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Cancer Epidemiology Biomarkers & Prevention Vol. 8, 709-713, August 1999
© 1999 American Association for Cancer Research

Ingestion of Green Tea Rapidly Decreases Prostaglandin E2 Levels in Rectal Mucosa in Humans1

David A. August, Janelle Landau, Deborah Caputo, Jungil Hong, Mao-Jung Lee and Chung S. Yang2

Department of Surgery [D. A. A.] and The Clinical Research Center [D. C.], University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901; The Laboratory for Cancer Research, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854-8020 [J. L., J. H., M-J. L., C. S. Y.]; and The Cancer Institute of New Jersey, New Brunswick, New Jersey 08901 [D. A. A., C. S. Y.]


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The objective of this Phase I/II study was to assess the potential for green tea to be used as a colorectal cancer chemopreventive agent. This study measured the dose-related biological effects of administration of a single dose of green tea on the rectal mucosa of normal volunteers. Volunteers were admitted to the Robert Wood Johnson Medical School Clinical Research Center for 24 h. Baseline blood and rectal biopsy samples were obtained before the volunteers drank 0.6, 1.2, or 1.8 g of green tea solids dissolved in warm water. Blood samples were taken 2, 4, 8, and 24 h after the tea administration. Rectal biopsies were obtained at 4, 8, and 24 h. Prostaglandin E2 (PGE2) levels were analyzed by ELISA. Tea polyphenol levels in the blood, urine, and rectal tissue were measured by high-performance liquid chromatography using a Coulochem electrode array detection system. Statistical comparisons were made using ANOVA. Decreased levels of PGE2 in rectal mucosa were observed at 4 and 8 h after consumption of green tea. There was no correlation between inhibition of PGE2 and tissue or plasma levels of tea polyphenols. Ten of 14 subjects demonstrated a response to green tea, as evidenced by at least a 50% inhibition of PGE2 levels at 4 h. We conclude that green tea constituents have biological activity in inhibiting PGE2 synthesis. Given the 71% "response rate," we believe these data support the study of green tea as a colorectal chemopreventive agent in more long-term Phase II trials.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
In the United States, colorectal cancer is the third most common cancer in men and the second most common cancer in women; it is also the second leading cause of cancer deaths overall (1) . Although the mortality rate has been falling over the past 5 decades, the incidence of colorectal cancer has increased slightly since the early 1970s (2) . The frequency of colorectal cancer in the American population and the personal and economic impact of treatment and associated morbidity make it a potentially rewarding target for preventive strategies. Although early detection and treatment have been demonstrated to reduce colorectal cancer mortality, primary prevention potentially offers far greater benefits by reducing morbidity and the costs of colorectal cancer treatment (3) .

Tea (Camellia sinensis) has been suggested as a possible cancer-preventive agent (4) . Most tea is consumed in the form of black tea (78%, primarily in Western countries) or green tea (20%, primarily in Asian countries; Ref. 4 ). Green tea contains a variety of polyphenols, including flavanols, flavandiols, flavanoids, and phenolic acids. Flavanols (catechins) are the major tea polyphenols. The major components responsible for the putative anticarcinogenic activities of tea are not clearly known. In green tea, however, the catechins EGCG,3 EGC, (-)-epicatechin-3-gallate, and EC are believed to be the active components because inhibition of carcinogenesis has been demonstrated with EGCG and mixtures of these polyphenols (4, 5, 6, 7, 8, 9) . Data from animal models of carcinogenesis demonstrate a protective effect of green tea and catechins against carcinogenesis in skin, lung, esophagus, stomach, duodenum, liver, and pancreas (4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19) .

Several animal studies have demonstrated a protective effect of green tea on colon carcinogenesis (20, 21, 22, 23) . Rats that were chemically induced to form colon tumors were protected by low doses of green tea polyphenols (0.01% or 0.1% in the drinking water; Ref. 20) . In another study using very low doses of green tea (0.05%, 0.01%, or 0.002%), rats ingesting the tea had a significantly lower incidence of colon carcinomas (21) . Yet, a more recent study using a similar model did not find significant inhibition of colon carcinogenesis by black tea (24) .

Epidemiological studies of the relationship between tea consumption and human cancer are plagued by multiple confounders and are not conclusive (25) . The epidemiological evidence seems suggestive of a protective effect of tea consumption against the development of colorectal, uterine, and gastric cancers (4 , 26 , 27) . Factors that confound the interpretation of these types of studies include influences of the temperature of the tea on the increased risk for esophageal cancer (26) , type of tea consumed (green versus black), variations in methods of tea preparation, and lifestyle factors that may be associated with tea drinking.

