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Green Tea

Botanical Name: Camellia sinensis L. Kuntze.
Pharmacopoeial Name: Folium Camellia sinensis (Theae folium).
Synonym: Thea sinensis L.
Common Names: Tea, cha. Various prefixes, such as the country name (e.g., Ceylon), district (e.g., Assam), grade or part (e.g., pekoe [buds]), or degree of fermentation (e.g., green, oolong, black), are used to differentiate various commercial tea products by common name.

Summary Table

Drug/Class Interaction Type	Mechanism and Significance	Management
Corticosteroids, topical /	Tea additively increases anti-inflammatory effects of drug in refractory atopic dermatitis. Coadministration enables lower dose. May apply to tacrolimus/steroid combinations.	Include green tea extract (GTE) in integrative protocols for refractory atopic dermatitis.
Doxorubicin Anthracycline chemotherapy /	Chemosensitization by L-theanine and polyphenols; cardioprotection by polyphenols. Experimentally demonstrated, not clinically established.	Coadminister GTE and L-theanine during anthracycline chemotherapy.
Iron salts, nonheme	Concurrent consumption of tea with iron salts may reduce bioavailability of iron. Only significant in patient groups with, or at high risk of, iron deficiency anemia.	Use heme iron where supplementation necessary, or temporally separate tea and iron salt dosing and use Fe-absorption enhancers.
Methicillin Beta-lactam and other antibiotics	Coadministration with beta-lactam antibiotics reverses MRSA resistance. May be of more general clinical significance, synergism demonstrated for various antibiotics.	Coadminister GTE with beta-lactam antibiotics to increase efficacy, especially for suspected drug-resistant strains.
SERMs Aromatase inhibitors	GTE enhances tamoxifen-induced apoptosis in vitro and inhibits aromatase. Interactions not clinically established.	Consider GTE coadministration with adjuvant endocrine therapies in estrogen-dependent malignancy.
Trastuzumab	Possible additive effects on HER-2/neu inhibition; not clinically established. Tyrosine kinase inhibition may have more general significance.	Consider coadministration in integrative protocols for HER-2/neu–overexpressing cancers.
Warfarin Anticoagulant or antiplatelet agents	Possible antiplatelet effects; one unreliable report of warfarin interaction. Clinical significance unknown, probably minor.	Monitor INR; monitor for signs of bleeding. Low levels of GTE unlikely to be problematic.
MSRA , Methicillin-resistant Staphylococcus aureus; SERMs , selective estrogen response modulators; INR , international normalized ratio.

herb description

Family

Theaceae (Ternstroemiaceae).

Related Species

At least one subspecies and several cultivars are described.

Habitat and Cultivation

Tea plants are actually evergreen trees maintained as tea bushes by pruning in cultivation to shrub height to enable hand harvesting of the young leaves. Tea (Cha) originally was native to the Yunnan province in southwestern China and initially spread to several different areas in China and India, but it has been in cultivation for so long in rain forest zones throughout many Southeast Asian countries that wild-type plants are now rare. China and India are the largest cultivators, and India is the largest exporter. Pu’erh tea (Pu Erh Cha) is derived from the leaves of old tea trees on six specific mountains in Yunnan, fermented and aged through specific processes, and is considered a separate beverage with significantly different characteristics and medicinal actions.

Parts Used

Young leaves, tips, and leaf buds.

Common Forms

Dried Leaf.

Powdered Green Tea Leaf.

Dry Extracts: Derived from ethanolic extracts, preparations may vary; some may be decaffeinated, standardized to total catechins of greater than 25%. Concentrates of specific tea polyphenols, up to 97% catechins, and other compounds, such asL-theanine (analog ofL-glutamine), are marketed as nutrient preparations and therapeutic agents.L-Theanine is also produced in high yield by microbial fermentation for use in nutriceutical products.

herb in clinical practice

Overview

Tea is the most common beverage in the world (other than water). Tea belongs to the universally popular category of xanthine-containing beverages, such as coffee, cola, maté, and cocoa, the popularity of which is partly related to their caffeine content. Commercially, the principal types are green tea and black tea. Green tea is stabilized and dried immediately after harvesting, then rolled. This processing method means the crude herb approximates as closely as possible to its natural state at harvesting; thus green tea is designated as the “medicinal” form of the herb, as derived from tea bushes. Black teas are dried after the rolling process, allowing oxidative enzymatic changes to take place, principally polymerization of the flavan-3-ols into the characteristic oligomeric red-brown theaflavins and thearubigins, as well as the polymeric tannins, which are absent from green tea.

Research interest in green tea compounds has accelerated dramatically in the last decade, with epidemiological, experimental, and clinical evidence for chemopreventive, antiproliferative, and cardioprotective benefits of tea polyphenols. These activities are the result of a variety of pharmacological mechanisms, including antioxidant effects, cell cycle effects, and signal transduction effects. ^1-4

Green tea has not traditionally been considered part of the Western herbal materia medica until the rather recent interest in its chemopreventive properties. The usual authoritative sources of botanical medicine have not, to date, produced therapeutic monographs on the plant. In herbal medicine, tea has primarily been regarded as a dietary source of caffeine and astringent tannins and is regarded as a milder stimulant than the caffeine-containing cola and guaraná, which have been preferred when caffeine-containing herbs were indicated. McKenna et al. ⁵ reviewed the general literature on tea in 2002. Interest in the chemopreventive and cardioprotective properties of tea polyphenols have led to the manufacture of concentrated preparations of these compounds. Tea leaf is regulated as a food beverage (“generally recognized as safe,” GRAS) in the United States, whereas isolated and concentrated green tea polyphenols are classified as dietary supplements.

Historical/Ethnomedicine Precedent

Traditional Chinese use of green tea leaf (Lu Cha) is primarily for gastrointestinal complaints, for which it is combined with other herbs to treat nausea and vomiting and as an antidiarrheal (astringent). It is also used for headaches and dispelling “damp.” In Ayurvedic medicine, green tea is similarly considered a diuretic, astringent, and mild stimulant. As noted, Pu’erh tea (Pu Erh Cha) is considered a separate medicinal agent, significantly rarer and highly valued, with distinct qualities and uses. Pu Erh Cha is considered “Earth” in nature and Lu Cha “Wood” in nature.

Known or Potential Therapeutic Uses

Atherosclerosis; adjunct to some antimicrobial and antineoplastic pharmacotherapies for microbial infections; cardioprotection and reduction of cardiovascular risk factors; chemoprotection; chemoprevention of colon, pancreatic, esophageal, and other cancers; central nervous system (CNS) stimulation; gingival and periodontal infection; headache; hypercholesterolemia; mild diarrhea; thermogenesis (and weight loss); renal insufficiency.

Key Constituents

Methylxanthines, principally caffeine (2%-4%); polyphenols (30%-40%), four principal compounds: (−)-epicatechin (EC), (−)-epigallocatechin (EGC), (−)-epicatechin gallate (ECG), and (−)-epigallocatechin gallate (EGCG).

Other constituents include various flavonols, including proanthocyanidins, amino acids (principallyL-theanine), protein, vitamins (ascorbate, B group), minerals, and organic acids.

Note: The abbreviations EC, EGC, ECG, and EGCG are used throughout this monograph to designate the four principal catechin compounds.

Therapeutic Dosing Range

Infusion of Dried Leaf: 1.0 to 3.0 g as required; 1 cup delivers 300 to 400 mg of polyphenols; up to 5 cups per day as a beverage.

Powder: 4 to 12 g by decoction, typical modern Chinese dosing.

Standardized Extract: Polyphenols range from 25% (Exolise, Arktopharma) to 97% (Tegreen, Pharmanex LLC) polyphenols to deliver up to approximately 750 mg of polyphenols per dose.

interactions review

Strategic Considerations

Beverage consumption of tea needs to be delineated from therapeutic administration of polyphenol-rich green tea extracts (GTEs). The popularity of beverage tea consumption, particularly in the form of black tea, is often considered to be based primarily on its caffeine content. Caffeine, an ingredient of hundreds of over-the-counter (OTC) medications, is well known for its CNS-stimulating and adenosine receptor–mediated effects. In beverage use, green tea delivers only 50 to 100 mg caffeine per cup, about half (or less) the quantity of caffeine in a cup of coffee. Some authors, when reviewing green tea interactions, have resorted to listing well-known caffeine-drug interactions without contextualization of beverage versus therapeutic use of tea, or distinction between green tea and black tea forms, and despite the lack of evidence that normal dietary tea consumption induces caffeine-drug interactions.

