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1. Green Tea Catechins

Green tea (GT) derived from the leaves of the Camellia sinensis plant is a rich source of the polyphenols known as catechins. A 240 mL or 8 ounce serving of GT contains, in solution, 300 mg catechins: (-)- epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin, (EGC), (-)-epicatechin-3-gallate (ECG), (-)-epicatechin (EC) [1], and approximately 30 mg of the stimulant caffeine. The catechins are potent antioxidants that can react with and reduce many different reactive oxygen species [2]. While once thought to inhibit carcinogenesis chiefly by inactivation of dietary oxidants, catechins have been shown to have additional properties inside cells that may contribute to the perceived health benefits of drinking GT ^[3][4][3,4]. These include interactions with intracellular proteins so to alter: apoptosis, transformed cell proliferation, angiogenesis, DNA repair, and enzymatic detoxification of ROS, etc. ^[2][4][5][2,4,5].

2. GT Inhibition of Rodent Cancer

Published reviews detail the many rodent studies documenting the ability of GT extract or GT polyphenol consumption to prevent digestive tract tumors ^[6][7][6,7]. Studies of the oral cavity and the esophagus include usage of hamster, rat, and mouse models to show that GT extract or purified polyphenols in drinking water can inhibit the induction of tumors by various carcinogens at both sites ^{[8][9][10][11][12][13]}[8–13]. At least five published studies alone have shown a cancer preventive effect of GT or GT polyphenols on oral cancer induced by 3 different carcinogens ^{[8][9][12][20][21]}[8,9,12,20,21]. GT form or method of application may have differed, and dose may have had some species specificity, but all these studies saw a positive result as shown in Table 1.

Table 1.

Extract/polyphenol effects on rodent oral squamous cell carcinoma models.

¹ GT polyphenol given after 4-Nitroquinoline 1-oxide (4-NQO) oral application completed

² GT extract given for 18 weeks, after 7,12-dimethylbenz[a]anthracene (DMBA) oral application completed

³ GT extract given 2 weeks before and then concurrent with 15 weeks DMBA oral application

⁴ ECGC injections after syngeneic mouse tumor cell injections

⁵ ECGC given daily for last 24 weeks of N-Nitrosodiethylamine (NDEA) oral application

⁶ Inhibition of incidence of OSCC; or for Swiss albino mice only, moderate to severe dysplasia of tongue

⁷ NS: not significant

3. GT Inhibition of Human Cancer

Human studies have not shown the same consistently high level of efficacy of GT or GT polyphenols in prevention of oral cancer or any other cancers ^[4][6][7][4,6,7]. Epidemiological studies of esophageal cancers revealed overall little or no association between GT drinking and cancer rates ^[20][21][20,21]. Interestingly, in cohort analyses stratified by sex, protective associations between GT and esophageal cancer were observed for Chinese women [21], and in a case-control study for non-tobacco/non-alcohol users and women users [20]. Studies of oral cancer are similarly variable with limited evidence for GT drinking being a cancer preventive based on epidemiology, though curiously there was a tendency for a benefit in females in a prospective cohort study [22]. An early randomized trial of oral squamous cell carcinoma (OSCC) prevention showed reduction in dysplastic lesions by consuming a GT extract in capsules combined with direct application of 1 g GT extract to the lesion [23] but a later trial showed no statistically significant benefit of GT in capsules as shown in Table 2 [24]. Notably, GT polyphenols are typically consumed in capsules when tested in recent clinical trials on cancer prevention, unlike human epidemiological studies, which may contribute to results ^[24][25][26][24–26]. Conflicting findings have also been seen for GT consumption and incidence rates for a number of other cancers, with modestly lower rates of liver and prostate cancer of self-reported tea drinkers based on meta-analysis ^{[27][28][29][30]}[27–30]. Furthermore, recent trials designed to examine GT effects on breast cancer risk noted liver toxicity among 5% of the study subjects taking capsules with the equivalent of 5 cups decaffeinated GT daily [26]. Overall, a clear association between GT or GT polyphenol consumption and human cancer prevention has not been verified.

3.1. Does GT induce changes in gene expression in cell of the digestive tract?

Assaying RNA or protein level changes in tissue after consumption of potential bioactive compounds, such as GT, is a rapid method to show if the compound has an effect on the tissue, and may help discern if effects relevant to cancer inhibition occur. There are a limited number of studies published on GT polyphenol effects on epithelial gene expression (or RNA levels) under conditions of carcinogenesis  in vivo in rodents but they show clear cut differences in gene expression in rodent tissues after green tea extract is added to the drinking water. .

Published studies of epithelial gene expression changes, induced by catechin or GT extract consumption, in humans, are rare. In a randomized placebo-controlled trial of subjects with oral premalignant changes, immunohistological examination of oral mucosa after 3 months of GT-extract consumption revealed no changes in a range of proteins after exposure. In a subset of those with reduced dysplasia, Cyclin D1 and Vascular Endothelial Growth Factor (VEGF) mucosal levels decreased [24]. Brush biopsy offers a noninvasive and validated method optimized for miRNA measurement of oral epithelial cells [50]. After 4 weeks of GT drinking, human tissue exposed to probably the highest concentration of undiluted tea in the body, the tongue epithelium, showed on average no changes in gene expression due to inter-subject variability in levels of miRNA. Only after differential co-expression analysis, which can correct for a lack of a response in some subjects, did GT-induced changes in miRNA expression become evident ^[51][52][53][51,52,53]. The question arises why doesn't catechin consumption cause clear cut, reproducible changes in gene expression in groups of people?

