Prostate Cancer, Nutrition, and Dietary Supplements (PDQ®)–Health Professional Version - National Cancer Institute

Prostate Cancer, Nutrition, and Dietary Supplements (PDQ®)–Health Professional Version

Green Tea

Overview

This section contains the following key information:

All tea originates from the Camellia sinensis (L.) Kuntze plant, and the methods by which the leaves have been processed determine the type of tea produced. For green tea, the leaves are steamed and dried.
Some research suggests that green tea may have a protective effect against cardiovascular disease and against various forms of cancer, including prostate cancer.
Catechins are polyphenol compounds in tea that are associated with many of tea’s proposed health benefits.
Green tea catechins (GTCs) include (−)-epigallocatechin-3-gallate (EGCG), (−)-epicatechin (EC), (−)-epigallocatechin (EGC), (−)-epicatechin-3-gallate (ECG), and the less-studied oligomeric proanthocyanidins derived from these catechin monomers.
Laboratory, preclinical, and early-phase clinical trials have identified EGCG as one of the most potent modulators of molecular pathways thought to be relevant to prostate carcinogenesis. EGCG has been shown to act as an androgen antagonist and can suppress prostate cancer cell proliferation, suppress production of prostate-specific antigen (PSA) by prostate cancer cells, and demonstrate potent and selective proapoptotic activity in prostate cancer cell lines in vitro.
Oral intake of either a GTC solution or EGCG alone was associated with significant reductions in tumor size, reduced multiplicity, and reduced development of prostate cancer in studies with transgenic adenocarcinoma of the mouse prostate (TRAMP) mice.
In Asian countries with a high per capita consumption of green tea, prostate cancer mortality rates are among the lowest in the world, and the risk of prostate cancer appears to be increased among Asian men who abandon their original dietary habits upon migrating to the United States. Case-control and cohort studies, so far, have variously shown beneficial or neutral results, with the exception of one study that has shown an increased risk of the developing advanced prostate cancer with consumption of green tea.
GTCs have been well tolerated in clinical studies that target disease-free men, men with precursor lesions, and men with prostate cancer. Side effects were reduced with a decaffeinated formulation and when green tea was consumed in nonfasting conditions. The most common side effects related to GTC were mild gastrointestinal symptoms.
At least two randomized controlled trials have shown an overall decreased rate of progression to atypical small acinar proliferation or prostate cancer in men with high-grade prostatic intraepithelial neoplasia (HGPIN) treated with GTCs.

General Information and History

Sailors first brought tea to England in 1644, although tea has been popular in Asia since ancient times. After water, tea is the most-consumed beverage in the world.[1] Tea originates from the C. sinensis plant, and the methods by which the leaves are processed determine the type of tea produced. Green tea is not fermented but is made by an enzyme deactivation step whereby intensive heat (i.e., roasting the freshly collected tea leaves in a wok or, historically, steaming the leaves) is applied to preserve the tea's polyphenols (catechins) and freshness. In contrast, the enzyme-catalyzed polymerization and oxidation of catechins and other components produces darker-colored black tea.[2] Oolong, a third major type of tea, contains polyphenols that are partially oxidized.[1]

In this PDQ information summary, tea refers to the leaves of the C. sinensis plant or the beverage brewed from those leaves.

Some observational and interventional studies suggest that green tea may have a protective effect against cardiovascular disease,[3] and there is evidence that green tea may protect against various forms of cancer.[4] Many of the health benefits associated with tea have been attributed to polyphenols. GTCs include EGCG, EC, EGC, ECG, and oligomeric proanthocyanidins derived from these catechin monomers. Among these compounds, EGCG is the most abundant catechin in green tea and has been widely researched;[5] however, it is also classified as a promiscuous compound.[6] Laboratory, preclinical, and early-phase clinical trials have identified EGCG as one of the most potent modulators of molecular pathways thought to be relevant to prostate carcinogenesis.[5] Tea leaves also contain considerable amounts of oligomeric catechins, in particular, oligomeric proanthocyanidins. Together with the catechin monomers, they constitute the green tea polyphenols (GTPs). GTP composition and the ratio of monomeric to oligomeric catechins can vary widely, depending on processing and source of the tea leaves. Considering that EGCG and other monomeric catechins interfere with in vitro assays and exhibit a wide range of biological effects,[6,7] this indicates that the chemical factors responsible for the actual in vivo health benefits of green tea are mostly unknown.