Caffeine interactions are properly classified in the domain of the drug-drug interaction literature; for example, Stockley ' s Drug Interactions ⁶ lists more than 70 interactions between caffeine and other drugs. Caffeine, along with related methylxanthines such as theophylline, is cleared oxidatively by cytochrome P450 (CYP450) 1A2, so drugs that strongly inhibit 1A2 (e.g., fluvoxamine, quinolone antibiotics) can accentuate the adverse effects of caffeine consumption in chronic high-level tea consumption. The clinical importance of these effects is not established, however, and case reports are lacking. Caffeine has been shown to contribute to chemopreventive effects of GTEs in the few studies that have made direct comparisons among tea, decaffeinated tea, and caffeine. ^7-9

The principal health benefits of chemoprevention and cardioprotection associated with dietary tea consumption are related to its polyphenol content. The amount of polyphenols in green tea infusions is about 300 to 400 mg per cup, whereas standardized GTEs can contain up to 97% polyphenols, and some may be decaffeinated. Relatively high doses of green tea infusion are required for therapeutic use because of the poor intrinsic oral bioavailability of the polyphenols; 10 cups of green tea per day (not uncommon in Japan) could arguably be considered the transition between beverage and therapeutic dose exposure. Black tea contains considerably less flavan-3-ol catechins, which are transformed by fermentation into oligomeric derivatives, the thearubigins and theaflavins, which are not found in unfermented green tea products. ¹⁰

Typical concerns about potential adverse effects of cardioprotective herbs on hemostasis and possible interactions with anticoagulants are discussed later in relation to tea compounds. The mechanisms underlying the chemopreventive and anticancer effects of green tea are currently subject of much investigation, and emerging data on tea polyphenols’ synergistic effects with chemotherapy, modification of drug resistance, and multiple effects on signal transduction are emerging from in vitro and cell-line studies, with potentially valuable implications for integrative cancer therapeutics. These potential interactions are reviewed here, although clinical data are currently anecdotal. However, at least two significant caveats must be considered when in vivo extrapolations are made from the experimental findings. Current epidemiological data on the chemopreventive effects of green tea are positive, at least for breast cancer, although the data are limited and clinical trial evidence is lacking. ¹¹

First, cell-line studies using concentrations of tea polyphenols in the 100 to 1000 micromolar (μM) range cannot be extrapolated to beverage consumption because of the low oral bioavailability of these compounds. The different polyphenols and their metabolites do have differing bioavailabilities; EGCG is less bioavailable than the other compounds, possibly because it is the only tea polyphenol that is a substrate as well as inhibitor of intestinal P-glycoprotein; P-gp is inhibited by all the tea polyphenols, with EGCG being the most potent inhibitor. ¹² A human study of single–oral dose kinetics of EGCG found that higher doses (800 mg) achieved significantly greater area under curve (AUC) and maximum concentration (Cmax) levels than lower doses (200 and 400 mg), suggesting a saturable first-pass mechanism. ¹³ Biotransformation of green tea polyphenols is complex and involves glucuronidation, sulfation, and methylation by catechol- O-methyltransferase (COMT) as well as intestinal flora–mediated ring fission products that are further metabolized to phenylacetic and phenylpropionic acids. The activities of the different intermediate metabolites remain unclear, although their bioavailability is higher than that of EGCG. ¹⁴ Preliminary evidence also suggests that significant differences may exist between rodent and human microsomal metabolism of tea polyphenols. ¹⁵

Second, although derivative literature often ascribes the effects of green tea polyphenols to their antioxidant properties, some of their in vitro activity may result from pro-oxidant actions. EGCG is unstable in cell culture conditions and tends to undergo auto-oxidation, producing superoxide radicals and hydrogen peroxide (H2O2). ¹⁶ Hou et al. ¹⁷ suggested that EGCG-related peroxide formation may underlie cell-line effects such as apoptosis induction and that free radicals may be responsible for the observed EGCG-induced inhibition of growth factor receptors EGFR and PDGR. It is unclear whether such pro-oxidative reactions occur in vivo as a result of the low oxygen partial pressures and high antioxidant capacity found in vivo.

The phenomenon of in vitro pro-oxidant effects is likely an artifact of the in vitro absence of antioxidant networks. Logically, only in vitro systems that include physiological levels of albumin, glucose, uric acid, and glutathione and typical serum levels of diet-derived antioxidants would be reasonable in terms of extrapolating to the in vivo situation. Most in vitro systems do not attempt to replicate in vivo antioxidant networks.

Effects on Drug Metabolism and Bioavailability

Green tea compounds may affect all three phases of drug transport and metabolism and thus potentially participate in pharmacokinetic interactions with drugs. Animal and in vitro evidence suggests that polyphenols inhibit Phase I drug metabolism by CYP450 enzymes 1A1 and 1A2. ^18-23One study using recombinant human CYP450 in a genetically engineered bacterial model found EGCG appears to have nonspecific inhibitory effects on 1A1, 1A2, 2A6, 2C19, 2E1, and 3A4. ²⁴ Different forms of tea exhibit different effects on rat liver enzyme activity in a study of rats fed different teas for 4 weeks; for example, oolong and Earl Grey tea induced increases in 3A4 activity but green tea did not, and 1A2 was unaffected by any tea, but 1A1 was affected by both green and fermented teas. ²⁵ These studies suggest that different tea compounds may exert different effects on various drug-metabolizing enzymes, especially those involved in carcinogen metabolism. At this time, however, the clinical effects in humans remain to be established.

Phase II conjugation reactions are mediated by conjugases and transferases. Tea polyphenols not only are substrates for glucuronidation and sulfation, but also have demonstrated significant induction effects on uridine diphosphate (UDP) glucuronosyltransferase (UGT) and sulfotransferase isoforms (SULTs) as well as glutathione transferase in rodent models and in vitro. ^15,26-32Again, these effects have not been studied in vivo in humans, although it is plausible that they may underlie the chemopreventive effects of green tea against certain carcinogenic and tumorigenic agents.

Phase III, mediated by drug transporters, principally P-gp, is also modulated by all the tea polyphenols, but EGCG appears to be the most potent inhibitor. ^12,16,33-38There is some evidence that additional drug transporter proteins, including the organic anion-transporting polypeptide (OATP), may be inhibited by tea polyphenols. ^39-41No single polyphenol component appears to be responsible for the inhibitory effect of GTE on multidrug resistance–associated protein 2 (MRP-2), found in intestinal cells. ⁴² The amino acid theanine has specific effects on the glutamate transporter, which is considered to be the mechanism underlying an interaction between theanine (and whole green tea) and anthracycline agents such as doxorubicin. ^43-46At this time, the firmest evidence that tea polyphenols may exhibit significant pharmacokinetic interactions with prescription drugs relates to effects on Phase III drug transporters. Further studies are required to elucidate the details of their effects on Phase I and Phase II enzymes, for which in vivo human data are currently lacking.