A variety of mechanisms have been suggested for the anticarcinogenic effects of tea polyphenols. Tea polyphenols are antioxidants with the ability to scavenge superoxide anions, singlet oxygen, and lipid peroxy-radicals, and to bind metal ions (4 , 28, 29, 30) . These antioxidant functions of tea polyphenols are generally considered to be important to the anticarcinogenic activities of tea. Inhibition of tumor promotion-related enzymes, including ornithine decarboxylase (31 , 32) , protein kinase C (33) , lipoxygenase (34 , 35) , and cyclooxygenase (34 , 35) by tea preparations may also be important. These activities may be particularly important when considering the potential use of tea preparations for prevention of colorectal cancer.

The effect of green tea on human colon carcinogenesis is unknown. To explore the potential of green tea as a colorectal cancer preventative, we initiated a Phase I trial of the effect of a single ingestion of green tea on a set of colorectal carcinogenesis biomarkers—basal PGE2 levels, cyclooxygenase activity, crypt cell proliferation, and apoptosis—on the rectal mucosa of normal volunteers.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects.
A preliminary study to assess tissue penetration of tea polyphenols was carried out in 10 volunteer subjects scheduled to undergo abdominal surgery with resection of a portion of the intestine. Each of these preliminary subjects ingested 1.2 g of standardized green tea {approx}12 h before surgery. At the time of surgery, 1–10 g of full-thickness intestinal tissue (small bowel, colon, or rectum) was harvested, flash frozen in liquid nitrogen, and stored at –70°C for subsequent determination of tissue polyphenol levels.

For the formal Phase I trial, 15 normal volunteers (ages 22–57) were admitted to the Robert Wood Johnson Medical School Clinical Research Center. They were instructed to start a clear liquid diet devoid of fruit and vegetable juices and tea 36 h before the study and to cease all food and beverage intake, except water, 12 h before the study. None of the volunteers were pregnant or lactating; had renal, hepatic, cardiac, or pulmonary dysfunction, or a coagulopathy; had a history of inflammatory bowel disease or colorectal cancer; were taking nonsteroidal anti-inflammatory drugs or steroids at any time in the 4 weeks before the study; were strict vegetarians; were abusing illicit drugs or alcohol; or had drank greater than two 8-ounce portions of tea per day for 2 weeks before the study. Written, informed consent was obtained from all subjects. These studies were carried out with the approval of the Institutional Review Board of the University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School (protocol number 2095).

Treatment Protocol.
After a tap water enema, baseline blood and rectal biopsies were obtained at 8:00 a.m. Rectal biopsies were obtained with biopsy forceps introduced through an anoscope. A single dose (0.6, 1.2, or 1.8 g) of standardized green tea powder (courtesy of Thomas J. Lipton Co., Englewood Cliffs, NJ) containing {approx}10% by weight of polyphenols (36) was mixed in warm water and drunk by the volunteers at 9:00 a.m. Pooled urine samples were collected between 0–4 h, 4–8 h, and 8–24 h (hour 0 being the time of tea ingestion). Blood samples were drawn at 2, 4, 8, and 24 h, and rectal biopsies were obtained at 4, 8, and 24 h. Four to six rectal biopsies (10–20 mg of full-thickness samples of rectal mucosa) were collected at each time point; half were snap frozen in liquid nitrogen and half were fixed in 10% formalin. All rectal biopsies were obtained in a zone from 4–6 cm centimeters above the dentate line. Each biopsy specimen was obtained from fresh mucosa not previously sampled.

Analytic Methods.
Blood collected for clinical laboratory studies was analyzed in the Clinical Pathology Laboratory of Robert Wood Johnson University Hospital. Blood for tea polyphenol assay was centrifuged, and the plasma fraction was separated and immediately frozen at –70°C. Urine was collected with each void, pooled into appropriate time periods, and was stored frozen at –70°C.