Preclinical/Animal Studies

In vitro studies

Prostate cancer cells treated with EGCG (concentrations, 0–80 μM) demonstrated suppressed cell proliferation and decreased levels of PSA protein and mRNA in the presence or absence of androgen.[8]

In a 2011 study, human prostate cancer cells were treated initially with EGCG (concentrations, 1.5–7.5 μM) and then with radiation. The results showed that exposing cells to EGCG for 30 minutes before radiation significantly reduced apoptosis, compared with radiation alone.[9]

In another study, prostate cancer cells treated with EGCG (0–50 μM) exhibited dose-dependent decreases in cellular proliferation and increases in extracellular signal-regulated kinase (ERK) 1/2 activity. To further examine the effect of EGCG on the ERK 1/2 pathway, cells were treated with EGCG (0–50 μM) and a mitogen-activated protein kinase (MEK) inhibitor or phosphoinositide-3 kinase (PI3K) inhibitor. Inhibition of MEK did not prevent ERK 1/2 upregulation, although the increase in ERK 1/2 after EGCG treatment was partially inhibited with the PI3K inhibitor. These findings suggest that EGCG may prevent prostate cancer cell proliferation by increasing the activity of ERK 1/2 via a MEK-independent, PI3K-dependent mechanism.[10]

According to a 2010 study, EGCG treatment (20–120 μM) resulted in changes in expression levels of 40 genes in prostate cancer cells, including a fourfold downregulation of inhibitor of DNA binding 2 (ID2; a protein involved in cell proliferation and survival). In addition, forced expression of ID2 in cells treated with 80 μM EGCG resulted in reduced apoptosis, suggesting that EGCG may cause cell death via an ID2-related mechanism.[11]

Advances in nanotechnology—nanochemoprevention—may result in more-effective administration of EGCG to men at risk of developing prostate cancer. Prostate cancer cells were treated with EGCG-loaded (100 μM EGCG) nanoparticles or free EGCG. Although both treatments decreased cell proliferation and induced apoptosis, the nanoparticle treatment had a greater effect at a lower concentration than did free EGCG. This finding suggests that using a nanoparticle delivery system for EGCG may increase its bioavailability and improve its chemopreventive actions.[12] In one study, EGCG (30 μM) was encapsulated in nanoparticles that contained polymers targeting prostate-specific membrane antigen (PSMA). Prostate cancer cells treated with this intervention exhibited decreases in proliferation; however, the intervention did not affect nonmalignant control cells. The results suggest that this delivery system may be effective for selective targeting of prostate cancer cells.[13]

Research also suggests that glutathione-S-transferase pi (GSTP1) may be a tumor suppressor and that hypermethylation of certain regions of this gene (i.e., CpG islands) may be a molecular marker of prostate cancer. Increased methylation leads to silencing of the gene. A set of experiments investigated the effects of green tea polyphenols on GSTP1 expression. Treatment of different types of prostate cancer cells with green tea polyphenols (1–10 μg/mL Polyphenon E) resulted in re-expression of GSTP1 by reversing hypermethylation and by reducing expression of methyl-CpG–binding domain proteins, which bind to methylated DNA. These results indicate that green tea polyphenols may have chemopreventive effects via actions on gene-silencing processes.[14]

The results of a 2011 study suggested that green tea polyphenols may exert anticancer effects by inhibiting histone deacetylases (HDACs). Class I HDACs are often overexpressed in various cancers, including prostate cancer. Treatment of human prostate cancer cells with green tea polyphenols (10–80 μg/mL Polyphenon E) resulted in decreased class I HDAC activity and increased expression of Bax, a proapoptotic protein.[15]

Owing to the high concentrations of tea polyphenols used in some of the in vitro experiments, results should be interpreted with caution. Studies in humans have indicated that blood levels of EGCG are 0.1 to 0.6 µM after consumption of two to three cups of green tea and that drinking seven to nine cups of green tea results in EGCG blood levels still lower than 1 μM.[16,17]

Animal studies

Animal models have been used in several studies investigating the effects of green tea on prostate cancer. In one study, TRAMP mice were given access to water or GTC–treated water (0.3% GTC solution; this exposure mimics human consumption of 6 cups of green tea daily). After 24 weeks, water-fed TRAMP mice had developed prostate cancer, whereas mice treated with GTCs showed only prostatic intraepithelial neoplasia lesions, suggesting that GTCs may help delay the development of prostate tumors.[18] In another study, castrated mice were injected with prostate cancer cells and then treated daily with intraperitoneal injections of 1 mg EGCG or vehicle. Treatment with EGCG resulted in reductions in tumor volume and decreases in serum PSA levels compared with vehicle treatment.