Theanine

The amino acid constituentL-theanine (δ-glutamylethylamide) is the primary amino acid constituent of green tea and constitutes 1% to 3% of the dry weight of the dry leaf.L-Theanine has recently become available as a separate nutrient product after research suggested that it underlies the synergistic interactions of GTEs with anthracycline chemotherapeutic drugs, as well as having neuroregenerative and mood-elevating effects that may have applications in Alzheimer's disease and affective disorders. The currently knownL-theanine interactions are included in the next section (see Doxorubicin).

herb-drug interactions

Corticosteroids, Topical

Alclometasone (Aclovate, Modrasone), amcinonide (Cyclocort), beclomethasone, betamethasone dipropionate/valerate (betamethasone topical; Alphatrex, Beta-Val, Betaderm, Betanate, Betatrex, Diprolene AF, Diprolene, Diprosone, Luxiq, Maxivate, Teladar, Uticort, Valisone), clobetasol (clobetasol topical; Cormax, Dermoval, Dermotyl, Dermovate, Dermoxin, Eumosone, Lobate, Olux, Temovate, Temovate E, Topifort), clobetasone (Eumovate), clocortolone (clocortolone pivalate topical; Cloderm), desonide (DesOwen, Tridesilon), desoximetasone (Topicort, Topicort LP), desoxymethasone, dexamethasone (Aeroseb-Dex, Decaderm, Decadron, Decaspray), diflorasone (Apexicon, Florone, Maxiflor, Psorcon), diflucortolone (Nerisona, Nerisone), fluocinolone (Derma-Smoothe/FS, Fluonid, Synelar, Synemol), fluocinonide (Fluonex, Lidex, Lidex-E, Lonide, Vanos), fludroxycortide (flurandrenolone), fluocortolone (Ultralan), flurandrenolide (Cordran, Drenison), fluticasone (Cutivate), halobetasol (Ultravate), halcinonide (Halog), hydrocortisone 17-butyrate/acetate/probutate/valerate (hydrocortisone topical; Acticort100, Aeroseb-HC, Ala-Cort, Ala-Scalp HP, Allercort, Alphaderm, Bactine, Beta-HC, Caldecort Anti-Itch, Cetacort, Cort-Dome, Cortaid, Cortef, Cortifair, Cortizone, Cortone, Cortril, Delacort, Dermacort, Dermarest, DriCort, DermiCort, Dermtex HC, Epifoam, Gly-Cort, Hi-Cor, Hydro-Tex, Hytone, LactiCare-HC, Lanacort, Lemoderm, Locoid, MyCort, Nutracort, Pandel, Penecort, Pentacort, Proctocort, Rederm, S-T Cort, Synacort, Texacort, Westcort), mometasone (Elocon, mometasone topical), triamcinolone (Aristocort, Triderm, Kenalog, Flutex, Kenonel, triamcinolone topical); combination drug: triamcinolone and nystatin (Mycolog II).

	Beneficial or Supportive Interaction, Not Requiring Professional Management
	Prevention or Reduction of Drug Adverse Effect

Probability: 3. Possible
Evidence Base:

Preliminary

Effect and Mechanism of Action

Coadministration of tea with topical steroids improves dermatological response to these drugs in refractory atopic dermatitis. This may allow reduction of corticosteroid dose and lowered adverse drug effects.

Research

Uehara et al. ⁴⁷ conducted an open trial of 118 patients with refractory atopic dermatitis, who were instructed to continue with their pharmacological treatments, primarily topical steroids. Some patients (not specified) were taking oral histamines. An infusion of oolong tea was consumed three times a day, the beverage being made from 10 g dried tea infused in 1000 mL water for 5 minutes. After 1 month a significant improvement in skin lesions was recorded in 63% of patients. Benefits appeared after 1 to 2 weeks of treatment, and at 6 months, 54% of patients reported persistent improvement. The authors suggest that oolong tea extracts have antiallergenic properties and improve response to topical steroid pharmacotherapy. ⁴⁷ The mechanisms of the effect of tea polyphenols on atopic inflammatory responses are not known but may involve antioxidant effects.

Clinical Implications and Adaptations

The small study reporting beneficial effects of coadministration of tea with topical steroids is interesting for the low dose of tea used. Reduction of steroid anti-inflammatory dose is always a desirable goal when these agents are administered chronically. Increasingly, however, the treatment of choice in atopic dermatitis are the topical immunosuppressive agents (e.g., tacrolimus), which are often combined with topical corticosteroids in refractory cases of atopic dermatitis. ⁴⁸ Effects of tea polyphenols on this combination are unknown.

Doxorubicin and Related Anthracycline Chemotherapy

Evidence: Doxorubicin (Adriamycin, Rubex).

Extrapolated, based on similar properties: Cisplatin ( cisdiaminedichloroplatinum, CDDP; Platinol, Platinol-AQ), daunorubicin (Cerubidine, DaunoXome), epirubicin (Ellence, Pharmorubicin), irinotecan (camptothecin-11, CPT-11; Camp-to, Camptosar), mitoxantrone (Novantrone, Onkotrone).

Related but evidence lacking for extrapolation: Doxorubicin, pegylated liposomal (Caelyx, Doxil, Myocet).

	Potential or Theoretical Beneficial or Supportive Interaction, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Probability: 4. Plausible
Evidence Base:

Preliminary

Effect and Mechanism of Action

Tea polyphenols appear to reduce doxorubicin-induced cardiotoxicity by modifying lipid peroxidation and cardiomyocyte–fatty acid metabolism patterns. EGCG also increases tumor sensitivity to doxorubicin by inhibiting P-gp, which promotes efflux of the drug from malignant cells. Theanine further enhances the efficacy of doxorubicin through inhibition of glutamate transporters and modulation of the glutathione- Sconjugate exporter pump (GS-X). Preliminary data suggest that related anthracyclines and possibly unrelated classes of chemotherapy agents such as cisplatin and irinotecan may behave similarly when coadministered with tea polyphenols and theanine.

Research

Sugiyama, Sadzuka, and colleagues have conducted a series of investigations on the effects of theanine and EGCG on the modulation of sensitivity to doxorubicin in different cell lines, including Ehrlich ascites carcinoma cells, ^35,49 and in an animal model using M5076 ovarian sarcoma tumor–bearing mice, ^44-46,50,51 as well as in P388 leukemia cell–bearing animals. ³⁵ The effect of theanine at 10 mg/kg/day intraperitoneally in the animal model was a significant increase (2.9 times) in intratumor doxorubicin concentration and a significant decrease in hepatic metastasis development. Oral administration of green tea/theanine at 100 mg/kg/day for 4 days also led to a 55% reduction in tumor size compared with doxorubicin-only control animals. Theanine reduced concentrations of doxorubicin in normal tissues (lung, liver, kidney) but was found to increase doxorubicin concentration in hepatic metastases. Theanine also reduced myocardial lipid peroxidation. Theanine, itself a glutamate derivative, inhibits glutamate transporters, and this is now considered to be one mechanism for doxorubicin concentrations to be increased in tumor cells. The experimental findings are reviewed by Sugiyama and Sadzuka. ⁴⁶

Tea polyphenols also modulate P-gp by inhibiting the membrane adenosinetriphosphatase (ATPase). ^34,38 The well-documented cardioprotective effects of green tea polyphenols have been shown to reduce the toxicity of doxorubicin in cultured cardiomyocytes, as measured by fatty acid composition, conjugated diene concentration, and lactate dehydrogenase (LDH) release. The primary mechanism is antioxidant prevention of lipid peroxidation by the doxorubicin-induced superoxide and peroxide radicals. However, there is also a direct effect on unsaturated fatty acid metabolism involving the desaturating/elongating enzymes. ⁵²

Because iron-chelating compounds are also protective against anthracycline-induced cardiac damage, chelation by tea polyphenols may be an additional mechanism, but evidence for this is not available.

Clinical Implications and Adaptations

Experimental data suggest that anthracycline cardiotoxicity can be reduced by green tea polyphenols, and that the green tea component theanine can increase sensitivity to doxorubicin in drug-resistant cell lines. Clinical studies are required to confirm these effects in human patients; however, given the lack of adverse effects of theanine and the green tea polyphenols, employment of these natural compounds as adjuncts to anthracycline chemotherapy should be considered for inclusion in integrative support protocols during anthracycline chemotherapy.

Iron Salts (Nonheme Iron)

Impaired Drug Absorption and Bioavailability, Negligible Effect

Probability: 3. Possible
Evidence Base:

0 Consensus

Effect and Mechanism of Action

Tea polyphenols have been shown to form chelates with nonheme iron. A pharmacokinetic interaction may occur if green tea is coadministered with food containing nonheme iron, which may reduce the level of iron absorption. The clinical significance of this interaction on iron status is considered minimal.

