Catechin

Catechins are a type of phenolic compounds very abundant in tea, cocoa and berries to which are ascribed a potent antioxidant activity, especially to epigallocatechin-3-gallate (EGCG).

From: Encyclopedia of Reproduction (Second Edition), 2018

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Cianidanol

J.K. Aronson MA, DPhil, MBChB, FRCP, HonFBPhS, HonFFPM, in Meyler's Side Effects of Drugs, 2016

General information

Cianidanol is an antioxidant flavonoid that occurs especially in woody plants. It is one constituent of green tea. It has immunomodulatory properties, including effects on T lymphocytes and killer cells [1].

Of 40 patients with chronic active hepatitis, 22 took cianidanol 3 g/day and 18 took placebo [2]. Adverse reactions to cianidanol were fever (n = 4), hemolysis (n = 1), and urticaria (n = 1).

Serious adverse reactions were not observed when cianidanol was used to treat HBe-antigen-positive chronic hepatitis in 338 patients [3]. The only adverse reaction of note that appeared to be drug-related was transient pyrexia in 13, necessitating withdrawal of therapy in eight. Four patients also had a skin eruption.

Cianidanol

In Meyler's Side Effects of Drugs (Sixteenth Edition), 2016

General information

Cianidanol is an antioxidant flavonoid that occurs especially in woody plants. It is one constituent of green tea. It has immunomodulatory properties, including effects on T lymphocytes and killer cells [1].

Of 40 patients with chronic active hepatitis, 22 took cianidanol 3 g/day and 18 took placebo [2]. Adverse reactions to cianidanol were fever (n = 4), hemolysis (n = 1), and urticaria (n = 1).

Serious adverse reactions were not observed when cianidanol was used to treat HBe-antigen-positive chronic hepatitis in 338 patients [3]. The only adverse reaction of note that appeared to be drug-related was transient pyrexia in 13, necessitating withdrawal of therapy in eight. Four patients also had a skin eruption.

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Role of Catechins in Chemosensitization

Anand Swaroop Shukla, ... Anju Shrivastava, in Role of Nutraceuticals in Cancer Chemosensitization, 2018

Sources of Catechins

Catechins can be harvested from a variety of sources including many herbs, fruits, vegetables, beverages, algae, and confectionary items. But their contents and types vary considerably among various sources. The availability of diverse sources also varies around the globe, which is a major reason for the nonuniform intake in nutrition. High catechin content is reported to be present in fresh tea leaves, apricots, broad beans, black grapes, strawberries, wines, etc. Also, high concentrations of EC are reported to be found in apples, blackberries, broad beans, black grapes, cherries, chocolate, pears, and raspberries (Table 1) [6]. Geographic changes also alter the content and variety of catechins in each of its sources such as tea leaves and other sources from different sites that have varying contents of catechins [11].

Table 1. Major Sources of Catechins in Conventional and Nonconventional Foods

Source Total Amount of Catechins (mg/100 g) Abundant Type References
Fruits
Apple 10–43 EGCG [6,7]
Apricot 10–25 Epicatechins [6,7]
Cherry 5–22 EGCG [6,7]
Strawberry 2–50 Catechin [6,7]
Vegetables
Beans 35–55 [6,7]
Lemon EGCG [6,8]
Beverages
Black tea 6–50 EGCG [6,7]
Green tea 10–80 EGCG [6,7]
Cider 4 Catechin
Red wine 8–30 Catechin [6,9]
Algae
Green algae (Acetabularia ryukyuensis) 33.3, 500 ± 320 Catechin, epicatechin [10]
Eisenia bicyclis 38.6 Catechin gallate, epicatechin [10]
Red algae (Chondrococcus hornemannii) 217 ± 95, 1600 ± 76 Catechin, epigallocatechin [10]
Other food products
Chocolate 46–61 [6,7]

As green tea is the most common aromatic beverage around the globe, many epidemiological studies correlated the tea consumption and decreased risk of various metabolic disorders as well as mortality in a dose-dependent fashion. Eighty percent of all polyphenols present in green tea are contributed by catechins. Mainly, EGCG, EGC, ECG, and EC are found in green tea. EGCG is the most abundant and the most pharmacologically potent catechin found in green tea [12].