In a 2011 study, EGCG was shown to be an androgen antagonist; when added to prostate cancer cells, EGCG physically interacted with the androgen receptor’s ligand-binding domain. In addition, mice implanted with tumor cells and treated with EGCG (intraperitoneal injections of 1 mg EGCG, 3/wk) exhibited less androgen receptor protein expression than did mice that were treated with vehicle.[19]

In a 2009 study, TRAMP mice were started on a green tea polyphenol intervention (0.1% green tea polyphenols in drinking water) at various ages (meant to represent different stages of prostate cancer development).[20] The results showed that, although all of the green tea–fed mice exhibited longer tumor-free survival than did water-fed control mice, there was an advantage for the mice that were fed with green tea the longest.[20] In one study, EGCG treatment (0.06% EGCG in drinking water; this exposure mimics human consumption of 6 cups of green tea/d) was initiated in TRAMP mice at age 12 or 28 weeks. EGCG treatment suppressed HGPIN in mice treated at age 12 weeks; however, EGCG did not prevent prostate cancer development in mice that began treatment at age 28 weeks.[21]

Using the TRAMP mouse model,[22] one study demonstrated that oral infusion of GTP extract at a human-achievable dose (equivalent to 6 cups of green tea/d) significantly delayed primary tumor incidence and tumor burden, as assessed sequentially by magnetic resonance imaging; decreased prostate weight (64% of baseline) and genitourinary weight (72%); inhibited serum insulin-like growth factor (IGF)-1; restored insulin-like growth factor–binding protein-3 (IGFBP-3) levels; and produced marked reduction in the protein expression of proliferating cell nuclear antigen in the GTP-fed TRAMP mice, compared with water-fed TRAMP mice. Furthermore, GTP consumption caused significant apoptosis, which possibly resulted in reduced dissemination of cancer cells, thereby causing inhibition of development, progression, and metastasis to distant organ sites. In another study, 119 male TRAMP mice and 119 C57BL/6J mice were treated orally with one of three doses of Polyphenon E (200, 500, or 1,000 mg/kg/d) in drinking water ad libitum, replicating human-achievable doses. Safety and efficacy assessments were performed at baseline and when mice were 12, 22, and 32 weeks old. Results indicated that the number and size of tumors in treated TRAMP mice were significantly decreased, compared with untreated animals. In untreated 32-week-old TRAMP mice, prostate carcinoma metastasis to distant sites was observed in 100% of mice (8/8), compared with 13% of mice (2/16) treated with high-dose Polyphenon E during the same period.[23]

Animal safety studies

In a National Cancer Institute (NCI) Division of Cancer Prevention (DCP)–sponsored, 9-month, oral toxicity study, Polyphenon E was administered (200, 500, or 1,000 mg/kg/d) to fasted male and female beagle dogs. The study was terminated prematurely because of excessive loss of animals due to morbidity and mortality in all treatment groups. These studies have revealed some unique dose-limiting lethal liver, gastrointestinal, and renal toxicities. Gross necropsy revealed therapy-induced lesions in the gastrointestinal tracts, livers, kidneys, reproductive organs, and hematopoietic tissues of treated male and female dogs. In the 13-week follow-up study, the no-observed-adverse-effect–level was greater than 600 mg/kg per day of Polyphenon E.[24] When the study was conducted in nonfasted dogs under the same testing conditions and dose levels, the results were unremarkable. Nonspecific toxicity and a tenfold reduction in the maximum tolerated dose in fasted beagle dogs compared with fed beagle dogs were seen using a purified GTC containing less than 77% EGCG.[25] However, in the follow-up NCI DCP–sponsored study in fed dogs compared with fasted dogs using several Polyphenon E formulations, no deaths occurred, suggesting that fasting may have rendered the target organ systems more vulnerable to the effects of green tea extract.

In a study [23] of several doses of a standardized Polyphenon E targeting TRAMP mice, no liver or other toxicities were observed. Long-term (32 weeks) treatment with Polyphenon E (200, 500, and 1,000 mg/kg/d) was safe and well tolerated, with no evidence of toxicity in C57BL/6J mice. The C57BL/6J mice showed no differences in appearance or behavior, or changes in prostate and body weights after 32 weeks of treatment for all three doses of Polyphenon E. No discernible histopathological changes were observed in the liver, lung, or any prostate lobe of C57BL/6J mice treated with the three different doses of Polyphenon E. [23] Similarly, another preclinical study [26] did not observe liver or other toxicities with standardized EGCG at doses of up to 500 mg EGCG preparation/kg per day.