Research

Samman et al. ⁵³ performed a small open trial using radiolabeled iron added to meals over 4 days in healthy young women. The meals were identical except that green tea polyphenol extract or rosemary extract was added to the baseline test meal. A standard reference dose of an iron salt was also administered to examine variation in iron absorption characteristics. Addition of either natural agent to the meal caused a small decrease in iron absorption, slightly more with green tea than rosemary, a relative absorption decrease of 28% ( p<0.01).

A systematic review of available data on the inverse association between tea consumption and iron status examined 16 studies, including subgroups with high and low anemia risk status. Following adjustment for dietary factors there was no association between tea consumption and ferritin and hemoglobin status. ⁵⁴ Another systematic review of observational studies examining the effects of tea drinking on iron consumption concluded that restrictions on tea drinking were unnecessary in healthy people with no risk of iron deficiency. ⁵⁵ One often-quoted study suggests that infants age 6 to 12 months consuming 250 mL tea per day (median value) had a higher incidence of microcytic anemia than those who did not drink tea. ⁵⁶

Integrative Therapeutics, Clinical Concerns, and Adaptations

Standard medical advice for groups at risk of iron deficiency anemia is to drink tea between meals, waiting at least 1 hour after eating. ⁵⁷ Iron absorption enhancers such as ascorbic acid can be used in at-risk individuals, and administration of supplementary iron in the form of heme iron will tend to avoid any chelation problems based on the simple salts (e.g., ferrous sulfate, gluconate).

Methicillin and Related Beta-Lactam Antibiotics

Evidence: Methicillin (Staphcillin); beta-lactamase–resistant penicillins: cloxacillin (Cloxapen), dicloxacillin (Dynapen, Dycill), oxacillin (Bactocill); carbapenem antibiotics: meropenem (Merrem I.V.); combination drug: imipenem and cilastatin (Primaxin I.M., Primaxin I.V.).

Extrapolated, based on similar properties: Cephalosporin antibiotics, ciprofloxacin and other fluoroquinolone antibiotics, ketaconazoles, macrolide antibiotics, other penicillin antibiotics; combination drugs: amoxicillin and clavulanic acid (Augmentin, Augmentin XR, Clavulin, Nuclav); clavulanic acid and ticarcillin (Timentin).

Potential or Theoretical Beneficial or Supportive Interaction, with Professional Management

Probability: 1. Certain
Evidence Base:

Preliminary

Effect and Mechanism of Action

A synergistic interaction between tea polyphenols when combined with a broad range of beta-lactam antibiotics that appears to reverse beta-lactam resistance by modulating the bacterial phenotype in methicillin-resistant strains of Staphylococcus aureus(MRSA). The interaction may be an example of a general interaction between tea polyphenols and antimicrobial drugs.

Research

A number of experimental studies have demonstrated significant reductions in minimum inhibitory concentration (MIC) of methicillin, penicillin, oxacillin, and other beta-lactam antibiotics by two orders of magnitude. This effectively reverses resistance in several isolated MRSA strains by lowering MIC to below the resistance breakpoint. ^58-61 Initial studies used either EGCG or ECG, and there were discrepancies regarding the relative potencies of the two catechins, as well as a lack of data on the mechanisms involved and as to whether related polyphenolic compounds might exert similar effects. The mechanism of modulation of resistance may be multifactorial, including efflux pump disabling ⁶² and penicillinase inhibition, ⁶³ as well as direct binding to peptidoglycan in the bacterial membrane and intercalation in the membrane lipid layer. ^64,65

Stapleton et al. ⁶⁶ systematically tested ECG, EGCG, and several other gallates and catechins, measuring oxacillin activity against different MRSA isolates, and established that ECG has a greater capacity to modulate beta-lactam resistance than EGCG. They also found that the gallate moiety was essential for activity, and that ECG was also effective with the carbapenem antibiotics imipenem and meropenem. Recent investigations suggest that the synergistic effects with antimicrobials may extend to other drug-microbial combinations, such as macrolides with Helicobacter pylori,ketaconazoles with Candida albicans,and fluoroquinolones and Escherichia coli. ^67-71 A rodent model of prostatitis was used to demonstrate a synergistic effect between ciprofloxacin and green tea catechin. ⁷²

One small, controlled trial examined the effects of inhalation of tea catechins (2 mL containing 7.4 mg polyphenols with 3.7 mg EGCG via nebulizer three times daily for 4 weeks) in 12 elderly patients with confirmed MRSA titer in sputum samples versus 12 similar controls. Classification of MRSA was defined as cultured S. aureusshowing an oxacillin MIC of more than 4 mg/L. The trial included patients who had been treated with antibiotics, but during the trial period the catechins were administered alone. After 1 week the number of patients in the catechin group with detectable MRSA was significantly less than that of the controls. Hospital stay was also significantly reduced for the catechin group compared with controls. ⁷³ This trial suggests benefits to catechins taken alone in MRSA-positive patients, but did not investigate the effects of coadministration.

To date, clinical trials on combinations are unavailable.

Integrative Therapeutics, Clinical Concerns, and Adaptations

Methicillin-resistant S. aureusis a widespread cause of nosocomial infection. Experimental evidence strongly supports the use of tea catechins, particularly EGC, in combination with beta-lactam antibiotics. Although most relevant to the hospital setting, studies have yet to be undertaken. However, integrative practitioners dealing with community-acquired infections in vulnerable populations suspected of demonstrating antibiotic resistance might choose to coadminister tea polyphenol extracts to modulate the antibiotic resistance.

Selective Estrogen Response Modulators (SERMs), Aromatase Inhibitors

Evidence: Tamoxifen (Nolvadex).

Extrapolated, based on similar properties: Anastrozole (Arimidex), exemestane (Aromasin), letrozole (Femara), raloxifene (Evista), toremifene (Fareston).

Potential or Theoretical Beneficial or Supportive Interaction, with Professional Management

Probability: 6. Unknown
Evidence Base:

Preliminary

Effect and Mechanism of Action

A possible interaction is based on in vitro evidence that tamoxifen-induced apoptosis is increased by EGCG, possibly mediated by inhibitory effects on tumor necrosis factor alpha (TNF-α). Additional evidence suggests that tea polyphenols may also have aromatase inhibitor–like activity. The interaction is not clinically established.

Research

In a series of studies using human lung cancer PC-9 and breast cancer MCF-7 cell lines, Suganuma et al. ^74,75 investigated the induction of apoptosis by different tea polyphenols alone and in combination. They found that EC (which lacks the galloyl moiety and has no effect on apoptosis alone) synergistically increased the apoptotic effects of ECGC in a dose-dependent manner. Parallel effects were found on BALB/C-3T3 cells in which EC synergistically increased the effect of EGCG on inhibition of TNF-α (IC ⁵⁰ reduced from 60 to 7 μM), leading the investigators to posit a TNF-α–mediated mechanism. Using the same technique, they examined the effects of adding either sulindac (a classic NSAID) or tamoxifen to EGCG in the PC9 cell model and found that cotreatment by EGCG with either agent induced apoptosis more than when EGCG was given alone. The effect was smaller with tamoxifen than with sulindac. They replicated the effects of the combination on TNF-α inhibition in the BALB/C-3T3 cells, as well as in MCF7 cells, although these data were not presented.

Way et al. ⁷⁶ conducted a series of investigations into the mechanisms of EGCG and three black tea theaflavin compounds effects on HER-2/neu transfected MCF7 breast cells. They demonstrated that both EGCG and theaflavins inhibited tyrosine kinase phosphorylation, and further that EGCG/theaflavins could modulate the resistance of the HER-2/neu transfected cells to tamoxifen. The same study series also found the tea compounds showed significant aromatase inhibitory activity in rat ovarian and human placental microsomes. Aromatase inhibition by tea polyphenols has also been confirmed in a human placenta microsome assay, using a combination polyphenol extract (P-60) (IC ⁵⁰ = 28 μM). ⁷⁷ Because aromatase enzymes, predominantly in fat tissue, synthesize estrogen from adrenal androgens, pharmaceutical aromatase inhibitors are widely used in treatment of estrogen-dependent breast cancer in women without active ovarian function, to reduce estrogen levels further.

