Studies on the Prevention of Cancer and Cardiometabolic Diseases

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Studies on the Prevention of Cancer and Cardiometabolic Diseases by Tea: Issues on Mechanisms, Effective Doses and Toxicities Chung S Yang, and Jinsong Zhang J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.8b05242 • Publication Date (Web): 12 Dec 2018 Downloaded from http://pubs.acs.org on December 17, 2018

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Journal of Agricultural and Food Chemistry

An invited paper for the Special Issue “Chemistry, Flavor and Health Effects of Tea” in JAFC 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44

Studies on the Prevention of Cancer and Cardiometabolic Diseases by Tea: Issues on Mechanisms, Effective Doses and Toxicities Chung S. Yangǂ,§,* and Jinsong Zhang§,║ ǂDepartment

of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ §International Joint Research Laboratory of Tea Chemistry and Health Effects, Anhui Agricultural University, Hefei, Anhui, China ║State Key Laboratory of Tea Plant Biology and Utilization, School of Tea & Food Science, Anhui Agricultural University, Hefei, Anhui, China

Running Title: Cancer and cardiometabolic disease prevention by tea Key Words: Tea polyphenols, cancer, cardiometabolic diseases, toxicity Abbreviations: Akt, Ak transforming, also known as protein kinase B; AMPK, AMP-activated protein kinase; CVDs, cardiovascular diseases; COMT, catechol-o-methyltransferase; DTC, dithiocarbamates; EC, epicatechin; ECG, epicatechin-3-gallate; EGC, epigallocatechin; EGCG, (-)-epigallocatechin-3-gallate; Erk1/2, extracellular signal-regulated kinase 2; GTE, green tea extract; IGF, insulin-like growth factor; IR, insulin resistance; 67LR, 67kDa laminin receptor; MetS, metabolic syndrome; NOAEL, no-observed-adverse-effect-levels; Nrf2, nuclear factor erythroid 2-p45-related factor-2; PIN, prostate intraepithelial neoplasia; PPE, Polyphenon E; ROS, reactive oxygen species, RCT, recent randomized clinical trial; T2D, Type 2 diabetes; VEGF, vascular endothelial growth factor.

*Corresponding Author: Chung S. Yang, Ph.D., Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 088548020, Tel: (848) 445-5360 Email: [email protected]

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ABSTRACT

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This article presents a brief overview of studies on the prevention of cancer and cardiometabolic

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diseases by tea. The major focus is on green tea catechins concerning the effective doses used, the

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mechanisms of action, and possible toxic effects. In cancer prevention by tea, the laboratory results

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are strong, but the human data are inconclusive, and the effective doses used in some human trials

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approached toxic levels. In studies of the alleviation of metabolic syndrome, diabetes and

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prevention of cardiovascular diseases, the results from human studies are stronger in individuals

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who consume 3-4 cups of tea (600-900 mg of catechins) or more per day. The tolerable upper

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intake level of tea catechins has been set at 300 mg EGCG in a bolus dose per day in some

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European countries. The effects of doses and dosage forms on catechin toxicity, the mechanisms

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involved, and factors that may affect toxicity are discussed.

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INTRODUCTION

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The possible benefits of tea consumption on health have been extensively studied. This article

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updates our previous reviews1-4 and discusses highlights in studies on the prevention of cancer,

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obesity, metabolic syndrome (MetS), Type 2 diabetes (T2D) and cardiovascular diseases (CVDs)

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by tea. Most of the activities are shown to be due to tea polyphenols. In green tea, (-)-

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epigallocatechin-3-gallate (EGCG) is the most abundant and most biologically active polyphenol.

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Other green tea polyphenols: epicatechin-3-gallate (ECG), epigallocatechin (EGC) and

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epicatechin (EC), also contribute to the biological activities. These polyphenols are also known as

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catechins and their structures are shown in Figure 1. Because many of the studies have been

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covered in previous reviews1-4 and in other articles in this special volume, this article presents our

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analysis and perspectives on research in this area. To illustrate this point, results from our own

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laboratories are used in many cases, because of our familiarity of the data.

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We will discuss some recent results and key conclusions from laboratory and human

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studies on cancer prevention by tea and tea catechins, especially concerning their mechanisms of

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action, effective doses and possible relevance in human cancer prevention. In some recent human

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intervention trials on cancer, the previously presumed safe doses of tea polyphenols actually

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approached toxic levels5-7. In the intervention studies on metabolic syndrome and cardiovascular

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diseases, individuals consuming 3-4 cups of tea (600-900 mg of catechins) or larger amounts daily

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were more likely to receive beneficial effects1-3. These doses are higher than the tolerable upper

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intake level of catechins, set at 300 mg EGCG by some European countries8. The liver toxicity in

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some individuals caused by the use of tea extract-based dietary supplement is well-recognized8.

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How to harness the properties of tea catechins for human health maintenance and avoid toxicity is

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also a major topic for discussion in this article. The effective catechin doses for disease prevention,



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the effects of doses and dosage forms on toxicity, and factors that may influence catechin toxicity

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are discussed.

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The chemistry and many other properties of tea constituents have been discussed in

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previous reviews9-10 and in other articles in this special volume. Herein, we discuss two properties

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that are important for discussion on mechanisms of action of catechin – redox property and binding

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activities – using EGCG as an example. The antioxidant activity of EGCG is well-established11.

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The phenolic groups of EGCG could quench reactive oxygen species (ROS) and other radicals. In

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addition, the multiple phenolic groups could chelate metal ions to prevent the formation of ROS.

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On the other hand, EGCG can also be a pro-oxidant to produce ROS, both in vitro and in vivo,

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even though the mechanisms may be different3, 11. At moderate doses, the production of ROS

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and/or the formation of the EGCG quinone by EGCG oxidation could activate the nuclear factor

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erythroid 2-p45-related factor-2 (Nrf2)-dependent cytoprotective enzymes11, and this would be

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beneficial in the protection against oxidative stress. At even higher doses, however, the excessive

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amount of ROS produced by EGCG would deplete cellular antioxidants and damage the

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cytoprotective enzymes, leading to cytotoxicity11.