Human Studies

Epidemiologic studies

The relationship between green tea intake and prostate cancer has been examined in several epidemiological studies.

Two meta-analyses examined the consumption of green tea and prostate cancer risk, with one meta-analysis including black tea.[27,28] For green tea, seven observational studies were identified, and most were from Asia. The results indicated a statistically significant inverse association between green tea consumption and prostate cancer risk in the three case-control studies, but no association was found in the four cohort studies. For black tea, no association was found between black tea consumption and prostate cancer risk.[27] The inconsistent results reported in these population studies may be attributed to confounding factors that include consumption of salted or very hot tea, geographical location, tobacco and alcohol use, and other dietary differences.[29-33] In Asian countries with a high per capita consumption of green tea, prostate cancer mortality rates are among the lowest in the world,[34] and the risk of prostate cancer appears to be increased among Asian men who abandon their original dietary habits upon migrating to the United States.[34] Overall, findings from population studies suggest that green tea may help protect against prostate cancer in Asian populations.[27,35] Currently, there are no epidemiological studies in other populations examining the association between green tea consumption and prostate cancer risk or protection from risk. With the increasing consumption of green tea worldwide, including by the U.S. population, emerging data from ongoing studies will further contribute to defining the cancer preventive activity of green tea or GTCs.

Intervention studies

Bioavailability

Phase I/II intervention studies have reported bioavailability of EGCG in plasma using single and repeated doses of EGCG, noting higher plasma EGCG concentrations in fasting conditions relative to fed conditions.[36-38] Studies using varying doses (400 mg, 800 mg EGCG) of GTCs and Polyphenon E administered in single and repeated dosing schedules for 3 to 6 weeks have reported median maximum concentrations of EGCG ranging from 68.8 ng/mL to 390.36 ng/mL (refer to Table 1).[38-40] Not all individuals in the treatment arms of these and other studies [31,41,42] had detectable levels of EGCG, indicating potential variation in individual absorption. Catechins other than EGCG were nondetectable or below quantifiable levels in the plasma in many trials.

Tissue levels of catechins have also been quite variable when examined. Notably, catechin levels in prostate tissue were low to undetectable after the administration of Polyphenon E in one preprostatectomy study.[39] An analysis of prostate tissue obtained from the green tea drinkers revealed that both methylated and nonmethylated forms of EGCG are found in the prostate following a short-term treatment with green tea, with 48% of EGCG in the methylated form.[39] Methylated forms of EGCG are not as effective as EGCG in inhibiting cell proliferation and inducing apoptosis in prostate cancer cells, suggesting that methylation status of EGCG may affect the chemopreventive properties of green tea. Methylation status may be determined by polymorphisms of the catechol-O-methyltransferase (COMT; the enzyme that methylates EGCG) gene.[43]

Table 1. Peak Plasma EGCG Levels

Source	EGCG Dose	Condition	Duration	Median Plasma EGCG Concentration (ng/mL)
EGCG = (−)-Epigallocatechin-3-gallate; kg = kilogram(s); mg = milligram(s); mL = milliliter(s); ng = nanogram(s); SD = standard deviation; wk = week(s); y = year.
[38]	400 mg	Fed, fasted	4 wk	155.4 (fed), 161.4 (fasted)
[38]	800 mg	Fed, fasted	4 wk	287.6 (fed), 390.36 (fasted)
[39]	800 mg (in Polyphenon E)	Fed	3–6 wk	68.8
[40]	2 mg/kg	Fasted	Single dose	77.9
[42]	200 mg (twice a day)	Fed	1 y	12.3 (SD, 24.8)

Prevention

In a single-center Italian study, 60 men diagnosed with HGPIN were randomly assigned to receive GTC capsules (GTCs, 600 mg/d) or a placebo every day for 1 year. After 6 months, 6 of the 30 men in the placebo group were diagnosed with prostate cancer, whereas none of the 30 subjects in the GTC group were diagnosed with prostate cancer. After 1 year, nine men in the placebo group and one man in the GTC group were diagnosed with prostate cancer (P < .01). These findings suggest that GTCs may help prevent prostate cancer in groups at high risk of the disease.[44] In 2008, follow-up results to this study were published, indicating that the inhibitory effects of GTCs on prostate cancer progression were long-lasting.[45] However, nearly all of the prostate cancer risk reduction in that study occurred at the 6-month biopsy, suggesting that the results may have been biased by a nonrandom distribution of occult prostate cancer at baseline.[34] No reduction in serum PSA was observed in the treatment arm of this study compared with placebo.