As a footnote, a rodent model found that GTE reduced tamoxifen-induced hepatic injury, following 7 days of tamoxifen at 45 mg/kg intraperitoneally, as indexed by transaminase levels as well as increases in glutathione and other antioxidant enzymes. ⁷⁸

Integrative Therapeutics, Clinical Concerns, and Adaptations

The current experimental data for possible synergy between tamoxifen and tea polyphenols are preliminary, and extrapolations cannot be reliably made until confirmation of the effects by human and clinical studies. The suggestions that TNF-α pathways may be modulated by estrogen, and that the activity of tamoxifen involves interaction with this and related factors, are supported in the literature, although the mechanisms are not fully understood. ^79,80 Given the activities of tea compounds on multiple molecular targets of the cancer process, coadministration of GTEs in hormone-dependent and hormone-independent mammary carcinoma with adjuvant chemotherapeutic agents warrants further study.

Trastuzumab

Trastuzumab (Herceptin).

Potential or Theoretical Beneficial or Supportive Interaction, with Professional Management

Probability: 4. Plausible
Evidence Base:

Preliminary

Effect and Mechanism of Action

Potential additive or synergistic interaction occurs between tea polyphenols, especially EGCG, and trastuzumab because of convergent pharmacodynamic HER-2/neu inhibition effects, probably associated with receptor tyrosine kinase activity. The interaction has been experimentally demonstrated, but clinical support is currently not available.

Research

The chemopreventive effects of tea polyphenols have been demonstrated in various animal models as well as by human epidemiological studies. The mechanisms are multifactorial and have been studied in a variety of cell culture models. ^{1-4,14,17,81-83}

The tea polyphenol EGCG inhibits receptor tyrosine kinase activity (IC ⁵⁰ = 1-2 μM). ⁸⁴ Masuda et al. ⁸⁵ demonstrated EGCG inhibition of EGFR autophosphorylation in head and neck squamous cell carcinoma and breast carcinoma cell lines. The same investigators later demonstrated significant inhibition of HER-2/neu activation in the same cell lines, although at high concentrations (10 and 30 µg); also, the sensitivity of both cell lines to paclitaxel (Taxol) was significantly increased by much lower doses of (0.1-1.0 µg/mL) of EGCG. ⁸⁶

Way et al. ⁷⁶ conducted a series of investigations into the effects of EGCG and three black tea theaflavin compounds on HER-2/neu transfected MCF7 breast cells. They demonstrated that both EGCG and theaflavins inhibited tyrosine kinase phosphorylation, and further that EGCG/theaflavins could modulate the resistance of the HER-2/neu transfected cells to tamoxifen. The same study series also found the tea compounds showed significant aromatase inhibitory activity in rat ovarian and human placental microsomes. ⁷⁶ The authors concluded that tea polyphenols could be useful in HER-2/neu–overexpressing cancers. Shimizu et al. ⁸⁷ used a colon cancer line overexpressing HER-3 and cyclooxygenase-2 (COX-2) and found that very low doses of ECGC inactivated EGFR, HER-2, and HER-3; decreased COX-2 and Bcl-xL proteins; and induced apoptosis.

Integrative Therapeutics, Clinical Concerns, and Adaptations

Concentrated tea polyphenol extracts are typically combined with other chemopreventive compounds in botanical and nutritional components of integrative cancer therapeutic protocols. Despite the preliminary nature of the experimental data, the available studies suggest tyrosine kinase inhibition is one of the pluripotent therapeutic activities of tea polyphenols, and that these may be effective in combination with trastuzumab (Herceptin) in diseases that overexpress the HER-2/neu receptor. Because this receptor is also present on myocardial cells, trastuzumab is associated with cardiotoxicity, which is exacerbated when combined with anthracycline agents, themselves cardiotoxic. ^68,88,89 Coadministration of anthracycline chemotherapy agents and trastuzumab is contraindicated because of the high incidence of clinical congestive heart failure that occurred in clinical trials of the combination. Even patients who have received anthracycline chemotherapy many years previously have an increased sensitivity to cardiotoxic effects of trastuzumab. In patients undergoing chemotherapy with trastuzumab, especially in patients who have previously received doxorubicin, coadministration of green tea polyphenol extracts in sufficient doses may ameliorate cardiotoxicity and increase drug effectiveness. Previous reservations about the applicability of cell-line studies with tea compounds are particularly pertinent to these extrapolations (see Strategic Considerations).

Evidence: Warfarin (Coumadin, Marevan, Warfilone).

Similar properties but evidence indicating no or reduced interaction effects: Anisindione (Miradon), dicumarol, ethyl biscoumacetate (Tromexan), nicoumalone (acenocoumarol; Acitrom, Sintrom), phenindione (Dindevan), phenprocoumon (Jarsin, Marcumar).

Interaction Possible but Uncertain Occurrence and Unclear Implications

Probability: 5. Improbable
Evidence Base:

Mixed

Effect and Mechanism of Action

An interaction was originally suggested by an isolated case report of significant INR reduction after consumption of green tea (beverage) in a patient stable on warfarin. The hypothesized mechanism of vitamin K content of green tea counteracting the effects of warfarin on vitamin K–dependent coagulation factor synthesis is unlikely. Antiplatelet rather than anticoagulant effects are more plausible.

Research

Kang et al. ⁹⁰ investigated the in vitro effects of tea catechins and EGCG on human platelet aggregation induced by adenosine, epinephrine, collagen, and calcium ionophore A23187 and found a dose-dependent inhibition of platelet aggregation but no change in any coagulation parameters. This confirmed an earlier report by Sagesaka-Mitane et al. ⁹¹ that the hot-water extracts of tea and EGCG inhibited collagen-induced aggregation in rabbit platelets. Son et al. ⁹² performed a series of tests on rabbit and rodent platelets with GTE and concluded that the antiplatelet activity observed in vitro was caused by inhibition of thromboxane A ² (TXA ² ) and prostaglandin D ² resulting from inhibition of arachidonic acid liberation and of inhibition of TXA ² synthase in response to collagen-induced aggregation.

Few human studies to date have examined the effects of tea on platelet aggregation. In a randomized crossover study, Duffy et al. ⁹³ examined the effects of acute and chronic black tea beverage consumption versus water placebo on 49 patients with coronary artery disease (CAD). They failed to detect any effects on platelet aggregation induced by adenosine diphosphate (ADP) or thrombin receptor activating peptide by the tea infusions at either acute or chronic doses. However, most patients in this study apparently continued with aspirin antithrombotic therapy, which confounds interpretation of the results. Wolfram et al. ⁹⁴ found that with 1 month of black tea consumption, healthy volunteers displayed gender differences in effect, with only females showing a slight decrease in ADP-induced platelet aggregation. Hodgson et al. ⁹⁵ examined a wide range of hemostasis parameters before and after the consumption of black tea (five cups per day for 4 weeks) by 22 volunteers. Platelet aggregation did not differ for collagen or ADP stimulation, and no differences in coagulation or fibrinolytic factor were observed after tea consumption. The same researchers performed a similar study on acute, single-dose tea consumption and similarly found no effects on postprandial platelet aggregation. ⁹⁶ The available evidence therefore suggests that although in vitro studies show a potential for antiaggregatory activity, these have not been reliably reproduced in vivo. Currently, no evidence exists for any effect on coagulation (as opposed to platelet) parameters of hemostasis.

