Green tea: the great healer

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Green tea promises to cure many of our ills but does it live up to expectations? Andrew Scott looks at the chemistry behind the health claims

The health-giving properties of green tea seem almost too good to be true. There is, however, a growing body of scientific evidence in support of the drink’s healing properties and the biochemical mechanisms behind its curative powers are now beginning to emerge.

Traditional Chinese and Japanese medicine has held green tea in high esteem for thousands of years, as a potent promoter of good health and long life. Epidemiological studies have found there to be fewer cancer cases in regions with a high consumption of green tea, while testing in mice has revealed that the beverage can protect against solid tumours. Research suggests that the simple infusion of Camellia sinensis leaves can help to protect the body from a wide range of conditions, including solid cancers, leukaemia, heart disease, arthritis, and diabetes.

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Many research groups are now using modern analytical techniques to identify the compounds responsible for the tea’s health benefits. The findings so far not only justify green tea consumption as a routine part of a healthy diet but also open an avenue of pharmacological research based on purifying or adapting the natural compounds to produce a new range of drugs.

Green cancer therapy

The search for active compounds has revealed a high concentration of polyphenols. These natural antioxidant molecules are credited with the anti-cancer and anti-ageing effects of many natural products, including berries and red wine. Their ability to protect against free-radical damage within cells is an aspect of chemistry that is fast becoming part of mainstream general knowledge, certainly among those who take an interest in food and health.

Chemical interest in green tea, however, has focused specifically on its major polyphenol epigallocatechin-3-gallate (EGCG), and the simpler epigallocatechin (EGC). The powers of these compounds go far beyond general antioxidant capacity and EGCG isolated from green tea can induce the death of a variety of different cancer cells.

Recent research on EGCG and cancer by Neil Kay’s team at the Mayo Clinic in Rochester, Minnesota, US, suggests that EGCG helps to kill cells of B-cell chronic lymphocytic leukaemia (CLL), one of the most common forms of the disease. The research has also revealed some aspects of the mechanism of EGCG’s anti-cancer activity to suggest that it fights cancer in a far more targeted and complex way than by simply acting as an antioxidant.

"Green tea appears to be a promising source of anti-allergenic agents"

Leukaemia cells are sustained in part by secreting a small protein molecule called vascular endothelial growth factor (VEGF). This binds to protein receptors embedded in the membrane of the leukaemia cells and can promote the resistance to cell death typical of this type of cancer.

EGCG inhibits the VEGF-related protection of cancer cells and when acting against solid tumours seems to be able to interfere with VEGF’s role in angiogenesis - when tumour cells encourage the growth of the new blood vessels that are needed to sustain them.

Research suggests that EGCG interferes with the chemical communication systems that the diseased cells need to survive by inhibiting VEGF’s ability to bind to its receptor. This receptor is one of many tyrosine kinase receptors, so called because VEGF binding activates an ability to catalyse the phosphorylation of specific tyrosine amino acid residues in other proteins. The activation of tyrosine kinase receptors generally stimulates a cascade of biochemical interactions leading to major changes in cell biochemistry and/or patterns of gene activity.

EGCG’s ability to act as a general inhibitor of tyrosine kinase receptors may at least partly explain why the molecule can have profound effects on many different types of disease states.

’Together with the US National Cancer Institute we are about to start a clinical trial of EGCG [on patients] with early stage CLL,’ says Kay. ’We know that it is fairly non-toxic and that oral administration can yield significant levels of EGCG in blood serum. If we see evidence of clinical activity in our initial trial we also have some plans to work with structural derivatives of EGCG. And if we can identify the exact mechanism of EGCG’s activity it would make the work with derivatives much easier.’ According to Kay, healthy volunteers have already taken EGCG and have shown ’no significant side effects’.

Other receptors in the body may also be affected by EGCG. The aryl hydrocarbon receptor activates genes when it binds to a range of aryl hydrocarbon ligands and is implicated in the carcinogenic response to environmental pollutants such as tobacco smoke and dioxins. Now Thomas Gasiewicz and colleagues at Rochester University, US, have found that EGCG and EGC inhibit the gene for this receptor.