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Another important property of EGCG is its tight binding to proteins, lipids, biological membranes

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and other macromolecules through multiple hydrogen-bonding and hydrophobic interactions2. For

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this reason, EGCG has been reported to bind many proteins – including enzymes, signaling

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proteins and receptors; these proteins were proposed as targets for the biological activity of EGCG.

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However, these data need to be interpreted with caution. After ingestion of EGCG, it goes through

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the intestinal tract, wherein it is expected to inhibit some enzymes, such as α-glucosidase,

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proteinases and lipases through direct contact. For internal organs, because only part of the

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ingested EGCG is absorbed systemically, it may not reach the specific enzyme or receptor at an


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effective inhibitory concentration in the tissue. In addition, some of the reported inhibitory actions

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are due to nonspecific irreversible binding. The smaller the amount of protein that was used in the

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experiment in vitro, the more effective EGCG would behave as an inhibitor. Therefore, the

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effective inhibitory concentrations reported for this type of binding may not be relevant in

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situations in vivo.

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STUDIES ON CANCER PREVENTION

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As was discussed in many previous reviews1, 4, the cancer preventive activities of green tea extract

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(GTE) and EGCG have been studied in a variety of cancer models. The prevention of cancers of

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the skin, lung, oral cavity, esophagus, stomach, small intestine, colon, liver, pancreas, prostate and

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mammary glands has been demonstrated. Even though the reported preventive activities varied in

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different animal models in studies using different tea or tea preparations, the overall evidence for

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cancer prevention by tea in laboratory studies is assessed to be strong. However, the results on

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human epidemiological studies are inconclusive1, 4.

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Epidemiological studies

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Of note is the interfering and confounding factors that may affect the results of epidemiological

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studies. For example, in a study in Shanghai, tea consumption was associated with lower risk for

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esophageal cancer in women, but not men, of which 75% were smokers. When the smokers were

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excluded from the analysis, the association was found in women and men12. On the relationship

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between tea consumption and stomach cancer in Japan, even though many case control studies

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have associated a lower odds ratio with tea consumption, several cohort studies did not find any

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significant association between tea consumption and risk for stomach cancer4. However, when six

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cohort studies were analyzed together, a lower risk of stomach cancer due to tea consumption was

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observed in non-smoking and non-drinking women, but not in the overall cohort13. These results 5 ACS Paragon Plus Environment


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suggest that the cancer preventive activity observed in animal models could be translated into

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humans, but the activity is mild and could be easily masked by smoking and other life-style related

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factors.

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Large cohort studies are useful in generating information on the effects of dietary habits and health.

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In a large cohort study (Ohsaki National Health Insurance Cohort Study) with 40,530 participants

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that were followed for 11 years with 4,209 deaths, Kuriyama et al. reported that tea consumption

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was dose-dependently associated with lower risk for deaths due to CVDs and deaths from all

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causes, but had no effect on cancer deaths14. On the other hand, in the Chinese Perspective

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Smoking Study involving 164,681 individuals followed for 11 years, Liu et al. reported that tea

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drinking was associated with reduced risk of deaths due to cancer and CVDs, as well as deaths

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from all causes15. In the recent report by Zhao et al. on the combined cohort of the Shanghai

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women's and Shanghai men's studies, involving a total of 6,571 deaths out of 136,432 individuals

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that were followed for 8.3 to 14.2 years, tea drinking was not associated with risk of cancer death,

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but decreased the deaths due to CVDs and all causes combined16. These large long-term cohort

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studies suggest that tea drinking was more effective in reducing the deaths or preventing the

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development of CVDs than cancer.

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Human intervention studies

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Concerning human intervention studies on cancer, even though some early studies on oral cancer

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and prostate cancer have generated exciting results17-18, more recent studies on these cancers have

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not reproduced the same excitement of the previous studies, even though some beneficial effects

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were also observed19-20. For example, in a double blind, phase II prostate cancer trial in Italy, 30

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men with high-grade prostate intraepithelial neoplasia (PIN) were given 300 mg of green tea

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polyphenols twice daily for 12 months and only one patient developed prostate cancer; whereas in 6 ACS Paragon Plus Environment

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the placebo group, nine of the 30 patients with high-grade PIN developed prostate cancer18. The

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difference was highly significant statistically. On the other hand, a recent randomized clinical trial

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(RCT) in Florida with a similar design in men with high-grade PIN and/or atypical small acinar

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proliferation (ASAP), supplementation of Polyphenon E (PPE) (containing 400 mg of EGCG) to

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49 men for 6-12 months did not prevent prostate cancer formation20. Nevertheless, decreased

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serum prostate specific antigen levels and decreased ASAP in some patients were observed

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compared to the placebo group (n=48)20. It is unclear whether the different results from these two

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studies is due to the dosage form used, the patient population studied or other reasons. Some recent

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early phase intervention studies on esophageal adenocarcinoma and breast cancer were limited to

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bioavailability and some biomarker studies7, 21. At present, the earlier optimistic expectation of

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cancer preventive activity by tea polyphenols has not materialized in human RCTs.

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Two of our recent studies raised concerns on the toxicity of tea polyphenols. In a recent

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completed intervention trial on breast cancer prevention with GTE – the Minnesota Green Tea

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Trial – with 1,075 healthy postmenopausal women, 573 women received oral supplements of GTE

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twice a day (total 1,315 mg catechins, including 843 mg EGCG) for one year and 508 women

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received placebos. The intervention decreased the mammographic density of those who enrolled

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at the ages of 50-55 years, but not in those enrolled at older ages5. It was also observed that 5.1%

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of the women in the GTE group had elevated serum alanine aminotransferase and aspartate

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aminotransferase activities, yielding an odds ratio of 7.06. The elevation was reversible after the

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individual stopped the intake of GTE. The dose of 1,315 mg catechins per day was thought to be

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a safe dose in the design of this trial. The reason why approximately 5% of the women on GTE

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experienced reversible liver toxicity is not clear and will be discussed in a subsequent section.