Reports

Taylor and Wilt ⁹⁷ reported a case of a 44-year-old man with Marfan's syndrome who was receiving Coumadin (7.5 mg daily) to establish an international normalized ratio (INR) of 2.5 to 3.5 after a mechanical aortic valve replacement procedure. He had been on this regimen for 14 months, although with a history of fluctuation in INR that was countered by anticoagulant dose adjustment. The patient presented for routine primary care and was found to have an INR of 3.79. He was advised to stabilize his intake of vitamin K–containing foods and was retested 22 days later without warfarin dose adjustment. The INR was 1.37. The patient could not be contacted but returned 1 month later for regular INR testing, when his INR was 1.14. He denied changes in diet, disease, medication, or warfarin dose, but he later admitted that he had commenced drinking green tea, between half and one gallon daily, before the previous INR of 1.37. He was instructed to discontinue the tea, and 1 week later the INR was 2.55. The authors suggested that the only explanation for the INR decrease was antagonism of warfarin by vitamin K in the green tea. ⁹⁷ This explanation seems improbable, however, because with the lipophilicity of phylloquinone, the vitamin K content of brewed tea is negligible, at 0.05 µg/100 g, versus the 1.43 mg/100 g of green tea leaf (USDA Nutrient Data Research figures). ⁹⁸ The possibility of tea inhibiting CYP450 1A2, which metabolizes the weaker R-enantiomer of warfarin, was not discussed. If the patient were a poor metabolizer at 2C9 (which metabolizes the more active S-warfarin enantiomer), this could have been a contributory factor. The report remains difficult to interpret and an isolated case without corroborative data.

Clinical Implications and Adaptations

Given the widespread consumption of tea as a beverage, any impact on hemostasis would be consequential from a public health point of view. The balance of data currently available suggests that the cardioprotective effects of tea polyphenols are unrelated either to vitamin K–dependent coagulation factor modulation or to in vivo antiplatelet effects. Nonetheless, standard practice is for patients using oral anticoagulation and antithrombotic therapies to avoid excessive tea beverage consumption.

Whether concentrated tea polyphenol extracts contain significant amounts of vitamin K is not currently known. In cases of intended coadministration of high doses of such extracts with anticoagulant drugs, standard monitoring of INR should be vigilantly followed, particularly before and immediately after commencement of the extract administration.

