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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
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
Doxorubicin and Related Anthracycline Chemotherapy
Iron Salts (Nonheme Iron)
Methicillin and Related Beta-Lactam Antibiotics
Selective Estrogen Response Modulators (SERMs), Aromatase Inhibitors
Trastuzumab
Warfarin and Related Oral Vitamin K Antagonist Anticoagulants
  • 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
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