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In another study, a Phase 1B RCT, the effects of PPE on patients with Barrett's esophagus

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were studied7. In a dose escalation design, 32 subjects received PPE at 200, 400 and 600 mg EGCG

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twice daily for 6 months. The esophageal EGCG levels were raised to around 35 pmol/g tissue for

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patients who received the two higher doses of PPE and the treatment might increase urinary

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prostaglandin E metabolite levels. For adverse effects, there were many cases of grade I and II

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nausea, grade I belching and elevation of serum alanine aminotransferase and lactate

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dehydrogenase. This study reported that PPE was well tolerated with the maximum tolerated dose

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not reached. The recommended dose was 600 mg twice a day. These are clinical recommendations

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based on the concept that in patients, lower levels of toxicity are acceptable. However, in this

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particular situation, tea polyphenols may not prevent the progression of Barrett’s esophagus to

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esophageal adenocarcinoma; instead, they may have deleterious effects in esophagi with

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inflammation. We have shown that in mice with an inflamed colon, application of tea polyphenols

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generated harmful effects22.

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Mechanistic consideration

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It is clear from the above discussions that, in contrast to the strong cancer preventive activities of

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tea or tea polyphenols shown in animal models, many human studies did not show a strong or

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clear-cut cancer preventive activity of tea consumption. One of the reasons for this gap is that in

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animal studies, investigators tend to select the best experimental conditions, including the doses

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of tea polyphenols, for the experiment. Whereas in human studies, many genetic, life-style and

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other interfering factors cannot be readily controlled or properly corrected for. The mechanisms of cancer prevention by the tea polyphenol EGCG have been reviewed1,

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4, 23,

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It should be mentioned that these data and most of the mechanistic information in the literature

and are not discussed in detail herein. Some of the proposed mechanisms are shown in Fig. 2.


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were derived from studies in vitro. When used properly, valuable information can be obtained from

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studies in cell lines. For example, the study of 67kDa laminin receptor (67LR) has been carried in

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a series of studies from cell lines to a xenograft model demonstrating that the activation of 67LR

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by EGCG could inhibit tumorigenesis by the implanted cancer cells24. However, this line of work

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would be more relevant to cancer therapy than cancer prevention. On the other hand, numerous in

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vitro studies were conducted without considering the redox and binding properties of the tea

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polyphenols, as well as the differences between in vitro and in vivo systems, such as the issue of

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bioavailability. Therefore, the mechanisms of action of tea polyphenols proposed based on those

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in vitro studies could be misleading. Apparently, mechanisms that have been confirmed in animal

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models should carry more weight. These mechanisms include the inhibition of the phosphorylation

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of c-Jun and extracellular signal-regulated kinase 2 (Erk1/2) in a lung tumorigenesis model;

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suppression of phosphoAkt (Ak transforming, also known as protein kinase B) and nuclear β-

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catenin levels in colon cancer models; inhibition of the insulin-like growth factor (IGF)/IGF-1R

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axis in colon, prostate and other cancer models; and suppression of vascular endothelial growth

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factor (VEGF)-dependent angiogenesis in lung and prostate cancer models1, 4. It is unclear whether

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these molecules are direct targets for EGCG or subsequent events of the primary action of tea

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polyphenols. It is also unknown whether some of these mechanisms are involved in human cancer

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prevention. In humans, the antioxidant action, as well as the enhanced ability to metabolic

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elimination of environmental carcinogens, could play a role4.

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PREVENTION OF OVERWEIGHT, DIABETES AND CARDIOVASCULAR DISEASES

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Overweight, obesity, T2D and CVDs are emerging as some of the major health issues in developed

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and many developing countries. There is a common mechanistic link for all of these disorders,

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caused by excessive consumption of calories and insufficient physical activities. Obesity related 9 ACS Paragon Plus Environment


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adipose inflammation is known to cause insulin resistance (IR), which leads to T2D and increases

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the risk for CVDs. These diseases are preceded by a group of chronic metabolic disorders known

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as MetS, which includes enlarged waist circumference, elevated serum levels of triglycerides,

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dysglycemia, reduced levels of high-density lipoprotein associated cholesterol, and high blood

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pressure. The effects of tea consumption on these abnormal metabolic conditions and diseases

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have been extensively studied in animal models and humans1-3.

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Studies in animal models

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Many studies in animal models, using high-fat diets or genetically induced obese/diabetic rodent

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models, have shown that oral administration of GTE or EGCG significantly reduced the gain of

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body weight and/or adipose tissue weight, lowered blood glucose or insulin levels, and increased

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insulin sensitivity. For example, in mice fed a high-fat (60% of the calories) diet, we found that

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EGCG (0.32% in diet) treatment for 16 weeks significantly reduced body weight gain, body fat

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and visceral fat weight25. It also attenuated IR, plasma cholesterol levels and monocyte

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chemoattractant protein levels25-26. Similar results were also observed in several recent studies27-

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32.

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triglycerides and plasma alanine aminotransferase concentration in mice fed a high-fat diet25-26.

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These findings have potential for practical applications in health maintenance.