Citations

1.Aggarwal BB, Shishodia S. Molecular targets of dietary agents for prevention and therapy of cancer. Biochem Pharmacol 2006;71:1397-1421.View Abstract
2.Khan N, Afaq F, Saleem M et al. Targeting multiple signaling pathways by green tea polyphenol (-)-epigallocatechin-3-gallate. Cancer Res 2006;66:2500-2505.View Abstract
3.Na H-K, Surh Y-J. Intracellular signaling network as a prime chemopreventive target of (−)-epigallocatechin gallate. Mol Nutr Food Res 2006;50:152-159.View Abstract
4.Yang CS, Sang S, Lambert JD et al. Possible mechanisms of the cancer-preventive activities of green tea. Mol Nutr Food Res 2006;50:170-175.View Abstract
5.McKenna D, Jones K, Hughes K, Humphrey S. Green tea. Botanical Medicines. 2nd ed. Binghamton, NY: Haworth Press; 2002:223-254.View Abstract
6.Stockley I. Stockley’s Drug Interactions. 6th ed. London: Pharmaceutical Press; 2002.
7.Huang MT, Xie JG, Wang ZY et al. Effects of tea, decaffeinated tea, and caffeine on UVB light–induced complete carcinogenesis in SKH-1 mice: demonstration of caffeine as a biologically important constituent of tea. Cancer Res 1997;57:2623-2629.View Abstract
8.Conney AH, Lu YP, Lou YR, Huang MT. Inhibitory effects of tea and caffeine on UV-induced carcinogenesis: relationship to enhanced apoptosis and decreased tissue fat. Eur J Cancer Prev 2002;11 Suppl 2:S28-36.View Abstract
9.Lu YP, Lou YR, Lin Y et al. Inhibitory effects of orally administered green tea, black tea, and caffeine on skin carcinogenesis in mice previously treated with ultraviolet B light (high-risk mice): relationship to decreased tissue fat. Cancer Res 2001;61:5002-5009.View Abstract
10.Beecher GR. Overview of dietary flavonoids: nomenclature, occurrence and intake. J Nutr 2003;133:3248S-3254S.View Abstract
11.Seely D, Mills EJ, Wu P et al. The effects of green tea consumption on incidence of breast cancer and recurrence of breast cancer: a systematic review and meta-analysis. Integr Cancer Ther 2005;4:144-155.View Abstract
12.Jodoin J, Demeule M, Beliveau R. Inhibition of the multidrug resistance P-glycoprotein activity by green tea polyphenols. Biochim Biophys Acta 2002;1542:149-159.View Abstract
13.Chow HH, Cai Y, Alberts DS et al. Phase I pharmacokinetic study of tea polyphenols following single-dose administration of epigallocatechin gallate and polyphenon E. Cancer Epidemiol Biomarkers Prev 2001;10:53-58.View Abstract
14.Lambert JD, Yang CS. Cancer chemopreventive activity and bioavailability of tea and tea polyphenols. Mutat Res 2003;523-524:201-208.View Abstract
15.Vaidyanathan JB, Walle T. Glucuronidation and sulfation of the tea flavonoid (−)-epicatechin by the human and rat enzymes. Drug Metab Dispos 2002;30:897-903.View Abstract
16.Hong J, Lu H, Meng X et al. Stability, cellular uptake, biotransformation, and efflux of tea polyphenol (−)-epigallocatechin-3-gallate in HT-29 human colon adenocarcinoma cells. Cancer Res 2002;62:7241-7246.View Abstract
17.Hou Z, Lambert JD, Chin KV, Yang CS. Effects of tea polyphenols on signal transduction pathways related to cancer chemoprevention. Mutat Res 2004;555:3-19.View Abstract
18.Maliakal PP, Coville PF, Wanwimolruk S. Tea consumption modulates hepatic drug metabolizing enzymes in Wistar rats. J Pharm Pharmacol 2001;53:569-577.View Abstract
19.Maliakal PP, Wanwimolruk S. Effect of herbal teas on hepatic drug metabolizing enzymes in rats. J Pharm Pharmacol 2001;53:1323-1329.View Abstract
20.Feng Q, Torii Y, Uchida K et al. Black tea polyphenols, theaflavins, prevent cellular DNA damage by inhibiting oxidative stress and suppressing cytochrome P450 1A1 in cell cultures. J Agric Food Chem 2002;50:213-220.View Abstract
21.Williams SN, Pickwell GV, Quattrochi LC. A combination of tea (Camellia senensis) catechins is required for optimal inhibition of induced CYP1A expression by green tea extract. J Agric Food Chem 2003;51:6627-6634.
22.Krishnan R, Maru GB. Inhibitory effect(s) of polymeric black tea polyphenol fractions on the formation of [(3)H]-B(a)P-derived DNA adducts. J Agric Food Chem 2004;52:4261-4269.View Abstract
23.Krishnan R, Raghunathan R, Maru GB. Effect of polymeric black tea polyphenols on benzo(a)pyrene [B(a)P]-induced cytochrome P4501A1 and 1A2 in mice. Xenobiotica 2005;35:671-682.View Abstract
24.Muto S, Fujita K, Yamazaki Y, Kamataki T. Inhibition by green tea catechins of metabolic activation of procarcinogens by human cytochrome P450. Mutat Res 2001;479:197-206.View Abstract
25.Niwattisaiwong N, Luo XX, Coville PF, Wanwimolruk S. Effects of Chinese, Japanese and Western tea on hepatic P450 enzyme activities in rats. Drug Metabol Drug Interact 2004;20:43-56.View Abstract
26.Bu-Abbas A, Clifford MN, Ioannides C, Walker R. Stimulation of rat hepatic UDP-glucuronosyl transferase activity following treatment with green tea. Food Chem Toxicol 1995;33:27-30.View Abstract
27.Bu-Abbas A, Clifford MN, Walker R, Ioannides C. Contribution of caffeine and flavanols in the induction of hepatic Phase II activities by green tea. Food Chem Toxicol 1998;36:617-621.View Abstract
28.Xu M, Dashwood RH. Chemoprevention studies of heterocyclic amine-induced colon carcinogenesis. Cancer Lett 1999;143:179-183.View Abstract
29.Embola CW, Sohn OS, Fiala ES, Weisburger JH. Induction of UDP-glucuronosyltransferase 1 (UDP-GT1) gene complex by green tea in male F344 rats. Food Chem Toxicol 2002;40:841-844.View Abstract
30.Moyers SB, Kumar NB. Green tea polyphenols and cancer chemoprevention: multiple mechanisms and endpoints for phase II trials. Nutr Rev 2004;62:204-211.View Abstract
31.Zhong Z, Connor HD, Froh M et al. Polyphenols from Camellia sinenesis prevent primary graft failure after transplantation of ethanol-induced fatty livers from rats. Free Radic Biol Med 2004;36:1248-1258.View Abstract
32.Nishimuta H, Tsujimoto M, Ogura K et al. Inhibitory effects of various beverages on ritodrine sulfation by recombinant human sulfotransferase isoforms SULT1A1 and SULT1A3. Pharm Res 2005;22:1406-1410.
33.Wang EJ, Barecki-Roach M, Johnson WW. Elevation of P-glycoprotein function by a catechin in green tea. Biochem Biophys Res Commun 2002;297:412-418.View Abstract
34.Zhu A, Wang X, Guo Z. Study of tea polyphenol as a reversal agent for carcinoma cell lines’ multidrug resistance (study of TP as a MDR reversal agent). Nucl Med Biol 2001;28:735-740.View Abstract
35.Sadzuka Y, Sugiyama T, Sonobe T. Efficacies of tea components on doxorubicin-induced antitumor activity and reversal of multidrug resistance. Toxicol Lett 2000;114:155-162.View Abstract
36.Kitagawa S, Nabekura T, Kamiyama S. Inhibition of P-glycoprotein function by tea catechins in KB-C2 cells. J Pharm Pharmacol 2004;56:1001-1005.View Abstract
37.Lee K, Ng C, Brouwer KL, Thakker DR. Secretory transport of ranitidine and famotidine across Caco-2 cell monolayers. J Pharmacol Exp Ther 2002;303:574-580.View Abstract
38.Mei Y, Qian F, Wei D, Liu J. Reversal of cancer multidrug resistance by green tea polyphenols. J Pharm Pharmacol 2004;56:1307-1314.View Abstract
39.Vaidyanathan JB, Walle T. Transport and metabolism of the tea flavonoid (−)-epicatechin by the human intestinal cell line Caco-2. Pharm Res 2001;18:1420-1425.View Abstract
40.Vaidyanathan JB, Walle T. Cellular uptake and efflux of the tea flavonoid (−)-epicatechin-3-gallate in the human intestinal cell line Caco-2. J Pharmacol Exp Ther 2003;307:745-752.View Abstract
41.Fuchikami H, Satoh H, Tsujimoto M et al. Effects of herbal extracts on the function of human organic anion transporting polypeptide, OATP-B. Drug Metab Dispos 2006;34:577-582.View Abstract
42.Netsch MI, Gutmann H, Luescher S et al. Inhibitory activity of a green tea extract and some of its constituents on multidrug resistance–associated protein 2 functionality. Planta Med 2005;71:135-141.View Abstract
43.Sadzuka Y, Yamashita Y, Kishimoto S et al. [Glutamate transporter–mediated increase of antitumor activity by theanine, an amino acid in green tea]. Yakugaku Zasshi 2002;122:995-999.View Abstract
44.Sugiyama T, Sadzuka Y, Tanaka K, Sonobe T. Inhibition of glutamate transporter by theanine enhances the therapeutic efficacy of doxorubicin. Toxicol Lett 2001;121:89-96.View Abstract
45.Sugiyama T, Sadzuka Y. Theanine and glutamate transporter inhibitors enhance the antitumor efficacy of chemotherapeutic agents. Biochim Biophys Acta 2003;1653:47-59.View Abstract
46.Sugiyama T, Sadzuka Y. Theanine, a specific glutamate derivative in green tea, reduces the adverse reactions of doxorubicin by changing the glutathione level. Cancer Lett 2004;212:177-184.View Abstract
47.Uehara M, Sugiura H, Sakurai K. A trial of oolong tea in the management of recalcitrant atopic dermatitis. Arch Dermatol 2001;137:42-43.View Abstract
48.Furue M, Terao H, Moroi Y et al. Dosage and adverse effects of topical tacrolimus and steroids in daily management of atopic dermatitis. J Dermatol 2004;31:277-283.View Abstract
49.Sadzuka Y, Sugiyama T, Miyagishima A et al. The effects of theanine, as a novel biochemical modulator, on the antitumor activity of Adriamycin. Cancer Lett 1996;105:203-209.View Abstract
50.Sadzuka Y, Sugiyama T, Hirota S. Modulation of cancer chemotherapy by green tea. Clin Cancer Res 1998;4:153-156.View Abstract
51.Sugiyama T, Sadzuka Y. Combination of theanine with doxorubicin inhibits hepatic metastasis of M5076 ovarian sarcoma. Clin Cancer Res 1999;5:413-416.View Abstract
52.Hrelia S, Bordoni A, Angeloni C et al. Green tea extracts can counteract the modification of fatty acid composition induced by doxorubicin in cultured cardiomyocytes. Prostaglandins Leukot Essent Fatty Acids 2002;66:519-524.View Abstract