The levels of tea polyphenols in plasma, urine, and rectal biopsies were determined by a HPLC procedure (37) . In brief, the plasma, tissue, or urine was incubated with ß-glucuronidase and sulfatase to convert conjugated polyphenol species to the free forms. The resulting free tea polyphenols were extracted into ethyl acetate, dried under nitrogen, and redissolved in buffer. The individual catechins were analyzed by HPLC using a Coulochem electrode array detection system. To determine basal PGE2 levels, frozen colonic biopsy samples were homogenized at ice temperature in 0.3 ml of 0.1 M Tris-HCl buffer containing 5.6 µM indomethacin (pH 7.4) with a microtube pestel and vortexed thoroughly for 2 min. The homogenate was immediately analyzed for basal PGE2 levels by ELISA according to the manufacturer’s instructions (Cayman Chemical).

After fixation, rectal biopsies were embedded in paraffin and serially sectioned at 5 mm and stained with H&E for histological analysis. The proliferation pattern was analyzed by immunostaining with anti-Ki67 (MIB-1) antibody according to a previously published procedure (38) . The pattern of apoptotic cells was also analyzed. Apoptotic cells were visualized in histopathological sections that maintain crypt architecture by use of terminal deoxynucleotidyl transferase-mediated nick end labeling of apoptotic DNA strand breaks (39) .

All biomarker parameters were assayed and interpreted by an observer blinded to the treatment dose and to the timing of the biopsy (baseline versus some time point after ingestion of tea).

Statistical Analysis.
Percent inhibition of PGE2 was analyzed by a Student’s t test comparing baseline with the other time points. Time- and dose-dependent correlations and polyphenol concentration in tissue and plasma to PGE2 levels correlations were determined by {chi}2 analyses.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Preliminary Study of Tea Polyphenol Levels in Intestinal Mucosa.
Ten subjects (ages 28–80, five females) received 1.2 g of standardized green tea {approx}12 h before laparotomy. Grossly normal intestinal tissue was harvested from the operative specimens and analyzed for tea polyphenol content. The mean ± SE of the polyphenol tissue concentration (ng/g wet tissue) was 382 ± 146 for EGCG, 89 ± 28 for EGC, and 39 ± 23 for EC. These data indicate that significant levels of tea polyphenols were detectable after ingestion of a single, moderate "dose" of tea, equivalent to two to three cups of brewed tea.

Phase I Study.
Fifteen subjects (ages 22–57, two females) participated in the Phase I study. A total of 60 anoscopic biopsy procedures (4 per subject) were carried out. The only complication that occurred was one episode of persistent bleeding from a biopsy site requiring transport of the subject to an operating room for better visualization and suture ligation.

Tea Polyphenol Pharmacokinetics.
Plasma concentration versus time curves for EGCG and EC are shown in Fig. 1, ACitation and BCitation , respectively. Due to an interfering peak, HPLC results for EGC were obscured. Maximal plasma concentration (Cmax) was clearly dose dependent. Maximum plasma polyphenol concentrations occurred at 2 h after tea ingestion. The mean plasma half-life for each of the polyphenols was {approx}4 h for both EGCG and EC.



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  		Fig. 1. Plasma polyphenol concentration versus time curves. Green tea solids were given at three different doses (0.6 g, 1.2 g, and 1.8 g). The plasma concentrations (ng/ml) of EGCG and EC at 0, 4, 8, and 24 h are shown.

 
The highest EGC and EC levels were observed in urine samples collected between 0 and 4 h (Table 1)Citation . EGCG was not excreted in the urine, consistent with the previous results (37) . Tissue concentration/time data for the tea polyphenols in rectal mucosa were variable and not clearly dose dependent (Table 2)Citation .


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  		Table 1 Mean EGC and EC valuesa per green tea dose in urine over time

 

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  		Table 2 Mean EGC, EC, and EGCG valuesa per green tea dose in rectal biopsies over time

 
There was no evident correlation between the dose of tea ingested and the time-dependent concentration of polyphenols in the rectal mucosa.

Levels of PGE2.
Ingestion of green tea decreased rectal mucosal concentrations of PGE2 at 4 and 8 h after tea administration (Fig. 2Citation and Table 3Citation ). At 24 h, the PGE2 concentrations returned to the baseline levels. Although the high dose of tea (1.8 g) was more effective in lowering the PGE2 levels than the low (0.6 g) and moderate (1.2 g) doses, a good dose-dependent effect was not observed because the moderate dose did not produce lower PGE2 levels than the low dose. Seventy-one percent (10 of 14) exhibited a "response" to tea, as evidenced by a >50% reduction in basal PGE2 levels at 4 h after ingestion.



