scientific methods, scientists have dismissed the notion of green tea for its healing properties. However, in recent years, much attention has focused on the role of green tea for its antimicrobial, immunostimulatory, anticarcinogenic, and antiinflammatory capacities and for its protective effect against cardiovascular diseases. Green tea comes from the plant Camilla sinesis, which contains polyphenols such as epigallocatechin gallate (EGCG), epicatechin gallate, epigallocatechin, and epicatechin, which have antioxidant properties.1–3 The antimicrobial capacity of green tea is effective against various bacteria that cause diarrhea (e.g., Staphylococcus aureus, Staphylococcus epidermidis, Vibrio cholerae O1)4 and dental caries (e.g., Escherichia coli, Streptococcus salivarius, Streptococcus mutans).5 The mechanism proposed for these antimicrobial activities is that bactericidal catechins primarily act on and damage bacterial membranes.6 Also, as shown in Figure 1, the immunostimulatory capacity has been shown in studies that have documented EGCG stimulating the immune system to produce splenic B lymphocytes in mice7 and T lymphocyte and natural killer cell activity in tumor-bearing mice.8 The possible way in which these polyphenols function has been demonstrated by an animal study.9 As shown in Figure 2, oral or intravenous nutrients including immunomodulating nutraceuticals are sensed by nutrientspecific receptors or sensors in the portohepatic area which, through afferent vagal fibers, project onto the dorsomotor nucleus and interact with the hypothalamus. Changes in vagal afferent firing rate occur. An increase in vagal thymic and vagal lymph node efferent activity occurs, stimulating the increased release of T cells. Simultaneously, decrease in splenic efferents occurs, inhibiting the uptake of lymphocytes. The net effect is an increase in circulating cellular and humoral immunity.
G
Correspondence to: Tomoi Sato, MD, Department of Surgery, SUNY Health Science Center, University Hospital, 750 East Adams Street, Syracuse, NY 13210, USA. E-mail: [email protected]
Evidence of the anticarcinogenic capacity of green tea is based on accumulated epidemiologic human studies10 –12 and numerous animal models.13–16 In a prospective study in a Japanese population, a negative correlation was observed between green-tea consumption and the onset age of cancer. Among women, consumption of more than 10 cups (1800 mL; approximately 300 – 400 mg of EGCG) per day was associated with a significant decrease in cancer incidence with age.10 In a Chinese-population-based case-control study, newly diagnosed cancer patients (931 colon, 884 rectum, and 451 pancreas) and 1552 cancer-free individuals as a control showed an inverse correlation between daily consumption of green tea and risk of rectal and pancreatic cancers.11 The consumption of the brew from green-tea leaves (⬎300 g/mo in men and 200 g/mo in women) was associated with a significant reduction in these cancers. In another epidemiologic study, stage-I and -II breast cancer patients in Japan who consumed more than 5 cups (about 750 mL) per day had a significantly lower recurrence rate (16.7%) and longer disease-free years (3.6 y) than did patients who consumed fewer than 4 cups per day (24.3% and 2.8 y, respectively).12 The anticarcinogenic capacity of green tea has also been reported in experimental animal studies: in tobacco-specific nitrosamine-induced lung tumorigenesis in A/J mice,13 in N-nitrosomethylbenzylamineinduced esophageal tumors in rats,14 in ultraviolet-induced skin tumors in hairless mice,15 and in N-butyl-N-(4-hydroxybutyl)nitrosamine induced urinary tumors in rats.16 It is likely that green tea acts on various kinds of cancers in different organs. Possible mechanisms for the anticancer properties of green tea have been proposed from several laboratories. Parshad et al.17 reported the protective action of polyphenols. Green tea polyphenols significantly decreased fluorescent light-induced chromatid breaks in human fibroblasts GM5757 cells (19.3 versus 34.0 chromatid breaks/ 100 metaphase cells).17 Using computer modeling with the urokinase active site serving as a template EGCG, Jankun et al.18 reported the inhibitory effect of EGCG on urokinase, a proteolytic enzyme necessary for invading tissue and/or metastasizing neoplastic cells, resulting in prevention of tumor growth and metastasis.18 Another
Nutrition 16:315–317, 2000 ©Elsevier Science Inc., 2000. Printed in the United States. All rights reserved.