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Polyphenols in Chronic Diseases and their Mechanisms of Action

Anand A. Zanwar, ... Subhash L. Bodhankar, in Polyphenols in Human Health and Disease, 2014

Catechin is present in many dietary products, plants, fruits (such as apples, blueberries, gooseberries, grape seeds, kiwi, strawberries), green tea, red wine, beer, cacao liquor, chocolate, cocoa, etc. Tea and red wine are some of the most popular beverages in the world. The antioxidant action of catechin is well-established by various in vitro, in vivo and physical methods. Catechin affects the molecular mechanisms involved in angiogenesis, extracellular matrix degradation, the regulation of cell death, and multidrug resistance in cancers and related disorders. A positive correlation between green tea consumption and cardiovascular health due to several actions such as antioxidative, antihypertensive, anti-inflammatory, antiproliferative, antithrombogenic, and anti-hyperlipidemic etc., is well established based upon epidemiological and experimental studies. Clinical studies have shown the beneficial effects of catechin due its antioxidant action.

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Green Tea Effects on Age-Related Neurodegeneration

José Paulo Andrade MD, PhD, Marco Assunção MD, PhD, in Diet and Nutrition in Dementia and Cognitive Decline, 2015

Summary Points

Catechins of the green tea are substances with pleiotropic effects that exert neuroprotective effects by multiple mechanisms at the molecular level, influence of several intracellular signaling pathways, and modulation of gene expression and protein functioning.

Catechins are able to cross the blood–brain barrier, reach the CNS, and regulate gene and protein expression in neurons.

The effects of catechins are determined at the molecular level in the limbic system through the increase of BDNF levels.

Catechins are potential therapeutical tools that can counterbalance neurodegenerative events associated with aging and related diseases.

There are several clinical trials evaluating the beneficial effects of catechins in the treatment or recovery of cognitive function in several neurodegenerative diseases related to aging.

The advice to consume green tea moderately may contribute to improving the quality of life in the elderly.

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Harmful and Protective Effects of Phenolic Compounds from African Medicinal Plants

Armelle T. Mbaveng, ... Victor Kuete, in Toxicological Survey of African Medicinal Plants, 2014

20.5.1 Catechin

Catechin (18) is a naturally occurring flavonol and a well-demonstrated antioxidant phytochemical originally derived from catechu, which is the tannic juice or boiled extract of Acacia catechu L.f (Fabaceae) [78]. Catechin is a constituent of several medicinal plants found throughout Africa such as Ficus mucuso [79], Ficus gnaphalocarpa [80], Ficus cordata (Moraceae) [81] and Khaya grandifoliola C.D.C. (Meliaceae) [82] harvested in Cameroon, Holothuria atra (Holothuriidae) [83], Thalassodendron ciliatum (Cymodoceaceae) [84] from Egypt, Psidium guajava (Myrtaceae) [85], Acalypha wilkesiana “Godseffiana” Muell Arg (Euphorbiaceae) [86] from Nigeria, Terminalia sericea (Combretaceae) [87], Peltophorum africanum (Fabaceae) [88] and Guibourtia coleosperma (Fabaceae) [89] from South Africa. Compound 18 is a pharmacologically active compound found to induce longevity in the nematode worm Caenorhabditis elegans [90], to inhibit intestinal tumor formation in mice [91], to inhibit the oxidation of low-density lipoprotein [92], to suppress expression of Kruppel-like factor 7 [93], to show an enhancement of the antifungal effect of amphotericin B against Candida albicans [94] and to prevent human plasma oxidation [95]. Transcriptomic studies also indicated that 18 could reduce atherosclerotic lesion development in apo E-deficient mice [96]. It was demonstrated that catechin-like compounds were strong therapeutic candidates for protection against the cognitive decline caused by the HIV. In fact, epicatechin, EGCG (19) and other catechin flavonoids may protect against neurotoxic oxidative stress caused by the HIV-Tat protein [97]. Epicatechin was found able to cross the blood–brain barrier and activate brain-derived neurotrophic factor (BDNF) pathways [97], suggesting its neuroprotective effects. Compound 18 was reported as histidine decarboxylase inhibitor, inhibiting the conversion of histidine to histamine suggesting to have beneficial effects through reduction of potentially damaging, histamine-related local immune response [98]. This phytochemical is also a selective monoamine oxidase inhibitor (MAOI) of type MAO-B, showing its ability to reduce the symptoms of Parkinson and Alzheimer diseases [99].