A larger, multicenter, randomized trial (NCT00596011) in the United States studied 97 men with either HGPIN or atypical small acinar proliferation who received a GTC mixture (Polyphenon E, 200 mg, bid).[42] Atypical small acinar proliferation is an entity that reflects a broad group of lesions of varying clinical significance with insufficient cytological or architectural atypia to establish a definitive diagnosis of prostate cancer.[9,27] Results indicated that a daily intake of a standardized, decaffeinated catechin mixture containing 400 mg EGCG per day for 1 year, accumulated in the plasma, was well tolerated,[42][Level of evidence 1A] but did not significantly reduce the incidence of prostate cancer in the treatment group with Polyphenon E (5/49, 10.2%) compared with the placebo group (9/48, 18.8%; P = .25). However, in a prespecified secondary analysis performed in men with HGPIN (without atypical small acinar proliferation) at baseline, Polyphenon E was associated with a significant decrease in the composite endpoint (prostate cancer plus atypical small acinar proliferation) (3/26 Polyphenon E vs. 10/25 placebo, P < .024), with these findings largely driven by the absence of atypical small acinar proliferation on end-of-study biopsy on the Polyphenon E arm (Polyphenon E [0/26] vs. placebo arm [5/25]). Because there is no clear evidence that HGPIN and atypical small acinar proliferation represent steps on a linear path to prostate cancer, these findings should be interpreted with caution. A comparison of the estimated overall treatment effect showed a significantly greater reduction of serum PSA in men treated with Polyphenon E compared with controls (-0.87 ng/mL; 95% confidence interval, -1.66 to -0.09).[42] Although the findings of this U.S. study appear to refute the large effect size suggested by the Italian study [42,44,45] that reported a 90% reduction in prostate cancer among men with HGPIN, overall, the randomized controlled trials have shown a decreased rate of progression to atypical small acinar proliferation or prostate cancer in men with HGPIN treated with GTCs.

Preoperative studies

Patients scheduled for radical prostatectomy were randomly assigned to drink green tea, black tea, or a soda five times a day for 5 days. Bioavailable tea polyphenols were found in prostate samples of the patients who had consumed green tea and black tea. In addition, prostate cancer cells were treated with participants’ serum, and the results showed that there was less proliferation using post-tea serum than using serum obtained before the tea intervention.[46] In an open label, phase II trial, 113 men with prostate cancer were randomly assigned to drink six cups of green tea, black tea, or water before radical prostatectomy.[47] Ninety-three patients completed the intervention. Although there were no significant differences in markers of proliferation, apoptosis, and oxidation in the prostatectomy tissue, only the men drinking green tea demonstrated small but significant decreases in PSA levels (P = .04).

In an open label, phase II clinical study, prostate cancer patients scheduled for radical prostatectomy consumed four Polyphenon E tablets containing tea polyphenols, providing 800 mg EGCG daily until surgery. The Polyphenon E treatment had a positive effect on a number of prostate cancer biomarkers, including PSA, vascular endothelial growth factor (VEGF), and IGF-1 (a protein associated with increased risk of prostate cancer).[48]

In a 2011 study, 50 prostate cancer patients were randomly assigned to receive Polyphenon E (800 mg EGCG) or a placebo daily for 3 to 6 weeks before surgery. Treatment with Polyphenon E resulted in greater decreases in serum levels of PSA and IGF-1 than did treatment with placebo, but these differences were not statistically significant. The findings of this study suggest that the chemopreventive effects of green tea polyphenols may be through indirect means and that longer intervention studies may be needed.[39]

Advanced prostate cancer

In a small, single-arm study, hormone-refractory prostate cancer patients received capsules of green tea extract twice daily (total polyphenols, 375 mg/d); not specified by polyphenol type) for up to 5 months. Although the green tea intervention was well tolerated by most study participants, no patient had a PSA response (i.e., at least 50% decrease from baseline), and all 19 patients were deemed to have progressive disease within 1 to 5 months.[49]