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Studies in humans

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Earlier systematic reviews and meta-analyses of short-term RCTs indicated the beneficial effects

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of tea consumption in reducing body weight and alleviating MetS33-34. Most of these studies used

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green tea or GTE (600-900 mg/day) for 8-12 weeks on normal weight or overweight subjects. A

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meta-analysis of metabolic studies showed that catechins and caffeine dose-dependently

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stimulated daily energy expenditure, while only the combination of catechin and caffeine

In addition, EGCG treatment markedly reduced the severity of hepatic steatosis, liver


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significantly increased fat oxidation35. A more recent meta-analysis of 10 RCTs indicated that tea

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or tea extracts could reduce waist circumference and the decrease of fasting insulin after an 8-week

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intervention, but did not affect other parameters measured36. However, there are also studies that

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showed negative results37-39. A meta-analysis of six RCTs on individuals with pre-diabetes/T2D

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shows no difference in fasting glucose and insulin levels, as well as hemoglobin A1c levels,

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between groups treated with green tea or GTE and the placebo group40. Some of the results are

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probably due to the rather low dose of EGCG (200 mg daily) used37. Reasons for the other studies

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are unknown and remain for further investigation.

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Results on epidemiological studies concerning effects of green tea consumption in

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alleviating MetS and diabetes have not been consistent1. For example, a prospective cross-

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sectional study with U.S. women showed that daily consumption of four or more cups of tea was

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associated with a 30% lower risk of developing T2D41. A retrospective cohort study of 17,413

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Japanese adults aged 40-65 years indicated that daily drinking more than six cups of green tea

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lowered the morbidity of diabetes by 33%42.

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participants) showed that individuals who drank 3-4 or more cups of tea per day had a lower risk

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of T2D43. A systematic review and meta-analysis of 12 eligible cohort studies suggest that tea

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consumption ( ≥ 3 cups/day) was associated with a lower T2D risk44. However, other studies did

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not observe benefits of tea consumption45-46. A recent large cohort study, the combined Shanghai

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Women’s Health Study and the Shanghai Men’s Health Study (n=52,315), indicated that current

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tea drinkers had an increased risk of T2D compared with non-current drinkers (HR=1.2), and a

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dose-response relationship was observed for the duration of tea drinking and amount of tea

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consumed47. A possible explanation of this surprising result from this well-established cohort was

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the presence of pesticide residue in tea as a contributing factor47. A similar explanation was also

A meta-analysis of seven studies (286,701



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given in the above review article by Yang et al.44 Hayashino et al. also attributed pesticide residue

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to the positive association between oolong tea consumption and T2D48. The association of

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pesticide exposure and the risk for T2D has been reported previously49-50.

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The possible reduction of CVD risk by polyphenols from tea and other dietary sources has 51-53).

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been extensively studied (reviewed in

Many human studies have shown that green tea

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consumption decreases plasma cholesterol levels and blood pressure, while improves insulin

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sensitivity and endothelial function (reviewed in

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participants) showed that supplementation of green tea significantly reduced systolic and diastolic

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blood pressure in pre-hypertensive and hypertensive individuals55. Another meta-analysis of 14

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RCTs also concluded that GTE supplementation significantly (though slightly) lowered blood

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pressure among overweight and obese adults56. In a large cohort in China (Dongfeng-Tongji cohort

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study involving 19,471 participants followed for 3.3 – 5.1 years), green tea consumption was

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associated with a reduced risk of coronary heart disease as well as related biomarkers in middle-

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aged and older Chinese population57. Similarly, in a large prospective study using the China

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Kadorie Biobank, involving 512,891 participants (aged 30-79) and a median follow-up of 7.2

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years, daily tea consumption was associated with a reduced risk of ischaemic heart disease58. In a

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recent multiethnic study of men and women (6508 participants with a median follow-up of 11.1

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years) in the U.S., tea drinking was associated with lower incidence of cardiovascular events and

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coronary artery calcification. However, coffee drinking was associated with an increased incidence

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of cardiovascular events59.

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Mechanistic considerations

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The beneficial effects of tea polyphenols on cardiometabolic health could be due to their actions

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in the gastrointestinal tract as well as systemic actions in different organs after absorption.

53-54).

A meta-analysis of 10 trials (834


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Together, these actions would reduce body weight, alleviate MetS and reduce the risk of T2D and

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CVDs.

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As reviewed previously, ingestion of green tea polyphenols has been shown to increase

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fecal lipid and total nitrogen contents, suggesting that polyphenols decrease digestion and

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absorption of lipids and proteins2. The decreased digestion of starch and sugar absorption by tea

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polyphenols has also been reported. Many publications showed that the gut microbiome is altered

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with the consumption of tea polyphenols and suggested a possible role of gut bacteria in promoting

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health. For example, recent publications reported that dietary green tea polyphenols at different

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doses attenuated body weight gain and decreased the ratio of Firmicutes to Bacteroidetes in mice

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fed a high-fat diet60-64. It is unclear, however, whether these results reflect the fact that the green

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tea polyphenol treatment prevented the high-fat diet induced changes in microbiota. The role of

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intestinal microbiota in mediating the beneficial effects of green tea remains unclear. In the 15

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recent human and rodent studies that are reviewed, many studies reported a correlation between

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the observed microbiota changes with lowering blood glucose levels or body weight. Bacteria

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species belonging to different genera was identified, but the impact of tea polyphenols at the phyla

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level were inconsistent among studies.

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The coordinated suppression of gluconeogenesis and lipogenesis, together with increased glucose

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utilization and lipolysis, by tea polyphenols2 suggest that their actions are mediated by key energy

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sensing molecules, such as AMP-activated protein kinase (AMPK). We will refer to this as the

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AMPK hypothesis. In response to falling energy status, AMPK is phosphorylated and activated to

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inhibit anabolism and promote catabolism to produce ATP65-67. The activation of AMPK by EGCG,

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green tea, black tea, Oolong tea and Puer teas has been demonstrated68-74; even though activation

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of AMPK was observed in adipose tissues and skeletal muscle, but not in the liver in some



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studies68-74. The activation of AMPK by EGCG was associated with the downregulation of

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phosphoenolpyruvate carboxykinase and glucose-6-phosphatase together with decreased glucose

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production in the liver, as well as to inactivate (phosphorylate) Acetyl-CoA carboxylase – the rate

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limiting enzyme of fatty acid synthesis75. The molecular mechanism by which EGCG activates

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AMPK is not clear, although the involvement of ROS has been suggested based on studies in vitro

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75.