3.2. Gut and Oral Bacteria May Metabolize GT Polyphenols

It is clear that green tea drinking can change oral bacteria in people ^[53][54]. There is also much evidence that gut bacteria metabolize dietary polyphenols. This can, in theory, transform the polyphenols into more bioavailable forms and stimulate uptake into digestive tract epithelium ^{[31][32][33][34]}. Years ago, it was shown that GT catechins can be metabolized by intestinal bacterial enzymes. Some GT metabolites are more readily taken up by cells than the parent compounds and still retain biological activities relevant to carcinogenesis at least in vitro ^[35][36]. This could allow one to conclude that digestive tract bacteria may contribute to the bioavailability of green tea catechins.

It is clear that green tea drinking can change oral bacteria in people [53,54]. There is also much evidence that gut bacteria metabolize dietary polyphenols. This can, in theory, transform the polyphenols into more bioavailable forms and stimulate uptake into digestive tract epithelium [31–34]. Years ago, it was shown that GT catechins can be metabolized by intestinal bacterial enzymes. Some GT metabolites are more readily taken up by cells than the parent compounds and still retain biological activities relevant to carcinogenesis at least in vitro [35,36]. This could allow one to conclude that digestive tract bacteria may contribute to the bioavailability of green tea catechins.

3.3. Model for How Variable Gut and Oral Microbiota may Affect GT Studies on Humans

People who are non-cohabitating show a great variety of oral and gut microbiota which is reduced in those who live together ^[37][38]. Diet ^[39][40], gut/oral health ^[41][42], and drugs ^[43][44] may further influence gut and oral microbiota. Clinical studies on GT-based prevention do not normally account for variation of aerodigestive tract microbiota or the foods, beverages, and medications ingested. As a result, one would predict that responses to supplemental polyphenol and GT itself would be variable. Whether one is assaying changes in cell function ^[45] or histological changes in cancer-prone sites ^[24], rarely is a consistent net positive result seen across a sample of human subjects. This may be due to the differences in GT metabolizing digestive tract microbes that we suggest are crucial for catechin uptake, turnover, and/or function ^[29][46]. As a result, levels of GT extract that may be appropriate for most individual humans are much too high, for example, in subjects with gut/oral microbes most efficient at converting GT polyphenols to metabolites that are bioactive. Conversely, a study on a rodent cohort consuming GT polyphenols, with bioactivity dependent on digestive tract microbiota which vary little, would reveal consistent changes in gene expression. This would ease GT dosage optimization in a rodent study and make it fairly likely that changes in cancer incidence would be observed. In clinical trials, using humans with variable gut/oral microbiota, that would not be the case ^[47]. For example, humans with high levels of gut/oral bacteria that metabolize GT polyphenol to functional, readily absorbed metabolites might show toxicity, while those with gut/oral bacteria that lack this metabolic activity may show no effect ^[26]. With heterogeneous populations, a dosage would be chosen tolerable to all but the most sensitive subjects. It would vary little between studies and be on-average ineffective and that is what has been observed (Table 2). This is in contrast to rodent studies where levels of catechins given to experimental subjects vary between studies (Table 1). One possible solution is to artificially convert GT polyphenols to forms that are more readily absorbed by cells ^[35][48]. Another would be to characterize subject specific GT toxicity, possibly by measuring each subject’s gut/oral microbiota and its ability to activate and inactivate GT catechins, prior to entry in the trial, or more directly measuring GT metabolites after a trial run of drinking GT.

People who are non-cohabitating show a great variety of oral and gut microbiota which is reduced in those who live together [37,38]. Diet [39,40], gut/oral health [41,42], and drugs [43,44] may further influence gut and oral microbiota. Clinical studies on GT-based prevention do not normally account for variation of aerodigestive tract microbiota or the foods, beverages, and medications ingested. As a result, one would predict that responses to supplemental polyphenol and GT itself would be variable. Whether one is assaying changes in cell function [45] or histological changes in cancer-prone sites [24], rarely is a consistent net positive result seen across a sample of human subjects. This may be due to the differences in GT metabolizing digestive tract microbes that we suggest are crucial for catechin uptake, turnover, and/or function [29,46]. As a result, levels of GT extract that may be appropriate for most individual humans are much too high, for example, in subjects with gut/oral microbes most efficient at converting GT polyphenols to metabolites that are bioactive. Conversely, a study on a rodent cohort consuming GT polyphenols, with bioactivity dependent on digestive tract microbiota which vary little, would reveal consistent changes in gene expression. This would ease GT dosage optimization in a rodent study and make it fairly likely that changes in cancer incidence would be observed. In clinical trials, using humans with variable gut/oral microbiota, that would not be the case [47]. For example, humans with high levels of gut/oral bacteria that metabolize GT polyphenol to functional, readily absorbed metabolites might show toxicity, while those with gut/oral bacteria that lack this metabolic activity may show no effect [26]. With heterogeneous populations, a dosage would be chosen tolerable to all but the most sensitive subjects. It would vary little between studies and be on-average ineffective and that is what has been observed (Table 2). This is in contrast to rodent studies where levels of catechins given to experimental subjects vary between studies (Table 1). One possible solution is to artificially convert GT polyphenols to forms that are more readily absorbed by cells [35,48]. Another would be to characterize subject specific GT toxicity, possibly by measuring each subject’s gut/oral microbiota and its ability to activate and inactivate GT catechins, prior to entry in the trial, or more directly measuring GT metabolites after a trial run of drinking GT.

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