possible mechanism proposed by Ahmad et al. was an induction of apoptosis and cellcycle arrest by EGCG.19 In that study, human epidermoid carcinoma A431 cells treated with 160 g/mL EGCG resulted in increased apoptosis to 80.9% versus 1.5% in vehicle-treated cells as analyzed by flow cytometry. Further, 80 g/mL EGCGtreated cells contained 74% of G0 and G1 cycle cells versus 41% in vehicle-treated cells. Green tea also has a known antiinflammatory effect. Because tumor necrosis factor-␣ (TNF-␣) among numerous kinds of cytokines plays a major role in inflammatory response, Yang et al.20 reported the effect of EGCG on lipopolysaccharideinduced TNF-␣ gene expression in the macrophage cell line, RAQ264.7, and the activity of nuclear factor-B, an oxidative stresssensitive transcription factor that controls the expression of different kinds of genes active in inflammation including cytokines.20 Pretreatment with 100 mmol/L EGCG decreased lipopolysaccharideinduced TNF-␣ mRNA expression to 50%, its production to 45%, and nuclear factorB-binding activity by 30% as compared with non-pretreatment control. This mechanism of the antiinflammatory effect of EGCG is the same as that of other known antiinflammatory agents (e.g., sodium salicylate, dexamethasone), suggesting that green tea could be effective for various kinds of inflammatory diseases, including Crohn’s disease.21 The protective effect of green tea against cardiovascular diseases was reported in a Japanese epidemiologic study.22 In that study, in Japanese men older than 40 y (n ⫽ 1371), increased consumption of green tea, especially more than 10 cups (about 1500 mL) per day, was associated with a decreased concentration of serum total cholesterol and low-density lipoprotein and with an increased concentration of high-density lipoprotein, and thus with a decreased atherogenic index (ratio of low-density to high-density lipoprotein). In mice fed an atherogenic diet, green-tea extract prevented an increase of serum lipid peroxides in a dose-dependent manner.23 Moreover, green-tea extract at 0.5 mol/L concentration increased the lag time of low-density lipoprotein oxidation to 211 min from baseline (79 min) in an in vitro low-density 0899-9007/00/$20.00 PII S0889-9007(99)00301-9
316
THE NUTRACEUTICAL BENEFIT, PART I
FIG. 1. Schematic representation of the site of action of green tea to enhance the cell-mediated and humoral immune system.
FIG. 2. Schema of the postulated effect of nutraceuticals on immune activity. The liver, brain, thymus, spleen, and a representative lymph node are shown. (Reproduced with permission from reference 9.)
THE NUTRACEUTICAL BENEFIT, PART I lipoprotein oxidation method.24 Based on these data, the antioxidant effect of green tea seems to decrease lipid oxidation, resulting in the prevention of atherosclerosis and cardiovascular diseases. Because green tea is safe (it is sterilized with boiling) and relatively cheap, drinking green tea can be recommended without risk for people suffering from carcinogenic, inflammatory, and cardiovascular diseases.
317
7.
8.
9.
10.