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Food-Borne Topoisomerase Inhibitors

Melanie Esselen, Stephan W. Barth, in Advances in Molecular Toxicology, 2014

5.2 Catechins

Catechins (flavan-3-ols) belong to the group of polyphenols. (−)-Epigallocatechin-3-gallate (EGCG), (−)-epigallocatechin (EGC), (−)-epicatechin-3-gallate (ECG), and (−)-epicatechin (EC) (Scheme 4.3) are the major polyphenols in green tea [103].

Scheme 4.3. Structures of major green tea catechins.

Tea, produced from the leaves of Camellia sinensis, is one of the most widely consumed beverages in the world [104]. It has been postulated that green tea polyphenols, in particular EGCG, modulate cellular signal transduction pathways associated with the prevention of several diseases, including cancer, diabetes mellitus, and cardiovascular diseases (reviewed in Refs. [105,106]). Green tea polyphenols, especially EGCG, received much attention over the past few years as a potential cancer chemopreventive. Cytotoxic and genotoxic effects of these compounds were also reported [107–111]. Interactions of catechins with topoisomerase isoenzymes seem to play a crucial role for the observed impact on DNA integrity.

Several studies showed that the green tea catechins ECG and EGCG do not affect topoisomerase activity as analyzed by the DNA relaxation assay using pBR322 plasmid DNA and calf thymus topo1 as assay partners [112], or only at higher concentrations (≤ 500 μM) using purified topo1 from the human colon carcinoma cell lines HCT 116, VACO 241, or SW 480 [113]. In a further investigation, EGCG, ECG, and EGC exhibit inhibitory properties on calf thymus topo1 with IC50 values of 5, 136, and 475 μM, respectively, whereas EC does not affect topo1 activity at concentrations up to 1 mM [114]. Overall, these results implicate that green tea catechins are only weak inhibitors of topo1. However, the substitution of a galloyl group at the 3 position and/or the hydroxyl group at the 3′ position indicates crucial structural characteristics for the observed topo1 inhibitory properties [113,114]. Using an immunofluorescence technique that employs specific antibodies to detect topo1–DNA intermediates in cells, the so-called TARDIS assay, Lopez-Lazaro et al. [115] show that EGCG (100 μM) potently increase the amount of topo1/DNA intermediates in K562 leukemia cells after 24 h of incubation.

Additionally, green tea catechins potently inhibit topo2 activity [80,114,116–118]. Further studies elucidated the underlying mechanism of action and characterized EGCG as a topo2 poison, without differentiating between 2α and 2β isoforms [112]. Recent studies suggested that the clinical effects of topo2 poisons may be related to individual enzyme isoforms, with the chemotherapeutic properties being attributed primarily to topo2α and the leukemogenic properties and off-target toxicity primarily mediated by topo2β [97,119]. Bandele and Osheroff [120] show that EGCG potently poisons both topo2α and topo2β. Furthermore, they characterize EGCG as topo2 poison with a redox-dependent mechanism of action that appears to act by covalently adducting the enzyme. These results are in line with the reported stabilization of topo2α and topo2β intermediates in K562 cells incubated with 100 μM EGCG [115]. EGCG was the first polyphenol which was reported to act as a covalent topoisomerase poison. Within the class of green tea polyphenols, EGC has also been characterized as a covalent topo2 poison in contrast to ECG and EC which do not affect topo2-induced DNA cleavage [83,120]. In summary, the activity of green tea catechins by targeting human type II topoisomerases is dependent on the presence of the three hydroxyl groups on the B-ring. The authors suggest that in a redox mechanism, the phenolic B-ring is converted to a reactive quinone. The galloyl group is reported as a second prominent structural characteristic that contributes to topo2 inhibitory effects because EGC is found to be less potent compared to EGCG. EGCG is an ester of EGC and gallic acid (GA). Lopez-Lazaro et al. [115] show that GA and pyrogallol (PG), the latter being the only shared structural feature between EGCG and GA, also potently increase topo2–DNA complexes. This indicates that the PG moieties of EGCG and GA contribute to the observed EGCG and GA-mediated cleavable complex formation [115].