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myotubes was suggested to involve an indirect mechanism by affecting mitochondrial ATP

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production76. Valenti et al. reported that EGCG inhibited mitochondrial oxidative phosphorylation

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and decreased ATP levels77. EGCG could serve as an electron transport inhibitor or uncoupler of

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oxidative phosphorylation to increase the AMP (ADP) to ATP ratio and activate AMPK. In such

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cases, the involvement of ROS may not be essential for AMPK activation. Our recent results78, as

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will be described in more detail in a later section, showed that pretreatment of mice with melatonin

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decreased the toxicity of subsequent administered EGCG by the quenching of ROS, but did not

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affect the action of EGCG in downregulating the genes mediating gluconeogenesis and

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lipogenesis78. If such action is mediated by the activation of AMPK, then the results suggest that

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ROS is not needed for AMPK activation in vivo. If this is the mechanism, we predict that the p-

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AMPK/AMPK ratio would increase a few hours after oral administration of EGCG to rodents

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when EGCG reaches the liver, adipose tissues and muscles. However, this increase of the p-

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AMPK/AMP ratio was only found in one strain of mice, but not in many other preliminary

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experiments in our laboratory (Yang et al., unpublished results). The AMPK hypothesis needs to

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be further tested.

In a recent publication, the activation of AMPK by mitochondria-derived ROS in C2C12 mouse

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The effects of tea polyphenols in lowering plasma cholesterol levels, preventing

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hypertension and improving endothelial function all contribute to the prevention of CVDs. The 14 ACS Paragon Plus Environment

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cholesterol lowering effect is likely due to the decrease of cholesterol absorption or reabsorption

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by polyphenols, as well as the decrease of cholesterol synthesis via the inhibition of HMG-CoA

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reductase1,

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mechanism for green and black tea polyphenols to decrease blood pressure, vasodilation and the

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severity of myocardial infarction53,

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effects, a very high dose (1% in diet) promoted, rather than attenuated, vascular inflammation in

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hyperglycemic mice84. In a recent cross-over RCT with 19 hypertensive patients, supplementation

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with black tea (150 mg polyphenols twice a daily for 8 days) increased functionally active

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circulating angiogenic cells and flow-mediated dilation85. These findings demonstrate that black

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tea also has vascular protective properties.

79.

Enhanced endothelial nitric oxide signaling has been suggested as a common

80-83.

While moderate doses of EGCG yielded beneficial

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We proposed that most of the observed beneficial effects of tea polyphenols can be

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explained by the decreased absorption of macronutrients and their systemic effects in coordinated

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metabolic regulation, such as the activation of AMPK. Actions that are independent of AMPK

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may also be involved, and some of these actions have been discussed86-88. The relative importance

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of these two modes of action depends on the types and amounts of tea consumed as well as the

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diets used. For example, with black tea, the decrease of nutrient absorption, especially with a high-

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fat diet, may play a more important role than its systemic effects, which are limited by the low or

349

no systemic bioavailability of theaflavins and thearubigins in black tea.

350

TOXICITY OF TEA CATECHINS AND POSSIBLE MODULATING FACTORS

351

Brewed tea is presumed to be a healthy beverage with no reported studies on the toxicity of tea in

352

clinical and laboratory settings before this century. Nevertheless, there were anecdotal reports of

353

stomach irritation after ingesting green tea, especially with an empty stomach. In the Chinese

354

classical writing, “Compodium of Materia Medica” by Li Shizhen in the Ming Dynasty, there were



355

statements concerning harmful effects of tea consumption in people who were “weak and frail”.

356

These were case reports on gastrointestinal diseases caused by the consumption of tea.

357

Toxicity of green tea polyphenols

358

In the past two decades, however, case reports of liver toxicity of tea began to appear in scientific

359

literature. These were mostly on individuals who took tea extract-based dietary supplements,

360

mainly for the purpose of weight reduction. For example, after taking 41-108 g of tea extract in

361

total doses, elevation of serum aminotransferase activities started to occur, and the elevated

362

aminotransferase returned to normal levels after stopping the supplement. In some cases, upon

363

re-challenging the dietary supplement, further injury of the liver occurred89-90. The toxicity has

364

been attributed to EGCG, the major constituent, although other catechins may also contribute to

365

the toxicity.

366

In the same time period, laboratory experiments on tea polyphenols started to emerge. For

367

example, an oral dose of 2,000 mg EGCG/kg was reported to be lethal to rats, while a dose of 200

368

mg EGCG/kg showed no toxicity91. In fasting dogs, a single bolus oral dose of 500 mg EGCG/kg

369

caused gastrointestinal damage and morbidity. However, the same dose given to pre-fed dogs in

370

divided doses showed no toxicity. The no-observed-adverse-effect-level (NOAEL) was reported

371

to be 500 mg EGCG/kg per day91. In our previous studies in mice, daily administration of 500-750

372

mg EGCG/kg i.g. caused dose-dependent liver toxicity and lethality92. In our recent studies,

373

administration of EGCG at 70 mg/kg i.p. on days 0 and 1 resulted in total death on days 2-4,

374

whereas 30 mg/kg was not toxic78. Apparently, the i.g. dose was much less toxic than the i.p. dose

375

because of limited systemic bioavailability of orally administered EGCG. It was also clear that

376

administration of a large dose of EGCG to an empty stomach would readily damage the

377

gastrointestinal tract and other organs, while divided doses will reduce or devoid of toxicity.


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The possible toxicity of tea extracts has raised concerns of the regulatory agents, and a

379

tolerable upper intake level was set at 300 mg EGCG per day for humans in some European

380

countries, such as France and Italy8, 93. There are three excellent review articles discussing the

381

toxicity of green tea polyphenols in humans and animals, as well as the tolerable upper intake

382

levels of tea catechins. Yates et al.8 and Dekant et al.93 reported that the NOAEL to be 600 mg

383

EGCG per day for humans. Hu et al.94 also reviewed the topic and proposed a safety level for

384

humans of 338 mg EGCG per day in a bolus dose and 704 mg EGCG in beverage dose.