53.Samman S, Sandstrom B, Toft MB et al. Green tea or rosemary extract added to foods reduces nonheme-iron absorption. Am J Clin Nutr 2001;73:607-612.View Abstract
54.Temme EH, Van Hoydonck PG. Tea consumption and iron status. Eur J Clin Nutr 2002;56:379-386.View Abstract
55.Nelson M, Poulter J. Impact of tea drinking on iron status in the UK: a review. J Hum Nutr Diet 2004;17:43-54.View Abstract
56.Merhav H, Amitai Y, Palti H, Godfrey S. Tea drinking and microcytic anemia in infants. Am J Clin Nutr 1985;41:1210-1213.View Abstract
57.Zijp IM, Korver O, Tijburg LB. Effect of tea and other dietary factors on iron absorption. Crit Rev Food Sci Nutr 2000;40:371-398.View Abstract
58.Shiota S, Shimizu M, Mizushima T et al. Marked reduction in the minimum inhibitory concentration (MIC) of beta-lactams in methicillin-resistant Staphylococcus aureus produced by epicatechin gallate, an ingredient of green tea (Camellia sinensis). Biol Pharm Bull 1999;22:1388-1390.View Abstract
59.Hu ZQ, Zhao WH, Hara Y, Shimamura T. Epigallocatechin gallate synergy with ampicillin/sulbactam against 28 clinical isolates of methicillin-resistant Staphylococcus aureus. J Antimicrob Chemother 2001;48:361-364.View Abstract
60.Hu ZQ, Zhao WH, Asano N et al. Epigallocatechin gallate synergistically enhances the activity of carbapenems against methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2002;46:558-560.View Abstract
61.Zhao WH, Hu ZQ, Okubo S et al. Mechanism of synergy between epigallocatechin gallate and beta-lactams against methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2001;45:1737-1742.
62.Sudano Roccaro A, Blanco AR, Giuliano F et al. Epigallocatechin-gallate enhances the activity of tetracycline in staphylococci by inhibiting its efflux from bacterial cells. Antimicrob Agents Chemother 2004;48:1968-1973.View Abstract
63.Zhao WH, Hu ZQ, Hara Y, Shimamura T. Inhibition of penicillinase by epigallocatechin gallate resulting in restoration of antibacterial activity of penicillin against penicillinase-producing Staphylococcus aureus. Antimicrob Agents Chemother 2002;46:2266-2268.View Abstract
64.Kajiya K, Kumazawa S, Nakayama T. Effects of external factors on the interaction of tea catechins with lipid bilayers. Biosci Biotechnol Biochem 2002;66:2330-2335.View Abstract
65.Caturla N, Vera-Samper E, Villalain J et al. The relationship between the antioxidant and the antibacterial properties of galloylated catechins and the structure of phospholipid model membranes. Free Radic Biol Med 2003;34:648-662.
66.Stapleton PD, Shah S, Anderson JC et al. Modulation of beta-lactam resistance in Staphylococcus aureus by catechins and gallates. Int J Antimicrob Agents 2004;23:462-467.View Abstract
67.Hirasawa M, Takada K. Multiple effects of green tea catechin on the antifungal activity of antimycotics against Candida albicans. J Antimicrob Chemother 2004;53:225-229.View Abstract
68.Yanagawa Y, Yamamoto Y, Hara Y, Shimamura T. A combination effect of epigallocatechin gallate, a major compound of green tea catechins, with antibiotics on Helicobacter pylori growth in vitro. Curr Microbiol 2003;47:244-249.View Abstract
69.Isogai E, Isogai H, Hirose K et al. In vivo synergy between green tea extract and levofloxacin against enterohemorrhagic Escherichia coli O157 infection. Curr Microbiol 2001;42:248-251.
70.Tiwari TP, Bharti SK, Kaur HD et al. Synergistic antimicrobial activity of tea and antibiotics. Indian J Med Res 2005;122:80-84.View Abstract
71.Hu ZQ, Zhao WH, Yoda Y et al. Additive, indifferent and antagonistic effects in combinations of epigallocatechin gallate with 12 non-beta-lactam antibiotics against methicillin-resistant Staphylococcus aureus. J Antimicrob Chemother 2002;50:1051-1054.View Abstract
72.Lee YS, Han CH, Kang SH et al. Synergistic effect between catechin and ciprofloxacin on chronic bacterial prostatitis rat model. Int J Urol 2005;12:383-389.
73.Yamada H, Ohashi K, Atsumi T et al. Effects of tea catechin inhalation on methicillin-resistant Staphylococcus aureus in elderly patients in a hospital ward. J Hosp Infect 2003;53:229-231.View Abstract
74.Suganuma M, Okabe S, Kai Y et al. Synergistic effects of (−)-epigallocatechin gallate with (−)-epicatechin, sulindac, or tamoxifen on cancer-preventive activity in the human lung cancer cell line PC-9. Cancer Res 1999;59:44-47.View Abstract
75.Suganuma M, Sueoka E, Sueoka N et al. Mechanisms of cancer prevention by tea polyphenols based on inhibition of TNF-α expression. Biofactors 2000;13:67-72.View Abstract
76.Way TD, Lee HH, Kao MC, Lin JK. Black tea polyphenol theaflavins inhibit aromatase activity and attenuate tamoxifen resistance in HER2/neu-transfected human breast cancer cells through tyrosine kinase suppression. Eur J Cancer 2004;40:2165-2174.View Abstract
77.Satoh K, Sakamoto Y, Ogata A et al. Inhibition of aromatase activity by green tea extract catechins and their endocrinological effects of oral administration in rats. Food Chem Toxicol 2002;40:925-933.View Abstract
78.El-Beshbishy HA. Hepatoprotective effect of green tea (Camellia sinensis) extract against tamoxifen-induced liver injury in rats. J Biochem Mol Biol 2005;38:563-570.View Abstract
79. De Jong PC, Blankenstein MA, van de Ven J et al. Importance of local aromatase activity in hormone-dependent breast cancer: a review. Breast 2001;10:91-99.View Abstract
80.Zhang X, Wang LY, Jiang TY et al. Effects of testosterone and 17-β-estradiol on TNF-α-induced E-selectin and VCAM-1 expression in endothelial cells: analysis of the underlying receptor pathways. Life Sci 2002;71:15-29.
81.Lambert JD, Yang CS. Mechanisms of cancer prevention by tea constituents. J Nutr 2003;133:3262S-3267S.View Abstract
82.Bode AM, Dong Z. Targeting signal transduction pathways by chemopreventive agents. Mutat Res 2004;555:33-51.View Abstract
83.Dorai T, Aggarwal BB. Role of chemopreventive agents in cancer therapy. Cancer Lett 2004;215:129-140.View Abstract
84.Liang YC, Lin-shiau SY, Chen CF, Lin JK. Suppression of extracellular signals and cell proliferation through EGF receptor binding by (−)-epigallocatechin gallate in human A431 epidermoid carcinoma cells. J Cell Biochem 1997;67:55-65.
85.Masuda M, Suzui M, Weinstein IB. Effects of epigallocatechin-3-gallate on growth, epidermal growth factor receptor signaling pathways, gene expression, and chemosensitivity in human head and neck squamous cell carcinoma cell lines. Clin Cancer Res 2001;7:4220-4229.View Abstract
86.Masuda M, Suzui M, Lim JT, Weinstein IB. Epigallocatechin-3-gallate inhibits activation of HER-2/neu and downstream signaling pathways in human head and neck and breast carcinoma cells. Clin Cancer Res 2003;9:3486-3491.View Abstract
87.Shimizu M, Deguchi A, Joe AK et al. EGCG inhibits activation of HER3 and expression of cyclooxygenase-2 in human colon cancer cells. J Exp Ther Oncol 2005;5:69-78.View Abstract
88.Suter TM, Cook-Bruns N, Barton C. Cardiotoxicity associated with trastuzumab (Herceptin) therapy in the treatment of metastatic breast cancer. Breast 2004;13:173-183.View Abstract
89.Perez EA, Rodeheffer R. Clinical cardiac tolerability of trastuzumab. J Clin Oncol 2004;22:322-329.View Abstract
90.Kang WS, Lim IH, Yuk DY et al. Antithrombotic activities of green tea catechins and (-)-epigallocatechin gallate. Thromb Res 1999;96:229-237.View Abstract
91.Sagesaka-Mitane Y, Miwa M, Okada S. Platelet aggregation inhibitors in hot water extract of green tea. Chem Pharm Bull (Tokyo) 1990;38:790-793.View Abstract
92.Son DJ, Cho MR, Jin YR et al. Antiplatelet effect of green tea catechins: a possible mechanism through arachidonic acid pathway. Prostaglandins Leukot Essent Fatty Acids 2004;71:25-31.View Abstract
93.Duffy SJ, Vita JA, Holbrook M et al. Effect of acute and chronic tea consumption on platelet aggregation in patients with coronary artery disease. Arterioscler Thromb Vasc Biol 2001;21:1084-1089.View Abstract
94.Wolfram RM, Oguogho A, Efthimiou Y et al. Effect of black tea on (iso-)prostaglandins and platelet aggregation in healthy volunteers. Prostaglandins Leukot Essent Fatty Acids 2002;66:529-533.View Abstract
95.Hodgson JM, Puddey IB, Mori TA et al. Effects of regular ingestion of black tea on haemostasis and cell adhesion molecules in humans. Eur J Clin Nutr 2001;55:881-886.View Abstract
96.Hodgson JM, Puddey IB, Burke V et al. Acute effects of ingestion of black tea on postprandial platelet aggregation in human subjects. Br J Nutr 2002;87:141-145.View Abstract
97.Taylor JR, Wilt VM. Probable antagonism of warfarin by green tea. Ann Pharmacother 1999;33:426-428.View Abstract
98.Booth SL, Madabushi HT, Davidson KW, Sadowski JA. Tea and coffee brews are not dietary sources of vitamin K-1 (phylloquinone). J Am Diet Assoc 1995;95:82-83.View Abstract

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Therapeutic Dosing Range

Strategic Considerations

Effects on Drug Metabolism and Bioavailability

Theanine

Effect and Mechanism of Action

Research

Clinical Implications and Adaptations

Effect and Mechanism of Action

Research

Clinical Implications and Adaptations

Effect and Mechanism of Action

Research

Integrative Therapeutics, Clinical Concerns, and Adaptations

Effect and Mechanism of Action

Research

Integrative Therapeutics, Clinical Concerns, and Adaptations

Effect and Mechanism of Action

Research

Integrative Therapeutics, Clinical Concerns, and Adaptations

Effect and Mechanism of Action

Research

Integrative Therapeutics, Clinical Concerns, and Adaptations

Effect and Mechanism of Action

Research

Reports

Clinical Implications and Adaptations