REFERENCES 11. 1. Cotelle N, Bernier JL, He´nichart JP, et al. Scavenger and antioxidant properties of ten synthetic flavones. Free Rad Bio Med 1992;13:211 2. Guo Q, Zhao B, Li M, Shen S, Xin W. Studies on protective mechanisms of four components of green tea polyphenols against lipid peroxidation in synaptosomes. Biochim Biophys Acta 1996;1304:210 3. Dreosti IE. Bioactive ingredients: antioxidants and polyphenols in tea. Nutr Rev 1996;54:S51 4. Toda M, Okubo S, Ohnishi R, Shimamura T. Antibacterial and bactericidal activities of Japanese green tea. Jpn J Bacteriol 1989;44:669 5. Rasheed A, Haider M. Antibacterial activity of Camellia sinensis extracts against dental caries. Arch Pharm Res 1998;21:348 6. Ikigai H, Nakae T, Hara Y, Shimamura T. Bacteri-
12.
13.
14.
15.
cidal catechins damage the lipid bilayer. Biochim Biophys Acta 1993;1147:132 Hu ZQ, Toda M, Okubo S, Hara Y, Shimamura T. Mitogenic activity of (⫺)epigallocatechin gallate on B-cells and investigation of its structure-function relationship. Int J Immunopharmacol 1992;14:1399 Yan YS. Effect of Chinese tea extract on the immune function of mice bearing tumor and their antitumor activity. Chin J Prev Med 1992;26:5 Niijima A, Meguid MM. Influence of systemic arginine-lysine on immune organ function: an electrophysiological study. Brain Res Bull 1998;45:437 Imai K, Suga K, Nakachi K. Cancer-preventive effects of drinking green tea among a Japanese population. Prev Med 1997;26:769 Ji BT, Chow WH, Hsing AW, et al. Green tea consumption and the risk of pancreatic and colorectal cancers. Int J Cancer 1997;70:255 Nakachi K, Suemasu K, Suga K, et al. Influence of drinking green tea on breast cancer malignancy among Japanese patients. Jpn J Cancer Res 1998; 89:254 Xu Y, Ho CT, Amin SG, Han C, Chung FL. Inhibition of tobacco-specific nitrosamine-induced lung tumorigenesis in A/J mice by green tea and its major polyphenol as antioxidants. Cancer Res 1992;52: 3875 Chen J. The effects of Chinese tea on the occurrence of esophageal tumors induced by N-nitrosomethylbenzylamine in rats. Prev Med 1992;21:385 Record IR, Dreosti IE. Protection by tea against
16.
17.
18.
19.
20.
21. 22.
23.
24.
UV-A ⫹ B-induced skin cancers in hairless mice. Nutr Cancer 1998;32:71 Sato D. Inhibition of urinary bladder tumors induced by N-butyl-N-(4-hydroxybutyl)-nitrosamine in rats by green tea. Int J Urol 1999;6:93 Parshad R, Sanford KK, Price FM, et al. Protective action of plant polyphenols on radiation-induced chromatid breaks in cultured human cells. Anticancer Res 1998;18:3263 Jankun J, Selman SH, Swiercz R, SkrzypczakJankun E. Why drinking green tea could prevent cancer. Nature 1997;387:561 Ahmad N, Feyes DK, Nieminen AL, Agarwal R, Mukhtar H. Green tea constituent epigallocatechin3-gallate and induction of apoptosis and cell cycle arrest in human carcinoma cells. J Natl Cancer Inst 1997;89:1881 Yang F, de Villiers WJ, McClain CJ, Varilek GW. Green tea polyphenols block endotoxin-induced tumor necrosis factor-production and lethality in a murine model. J Nutr 1998;128:2334 Alic M. Green tea for remission maintenance in Crohn’s disease? Am J Gastroenterol 1999;94:1710 Imai K, Nakachi K. Cross sectional study of effects of drinking green tea on cardiovascular and liver diseases. Br Med J 1995;310:693 Yamaguchi Y, Hayashi M, Yamazoe H, Kunitomo M. Preventive effects of green tea extract on lipid abnormalities in serum, liver and aorta of mice fed a atherogenic diet. Folia Pharmacol Japon 1991; 97:329 Luo M, Kanner K, Wahlqvist ML, O’Brien RC. Inhibition of LDL oxidation by green tea extract. Lancet 1997;349:360