In literature, it was extensively discussed that EGCG, EGC, and GA potently generate hydrogen peroxide (H2O2) in cell culture medium [109,121–123]. Therefore, a potential contribution of H2O2 to the observed topoisomerase inhibitory properties of these compounds has to be taken into account. In the presence of catalase, neither EGCG, EGC, GA, nor PG induces topoisomerase II/DNA cleavable complex formation, suggesting that H2O2 mediates these cellular activities [115].

With respect to food processing, an epimerization of EGCG into (−)-gallocatechin gallate during the brewing process of dried green tea leaves (GCG) has been reported [104,124]. Data about the bioactivity of such “degradation” products are limited so far. Timmel et al. [45] show that GCG enhances DNA cleavage mediated by both topo2 isoforms. Its topoisomerase inhibitory properties are equipotent to that of EGCG. Furthermore, GCG has been identified as a covalent topo2 poison. The authors mention that epimerization of EGCG does not limit its topoisomerase poisoning activity and conclude that the prominent chemical substituents (Scheme 4.4) are not influenced by stereochemical changes [45].

Scheme 4.4. Epimerization of EGCG into GCG during the brewing process and chemical structure of the postulated EGCG quinone [45,125].

It has to be mentioned that the natural source of catechins is green tea and that humans do not usually consume a single compound but rather a mixture of catechins within their diet. A consumer-relevant complex green tea extract, rich in catechins, also exhibits high potency to stabilize either the topo2α– or the topo2β–DNA intermediates. The authors demonstrate that EGCG contributes to the observed topoisomerase poisoning effects of the green tea extract. However, comparing the cleavage titrations of green tea extract and EGCG, it can be speculated that additional topo2-active compounds such as several bioactive flavonoids have to be present in the extract [120,126].

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Natural Products and Cancer Signaling: Isoprenoids, Polyphenols and Flavonoids

Chung S. Yang, ... Jinsong Zhang, in The Enzymes, 2014

4.1 Antioxidant and Pro-oxidative Activities In Vitro and In Vivo

Catechins are well recognized as antioxidants, but they can also be pro-oxidants and generate ROS. ROS can alter the functions of cellular proteins, lipid, and nucleic acids and lead to different diseases [21]. Oxidative damages to DNA cause mutation and genomic instability, which are major contributing factors in the initiation, promotion, and progression of carcinogenesis [22]. However, there are also suggestions that decreasing the amounts of ROS promotes tumor progression [23,24]. Therefore, the antioxidant and pro-oxidative activities of catechins have the potential to affect cancer signaling, depending on the bioavailability of catechins and context of the cellular environment. Although the antioxidant activity of tea catechins is well established in vitro [5], such activity in vivo is only observed under circumstances when the animals are under oxidative stress. For example, EGCG administration has been found to decrease the levels of lipid peroxidation and protein carbonylation in old rats, but not in young rats [25]. In animal models for carcinogenesis, ROS are induced by the treatment with carcinogens, and EGCG has been demonstrated to reduce the formation of 8-hydroxydeoxyguanosine (8-oxo-dG), a well-established marker for oxidative DNA damage that can mispair to induce mutations [26]. As endogenously formed ROS are important in promoting carcinogenesis, tea polyphenols may have important roles in quenching these species at different stages of carcinogenesis. In human studies, administration of green tea to smokers for 4 weeks has been shown to significantly reduce the number of 8-oxo-dG-positive cells [27]. Such antioxidant actions of tea catechins may be important in the prevention of carcinogenesis.

Tea catechins can be auto-oxidized to generate ROS in cell culture medium and cause cell death [7,28]. After entering the cells, EGCG may also induce the production of ROS in the mitochondria. In our studies, oral administration of EGCG to mice bearing human lung cancer H1299 cell xenograft tumors inhibited tumor growth, enhanced tumor cell apoptosis, and produced ROS in the tumor cells [29]. The observed ROS production in tumor cells is probably due to the lack of sufficient antioxidant enzymes in H1299 cells. It remains to be demonstrated whether the production of ROS is responsible for the induction of apoptosis in vivo. At modest doses (e.g., 0.5% EGCG in the diet), although increased levels of 8-oxo-dG and phosphorylated histone 2A variant X were seen in xenograft tumors, 8-oxo-dG production and toxicity were not observed in the liver, kidney, and other organs of the host mice [29]. At high doses (e.g., 750 mg/kg, i.g.), however, hepatotoxicity and ROS were observed [30]. These toxic responses are probably similar to the reported liver toxicity in individuals who took excessive amounts of tea extracts in dietary supplements used for the purpose of weight reduction [31,32].