385

Factors affecting toxicity of tea polyphenols

386

In the recent Minnesota Green Tea Trial in postmenopausal women, about 5% of the women taking

387

GTE had elevated serum aminotransferase activity6. It is unclear why in a population taking the

388

same dose of GTE, some had liver toxicity, but others did not. Three factors that may affect GTE

389

toxicity are discussed below.

390

a. Genetic polymorphism of catechol-O-methyltransferase (COMT)

391

COMT catalyzes the methylation of the phenolic groups at the 4- or 4`- position of EGCG, using

392

S-adenosyl methionine as a methyl donor. The purpose is to eliminate the catechol structure, which

393

is susceptible for oxidation to quinones, which can undergo redox cycling with molecular oxygen

394

to produce ROS. The COMT gene exists in low activity (L) and high activity (H) form. The COMT

395

hypothesis is that individuals with the LL genotype may be more susceptible to EGCG toxicity

396

than those with the high affinity forms. However, this hypothesis has not been verified. We found

397

that men carrying the LL genotype excreted less tea polyphenols in the urine than those with the

398

LH and HH genotype95, and the reason is not known.

399

b. Possible protective factors



400

In our recent study78, pretreatment of mice with melatonin (50 mg/kg, i.p.) for two days extended

401

survival time of mice subsequently treated with EGCG (70 mg/kg, i.p. on days 0 and 1), possibly

402

by decreasing oxidation stress. The pretreatment also reduced liver injury and hepatic Nrf2

403

activation caused by EGCG (55 mg/kg, i.p. for 4 days). However, it did not compromise the action

404

of EGCG (45 mg/kg i.p.) in the downregulation of genes mediating gluconeogenesis and

405

lipogenesis78. If the downregulation of these metabolism genes is mediated by AMPK, the results

406

suggest that ROS is not involved in the activation of AMPK. In theory, the induction of antioxidant

407

and cytoprotective enzymes, such as the Nrf2-dependent cytoprotective enzymes, would help to

408

reduce the toxicity of a subsequent administration of a high dose of EGCG. In fact, James et al.

409

have demonstrated that pre-administration of a moderate amount of EGCG, which enhances the

410

cytoprotective enzymes, protects the toxicity of subsequently administered EGCG96.

411

c. Possible factors that enhance toxicity

412

We have demonstrated recently that dithiocarbamates (DTC) enhance toxicity of EGCG. For

413

example, co-administration of EGCG (30 mg/kg, i.p.) and diethyldithiocarbamate – metabolite of

414

disulfiram – at a dose of 500 mg/kg i.p. synergistically induced liver toxicity and lethality97. The

415

proposed mechanism is that DTC increases the level of redox-active copper, which promotes

416

EGCG oxidation and toxicity in the liver. DTC are widely used in agriculture, industry and

417

therapeutics. The present demonstration-of-principle could have significant implications in

418

understanding tea consumption and environmental toxicity. This concept may be extended to

419

isothiocyanates, which are widely occurring in our diet. Isothiocyanates, upon conjugation with

420

GSH, can form DTC, which could enhance EGCG toxicity. On the other hand, isothiocyanates,

421

such as sulfuraphane and phenethyl isothiocyanates, are known inducers of Nrf2 and are proposed

422

to have cancer preventive activities. In principle, if the Nrf2 system is induced by exposure to


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423

isothiocyanates through the diet, it could reduce the toxicity of the subsequent exposure to large

424

doses of EGCG. In the same train of thought, other polyphenols from our diet, when ingested

425

together with EGCG both at large doses, could combine to cause liver toxicity by producing

426

excessive amounts of ROS and depleting the oxidant defense system in cells.

427

Dosage forms and toxicity – Doses in bolus versus beverage

428

Dosage form is a major factor affecting the toxicity of tea catechins. As illustrated in Figure 2A,

429

in a hypothetic situation, if a person drinks six cups of green tea throughout the day, the blood

430

catechin levels will increase after the initial dose and reach the peak value in 1-2 hours, then the

431

catechins are eliminated with a half-life of 1-3 hours10. Subsequent consumption of 5 additional

432

cups of tea, with an interval of 1-2 hours, will cause an accumulation of catechins in the blood and

433

tissues. However, they will still be below the threshold for toxicity. However, when the total

434

amount of tea catechins is taken in a bolus dose in capsules or pills, the blood and tissue levels

435

could reach levels over the threshold of toxicity. If a person drinks the “6 cups of tea” slowly and

436

continuously through the day, as some individuals might do in China, that would be similar to the

437

situation when tea catechins are put in animal diet in animal studies. As shown in Figure 2B, in

438

animal studies with catechins in the diet, the animals start eating when the room light is switched

439

off at 6:00 PM and do most of the eating at night, causing the blood and tissue catechin levels to

440

rise, plateau and then decrease after reducing their food intake in early morning. The blood and

441

tissue levels do not reach the threshold of toxicity. Whereas the same amount of catechins

442

administered i.g. in one dose can cause toxicity, and the toxicity may be avoided by giving the

443

same dosage in two or more administrations. In our previous studies, when EGCG was

444

administered at 500 mg/kg per day through the diet (containing 0.32% EGCG), the plasma level



445

measured was 231 ng/ml, whereas administration by i.g. produced a plasma peak level of 898

446

ng/ml92.

447

Therefore, even though a tolerable upper intake level was set at 300 mg EGCG per day in

448

some European countries, and an NOAEL has been reported to be at 600 mg EGCG per day8, it

449

does not mean that this is the limit of human consumption through beverage forms. Hu et al.94

450

proposed a safety level for human consumption of 338 mg EGCG in a bolus dose and 704 mg

451

EGCG in beverage dose per day. However, even in beverage forms, the possible toxicity depends

452

on whether the beverage is consumed in a short period of time or throughout the day.