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  		Fig. 2. Basal PGE2 levels (ng/mg of protein) at 0, 4, 8, and 24 h for three doses (0.6 g, 1.2 g, and 1.8 g) of green tea.

 

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  		Table 3 Percent inhibition of PGE2 formation over time after green tea consumption in colorectal tissue

 
Crypt Cell Proliferation and Apoptosis.
Because of wide variability in the histological appearance of immunohistochemical stains of rectal biopsies, presumably reflecting the wide biological variability in individuals (40) , there was no clearly evident effect of green tea ingestion on crypt cell proliferation or apoptosis (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
One strategy to reduce cancer-related deaths is through chemoprevention. Chemoprevention can be defined as controlling the occurrence of cancer by slowing, blocking, or reversing the development of the disease by the administration of naturally occurring or synthetic compounds. Chemopreventive compounds should ideally have: (a) little or no toxic effect; (b) high efficacy against multiple types of cancer; (c) oral administration; (d) known mechanisms of action; (e) low cost; and (f) human acceptance (41, 42, 43, 44) . On the basis of these criteria, it is logical that compounds found naturally in foods and drinks have been investigated. Tea is thought to meet these criteria because it is widely consumed, has no known toxicity, and has demonstrated inhibitory activity against carcinogenesis in animal models (4 , 22, 23, 24, 25) .

Our preliminary study demonstrated that measurable amounts of polyphenols are present in the gastrointestinal tissues. Our present and previous results (37) on plasma and urine concentrations of tea catechins indicated that these compounds are absorbed. The effect of p.o. administered tea was rapid; at 4 and 8 h after tea administration, PGE2 levels were significantly lower at all doses of tea. Although the 1.8-g dose seemed to be more effective in lowering PGE2 formation than the 0.6-g dose, a good dose-response relationship was not observed. This was probably due to the variability of the individuals and sampling procedure. There were no correlations between the inhibition of PGE2 formation and the tea polyphenol levels in the plasma or rectal tissue. This lack of correlation may be explained by individual variations and the difficulties caused by repeated rectal biopsies interfering with each other. The biopsy-induced inflammation may mask some of the effects of the tea. Of interest, however, is that although increased inflammatory changes were seen in the immunohistochemical slides over time, lowering of PGE2 levels was observed. Whereas an increase in inflammation may be explained by serial anoscopies, inhibition of PGE2 may be the result of tea administration. This is believed to be due to the inhibition of cyclooxygenase-2 activity in the rectum. Preliminary experiments, however, indicate that the level of cyclooxygenase in the rectal mucosa, as determined by Western blot analysis, was not significantly affected by the tea treatment (data not shown).

The immunohistochemical slides regarding proliferation and apoptotic rates were difficult to interpret. Individual variations in these rates were very high and make it difficult to determine the effect of tea on these biomarkers. Recent analysis of the variability in rectal mucosal proliferation measurements calls into question the ability of proliferating cell nuclear antigen to show treatment effects (40) . Potential sources of variation include the effect of bowel preparation, age, gender, diet, time of day, fluctuation over time, and biopsy location. Similar difficulties are likely to occur with the measurement of apo-ptotic cells, as with proliferation indices (45) . Because subjects were able to act as their own control over time, certain variables were likely to play a role in this study’s difficulty in assessing proliferation and apoptosis. Proliferation indices are known to have circadian rhythm (46) that could affect our ability to demonstrate tea treatment changes over a 24-h period.

Green tea has biological activity in the colorectal mucosa. Because PGE2 inhibition in other settings is related to a lower risk of certain cancers and the response rate among the subjects was 10 of 14 (71%), these data suggest a potential role for green tea as a chemopreventive agent against colorectal cancer. The data support proceeding with a longer-term Phase II study.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by NIH Grant CA56673, a grant from the Thomas J. Lipton Company, and facilities from Cancer Center support Grant CA 72720. Back

2 To whom requests for reprints should be addressed, at Laboratory for Cancer Research, College of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854-8020. Phone: (732) 445-5361; Fax: (732) 445-0687; E-mail: csyang{at}rci.rutgers.edu Back

3 The abbreviations used are: EGCG, (-)-epigallocatechin-3-gallate; EGC, (-)-epigallocatechin; ECG, (-)-epicatechin-3-gallate; EC, (-)-epicatechin; PGE2, prostaglandin E2; HPLC, high performance liquid chromatography. Back

Received 2/ 8/99; revised 5/28/99; accepted 6/ 3/99.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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