Cellular ROS may also activate the nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated signaling pathways to induce cytoprotective enzymes [33]. For example, oral gavage of EGCG (200 mg per kg) to C57BL/6J mice upregulated gene expression of γ-glutamyltransferase, glutamate cysteine ligase, and hemoxygenase 1 in the liver and colon, which were most likely mediated by the activation of Nrf2 [34]. Similarly, human volunteers supplemented with 800 mg PPE per day for 4 weeks increased glutathione S-transferase P activity in lymphocytes [35]. In an intervention study in a high aflatoxin exposure area in China, supplementation with 500 or 1000 mg green tea polyphenols per day for 3 months increased the median urinary aflatoxin B1-mercapturic acid levels by more than 10-fold compared to baseline [36]. This result is likely due to the induction of glutathione S-transferase by EGCG. It appears that levels of ROS produced by moderate doses of tea polyphenols activate Nrf2 to reduce oxidative stress, but high doses of tea polyphenols can produce high levels of ROS, which induce toxicity [31]. Thus, the biological effect of EGCG depends on the dose used and the context of the biological systems.

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Caffeine

D.P. Evatt, R.R. Griffiths, in Encyclopedia of Human Nutrition (Third Edition), 2013

Glossary

Catechins

A group of flavonoid compounds that are found in relatively high concentrations in green tea. The most abundant and likely pharmacologically-active catechin in green tea is epigallocatechin gallate.

Dependence (i.e., ‘Addiction’ in common parlance)

Defined by a cluster of cognitive, behavioral, and physiological features indicating that an individual continues to use a substance despite experiencing significant substance-related problems. Desire or inability to quit substance use, knowledge of harm caused by substance use, and withdrawal symptoms on quitting are common features of substance dependence.

Intoxication

A reversible substance-specific syndrome consisting of clinically significant maladaptive psychological or behavioral changes that develop during or shortly after substance use. Symptoms of caffeine intoxication include insomnia, nervousness, diuresis, gastrointestinal disturbance, muscle twitching, and tachycardia or cardiac arrhythmia.

Reinforcement

The degree to which a stimulus following a response increases the frequency of subsequent responses. Drug (or caffeine) reinforcement is defined by the ability of a drug to maintain drug self-administration or choice behavior.

Tolerance

An acquired decrease in responsiveness to a drug as the result of drug exposure. Tolerance can be defined as one or both of (1) the need to consume markedly increased amounts of a substance in order to achieve a desired effect or (2) a markedly diminished effect with repeated administrations of the same amount of a substance.

Withdrawal

Symptoms represent the emergence of physiological, cognitive, or behavioral changes that occur following cessation or reduction in chronic (e.g., daily) substance use.

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Dietary Bioactive Functional Polyphenols in Chronic Lung Diseases

S. Biswas, I. Rahman, in Bioactive Food as Dietary Interventions for Liver and Gastrointestinal Disease, 2013

5.3 Antioxidant Property

The antioxidant properties of catechins are yet to be fully established. Cell culture studies have shown that catechins are effective free radical scavengers. Catechins may act as indirect antioxidants in concert with vitamins C and E and antioxidant enzymes, such as superoxide dismutase and catalase and add to the total antioxidant capacity of the plasma. Although catechins might be able to prevent the oxidation of vitamin E per se, however, ingestion of green tea catechins does not appear to modify the plasma status of vitamins E and C in vivo. Since low antioxidant activity of catechins has been attributed to their very low distribution and the form of metabolites in plasma as compared to other antioxidants, it has led to the hypothesis that catechins may have cell-signaling activity, for example, activation of Nrf2 and inhibition of NF-κB (Figure 33.2). Among the catechins, EGCG is the most-effective antioxidant, especially quenching ROS.

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