453

CONCLUDING REMARKS

454

As discussed above, the beneficial health effects of tea catechins in the prevention of cancer and

455

cardiometabolic diseases have been demonstrated in animal models and in humans, even though

456

the results of some of the human studies are inconsistent. Some of the discrepancies between the

457

results in animal studies and human studies may be due to the lower doses of tea used in humans.

458

A critical issue is “what are the effective catechin doses for the beneficial effects?” There is no

459

precise information on this topic. As we discussed, 400 mg GTE twice (total 800 mg) a day18 or

460

657 mg of catechins twice a day5 have shown beneficial effects in prostate or breast cancer

461

prevention studies, respectively. In the prevention of obesity, MetS and T2D, daily consumption

462

of 3-4 cups of tea (600-900 mg/day) has been often cited as doses for individuals to begin having

463

a lower risk for disease. However, these are also the doses that start to produce liver toxicity in

464

some individuals5, and these are higher than the set levels of 300 mg EGCG for tolerable upper

465

intake level and 600 mg of EGCG for NOAEL8, 93. Tea consumption has not been reported in a

466

precise uniform way. A confusing issue is the use of "cups". In the United States, a “cup” is a

467

measurement of volume, equivalent to 236.58 ml. Whereas, in some other countries, a "cup" of tea


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468

is just a cup of tea and it may be of a different volume. The quantity of tea catechins consumed is

469

the real dose and this is even less well-defined, even though the USDA Database shows that a cup

470

of tea (236 ml) contains 300 mg catechins. In a recent study in Shanghai, the quantity of tea

471

consumption was expressed as grams of tea consumed per month47. For example, the medium level

472

of tea consumption was set at 200-250 g/month for men. If there is information on the approximate

473

catechin composition of the tea and the estimated average amounts of catechins that appear in

474

brewed tea, then the authors and readers can estimate the catechin consumption more accurately.

475

Another challenging question is on the mechanisms of actions and whether the reported

476

beneficial health effects of green tea involve the same mechanisms of action as those that produce

477

toxicity. At low doses of tea consumption, the catechins are likely to serve as direct antioxidants,

478

quenching ROS and preventing their formation (Figure 3). At moderate doses, they may produce

479

ROS, which can activate the Nrf2-dependent enzyme systems and exert cytoprotective functions11.

480

These antioxidant and cytoprotective activities are proposed to be a common mechanism by which

481

catechins contribute to the beneficial health effects of tea. For the prevention of specific diseases,

482

such as cancer, diabetes and CVDs, specific mechanisms discussed herein and in previous

483

reviews1-4 may be involved. It is unclear whether the anti-diabetic metabolic regulation, such as,

484

the upregulation catabolism and downregulation of anabolism of glucose and fatty acids

485

(possibly through AMPK), occur at similar moderate catechin intake. This will be a very

486

interesting area of future research. At higher doses of catechin intake, the ROS produced would

487

overpower the cytoprotective enzyme systems, causing cellular and tissue damage. An interesting

488

topic to be further investigated is whether the same amount of tea catechins in isolated forms (or

489

pure EGCG) are more toxic than the same amount of catechins in tea beverages. The possible



490

protective effects of caffeine and theanine against catechin toxicity have been discussed, and this

491

concept needs to be substantiated experimentally.

492

Acknowledgement

493

We acknowledge the support of U.S. NIH grant CA133021 and thank Ms. Vi P. Dan for her

494

assistance in drawing the figures and preparing this manuscript.