In a 2003 study, patients with androgen-independent metastatic prostate cancer consumed 6 g of powdered green tea extract daily for up to 4 months. Among 42 participants, 1 patient exhibited a 50% decrease in serum PSA level compared with baseline, but this response was not sustained beyond 2 months. Green tea was well tolerated by most study participants. However, six episodes of grade 3 toxicity occurred, involving insomnia, confusion, and fatigue. These results suggest that in patients with advanced prostate cancer, green tea may have limited benefits.[50]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

Adverse Effects

The safety of tea and tea compounds is supported by centuries of consumption by the human population. The bioavailability and tolerance to GTC at doses ranging from 600 to 1,000 mg EGCG at single and multiple doses, and a duration of a few days to 1 year has been well documented in phase I/II clinical trials.[36-40,43,46-50] The authors of a phase I trial of oral green tea extract in adult patients with solid tumors reported that a safe dose of green tea extract (1.0 g/m2, tid) was equivalent to seven to eight Japanese cups (120 mL) of green tea three times per day for 6 months.[51] The authors concluded that the side effects (neurological and gastrointestinal) of the green tea extract preparation were caffeine related, and not from EGCG. In four phase I, single-dose, and multidose studies that targeted healthy volunteers who took a botanical drug substance containing a mixture of catechins, Polyphenon E, and a dose range of 200 to 1,200 mg EGCG was well tolerated.[33,34,40-42,44,45] Adverse effects with a possible relationship to the study drug reported in these studies have been grade 2 to 3 and included asthenia, headache, abdominal pain, chest pain, diarrhea, dyspepsia, eructation, flatulence, nausea, vomiting, dizziness, vasodilation, and rash. These studies have demonstrated that although increased oral bioavailability occurs when GTCs are consumed in a fasting state, increased gastrointestinal toxicity is also more common. Gastrointestinal adverse effects were usually mild and seen most often at the higher dose levels. Onset of gastrointestinal events typically occurred within 2 to 3 hours of dosing and resolved within 2 hours. No grade 3 or higher events were reported with a possible relationship to the study drug.[48]

Green tea has been well tolerated in clinical studies of men with prostate cancer.[43,48] In a 2005 study, the most commonly reported side effects were gastrointestinal symptoms. These symptoms were mild for all but two men, who experienced severe anorexia and moderate dyspnea.[49] With the duration of intervention in these studies ranging from single, one-time administration to a maximum of 90 days, the safety data from these studies are limited to short-term safety of EGCG and GTCs.

Data from clinical trials [42,44] report long-term safety of EGCG containing GTCs, for use in men with precursor lesions of prostate cancer for prevention of prostate cancer. One study [44] administered approximately 300 mg EGCG per day for 1 year without any reported toxicities.

In the recently completed U.S. trial, 400 mg of EGCG containing Polyphenon E was administered for 1 year to nonfasting men with HGPIN and atypical small acinar proliferation. More possible and probable grade 2 through grade 3 events in men who received Polyphenon E were observed and compared with those in men who received placebo. Only one man who received Polyphenon E reported grade 3 nausea, which was determined to possibly be related to the study agent.[42]

In recent years, oral consumption of varying doses and compositions of green tea extracts (GTEs) has been associated with several instances of hepatotoxicity.[25,38,52-54] Most affected patients were women, and many were consuming GTEs for the purpose of weight loss. Although hepatotoxicity in most cases resolved within 4 months of stopping GTEs, there have been cases of positive rechallenge and liver failure requiring a liver transplant. One report described a case of acute liver failure that required a transplant in a woman who consumed GTE capsules.[53] The capsules contained Polyphenon 70A (a concentrated, enriched, and pasteurized hot-water extract of green tea) and 120 mg GTE. Because no other causal relationship could be identified, the treating physicians concluded that the fulminant liver failure experienced by this patient was most likely related to the consumption of over-the-counter GTE weight-loss supplements. In addition, the sale of an ethanolic GTE sold as a weight-reduction aid was suspended in 2003 after reports associated hepatotoxicity (four cases in Spain and nine cases in France) with its use.[54] Time to onset of hepatotoxicity following ingestion of GTEs ranged from several days to several months. Increased oral bioavailability occurs when GTEs are administered on an empty stomach after an overnight fast. Increased toxicity, including hepatotoxicity, is observed when Polyphenon E or EGCG is administered to fasted dogs.[25] The U.S. Food and Drug Administration's Division of Drug Oncology Products has recommended that Polyphenon E be taken with food by subjects participating in clinical studies. In addition, liver function tests should be considered while individuals are on treatment.

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