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63. Cheng, M.; Zhang, X.; Miao, Y.; Cao, J.; Wu, Z.; Weng, P., The modulatory effect of (-)epigallocatechin 3-O-(3-O-methyl) gallate (EGCG3''Me) on intestinal microbiota of high fat diet-induced obesity mice model. Food Res Int 2017, 92, 9-16. 64. Singh, D. P.; Singh, J.; Boparai, R. K.; Zhu, J.; Mantri, S.; Khare, P.; Khardori, R.; Kondepudi, K. K.; Chopra, K.; Bishnoi, M., Isomalto-oligosaccharides, a prebiotic, functionally augment green tea effects against high fat diet-induced metabolic alterations via preventing gut dysbacteriosis in mice. Pharmacol Res 2017, 123, 103-113. 65. Long, Y. C.; Zierath, J. R., AMP-activated protein kinase signaling in metabolic regulation. The Journal of clinical investigation 2006, 116 (7), 1776-83. 66. Hardie, D. G.; Ross, F. A.; Hawley, S. A., AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nature reviews. Molecular cell biology 2012, 13 (4), 251-62. 67. Hardie, D. G., AMPK: positive and negative regulation, and its role in whole-body energy homeostasis. Current opinion in cell biology 2015, 33, 1-7. 68. Murase, T.; Misawa, K.; Haramizu, S.; Hase, T., Catechin-induced activation of the LKB1/AMPactivated protein kinase pathway. Biochem Pharmacol 2009, 78 (1), 78-84. 69. Banerjee, S.; Ghoshal, S.; Porter, T. D., Phosphorylation of hepatic AMP-activated protein kinase and liver kinase B1 is increased after a single oral dose of green tea extract to mice. Nutr Res 2012, 32 (12), 985-90. 70. Zhou, J.; Farah, B. L.; Sinha, R. A.; Wu, Y.; Singh, B. K.; Bay, B. H.; Yang, C. S.; Yen, P. M., Epigallocatechin-3-gallate (EGCG), a green tea polyphenol, stimulates hepatic autophagy and lipid clearance. PloS one 2014, 9 (1), e87161. 71. Serrano, J. C.; Gonzalo-Benito, H.; Jove, M.; Fourcade, S.; Cassanye, A.; Boada, J.; Delgado, M. A.; Espinel, A. E.; Pamplona, R.; Portero-Otin, M., Dietary intake of green tea polyphenols regulates insulin sensitivity with an increase in AMP-activated protein kinase alpha content and changes in mitochondrial respiratory complexes. Molecular nutrition & food research 2013, 57 (3), 459-70. 72. Yamashita, Y.; Wang, L.; Wang, L.; Tanaka, Y.; Zhang, T.; Ashida, H., Oolong, black and pu-erh tea suppresses adiposity in mice via activation of AMP-activated protein kinase. Food Funct 2014, 5 (10), 2420-9. 73. Yamashita, Y.; Wang, L.; Tinshun, Z.; Nakamura, T.; Ashida, H., Fermented tea improves glucose intolerance in mice by enhancing translocation of glucose transporter 4 in skeletal muscle. J Agric Food Chem 2012, 60 (45), 11366-71. 74. Rocha, A.; Bolin, A. P.; Cardoso, C. A.; Otton, R., Green tea extract activates AMPK and ameliorates white adipose tissue metabolic dysfunction induced by obesity. European journal of nutrition 2016, 55 (7), 2231-44. 75. Collins, Q. F.; Liu, H. Y.; Pi, J.; Liu, Z.; Quon, M. J.; Cao, W., Epigallocatechin-3-gallate (EGCG), a green tea polyphenol, suppresses hepatic gluconeogenesis through 5'-AMP-activated protein kinase. J Biol Chem 2007, 282 (41), 30143-9. 76. Hinchy, E. C.; Gruszczyk, A. V.; Willows, R.; Navaratnam, N.; Hall, A. R.; Bates, G.; Bright, T. P.; Krieg, T.; Carling, D.; Murphy, M. P., Mitochondria-derived ROS activate AMP-activated protein kinase (AMPK) indirectly. J Biol Chem 2018, 293 (44), 17208-17217. 77. Valenti, D.; de Bari, L.; Manente, G. A.; Rossi, L.; Mutti, L.; Moro, L.; Vacca, R. A., Negative modulation of mitochondrial oxidative phosphorylation by epigallocatechin-3 gallate leads to growth arrest and apoptosis in human malignant pleural mesothelioma cells. Biochim Biophys Acta 2013, 1832 (12), 2085-96. 78. Wang, D.; Wei, Y.; Wang, T.; Wan, X.; Yang, C. S.; Reiter, R. J.; Zhang, J., Melatonin attenuates (-)epigallocatehin-3-gallate-triggered hepatotoxicity without compromising its downregulation of hepatic gluconeogenic and lipogenic genes in mice. J Pineal Res 2015, 59 (4), 497-507. 27 ACS Paragon Plus Environment


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Metabolites among Daily Green Tea Drinkers. International journal of molecular epidemiology and genetics 2010, 1 (2), 114-123. 96. James, K. D.; Forester, S. C.; Lambert, J. D., Dietary pretreatment with green tea polyphenol, (-)epigallocatechin-3-gallate reduces the bioavailability and hepatotoxicity of subsequent oral bolus doses of (-)-epigallocatechin-3-gallate. Food Chem Toxicol 2015, 76, 103-8. 97. Zhang, K.; Dong, R.; Sun, K.; Wang, X.; Wang, J.; Yang, C. S.; Zhang, J., Synergistic toxicity of epigallocatechin-3-gallate and diethyldithiocarbamate, a lethal encounter involving redox-active copper. Free Radic Biol Med 2017, 113, 143-156.

786



787

Figure legends

788

Figure 1. Chemical structure of major green tea catechins. EC, (-) epicatechin; ECG, (-)

789

epicatechin-gallate, EGC, (-) epigallocatechin; EGCG, (-)-epigallocatechin-3-gallate.

790 791

Figure 2. Possible targets for the cancer preventive activity of EGCG (A) and subsequent cellular

792

events (B). Some of these are direct binding targets; others are affected indirectly. The reported

793

effective concentrations, in IC50, Ki (inhibition constant) or Kd (dissociation constant) are shown

794

in μM. All these are from studies in vitro. When two values are given, the first value is from cell-

795

free systems and the second value is from studies in cell lines (modified from reference 23). For

796

more detailed description, please see

797

ROS, reactive oxygen species; DNMT, DNA methyltransferase; CDKs, cyclin-dependent kinases;

798

IGF1R, IGF1 receptor; HIF-1α, hypoxia-inducible factor 1-alpha; Pin1, peptidyl prolyl cis/trans

799

isomerase; DHFR, dihydrofolate reductase; MMPS, matrix metalloproteinases; G3BP, Ras-

800

GTPase-activating protein SH3 domain-binding protein; ZAP70, zeta-chain-associated protein

801

kinase 70; Bcl2, B-cell lymphoma 2; GRP78, glucose-regulated protein 78 kDa; 67LR, 67kDa

802

laminin receptor; STAT1, signal transduction activator of transcription 1; VEGFA, vascular

803

endothelial growth factor A; EGFR, epidermal growth factor; HGFR, hepatocyte growth factor

804

receptor; SIP, sphingosine-1-phosphate receptor.

23.

Abbreviations: EGCG, (-)-epigallocatechin-3-gallate;

805 806

Figure 3. Diagram illustrating the effects of different dosage forms of catechins and consequences

807

in toxicity. In humans (A), intake of six cups of tea throughout the day (black curves) versus the

808

same dose of catechins taken as a bolus dose (red). In mice (B), catechins administered in the diet

809

(green) versus the same amount of catechins administered i.g. in one dose (red).


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810

Figure 4. Proposed dose-dependent effects of catechins on health. At low doses, EGCG and other

811

catechins serve as direct antioxidants. At medium doses, catechins produce moderate levels of

812

ROS that induce Nrf2-dependent cytoprotective enzymes. Both of these mechanisms and other

813

specific mechanisms produce beneficial health effects in preventing cancer and cardiometabolic

814

diseases.

815 816



Figure 1

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Studies on the Prevention of Cancer and Cardiometabolic Diseases

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