Mimicking methotrexate

EGCG bears some structural similarities to a widely used anti-cancer drug, methotrexate. This drug targets the enzyme dihydrofolate reductase (DHFR), which is required for the synthesis of new DNA in tumour cells. A collaboration between the University of Murcia in Spain and the John Innes Centre in Norwich, UK, has recently shown that EGCG also binds to and inhibits DHFR. However, EGCG binds less tightly to the enzyme than drugs such as methotrexate and is expected to have fewer side effects.

’The group is now making derivatives of EGCG to try to modulate the binding affinity,’ says Roger Thorneley of the John Innes Centre team. The hope is that exploring the effect that chemical modifications have on the binding strength may yield compounds that will interfere more specifically with DHFR activity in cancer cells while having less effect on healthy cells. According to Thorneley, the group is now trying to understand the mechanism of EGCG binding by analysing high-resolution NMR spectra of the EGCG-enzyme complex.

The researchers in Murcia, led by Jos? Neptuno Rodr?guez-L?pez, are also very interested in taking advantage of the antioxidant power of EGCG and other green tea extracts for use in food preservatives that could be sprayed on fruit. This is a nice example of aspects of green tea’s potential that get less publicity than the high profile anti-cancer work. In this context, a team led by Peter Taylor of the University of London, UK, is exploring the antimicrobial properties of modified analogues of EGCG. One fascinating discovery is that a number of EGCG analogues can suppress the antibiotic resistance of some microbes.

Diverse diseases

The potential medicinal uses of EGCG and EGC are wide-ranging and researchers are uncovering specific activities for the compounds in diseases other than cancer.

David Buttle, from the division of genomic medicine at the University of Sheffield, UK, has gathered sufficient evidence of a protective effect of green tree against arthritis to declare: ’Green tea should be drunk as a prophylactic. If you have fairly severe joint damage it may be too late to do anything about it, but if you spend decades of your life drinking green tea in the end it may be beneficial’.

In laboratory tests using in vitro models that mimic the arthritic joint, he claims to have shown that EGCG protects against cartilage destruction. The precise chemical mechanism of this effect is not completely clear although EGCG does inhibit some of the protease enzymes that break down the proteins in cartilage. But it also appears to interfere with the signalling pathways involved in the damaging inflammatory response in other ways.

Buttle’s work on arthritis is currently stalled, due to a lack of funding, but he is actively moving on to investigate the potential of EGCG in prostate cancer. He cites various reasons why funding agencies and drug companies may be wary of exploring green tea chemistry, saying: ’The activities of EGCG are multi-faceted, and it may be difficult in laboratory models to dissect one activity from the others’. Also, the active compounds, such as EGCG, are poorly bioavailable relative to most drugs because they are degraded in the gut.

The growing problem of allergy is another area of huge significance in which green tea may have help to offer. Japanese researchers, led by Hirofumi Tachibana at Kyushu University in Fukuoka, have shown in vitro that EGCG binds to and blocks the IgE receptor of human basophil cells, which is involved in producing an allergic response. Other compounds in green tea show similar behaviour but, as in so many potential applications, EGCG appears to be the most potent, especially in its methylated form. ’Green tea appears to be a promising source for effective anti-allergenic agents,’ says Tachibana. ’If you have allergies you should consider drinking it.’

New possibilities for green tea compounds seem to be emerging every few months. This spring, Joe Vinson of the University of Scranton, Pennsylvania, US, reported that green and black tea could decrease glucose levels in diabetic rats and inhibit complications of diabetes including cataracts. Other work by Vinson and others suggests that both green and black tea can inhibit atherosclerosis.

Not all good news

There is, of course, a downside and green tea appears to have some potentially serious side effects. For example, high levels of green tea consumption at conception and during pregnancy have been linked to an increased incidence of neural tube defects such as spina bifida. This has been attributed to the ability of green tea compounds to interfere with folic acid availability.

There are also some concerns that in pure form, compounds such as EGCG may have a significant level of toxicity. Proline-rich proteins in saliva bind to dietary polyphenolic compounds such as EGCG and may sufficiently limit their potential toxicity when they are consumed as part of a mixed diet. But problems might occur when the natural digestive and metabolic processes are circumvented by administration of purified compounds such as EGCG in high doses.

Such thoughts are a reminder that caution is required even with natural and long-established foods and drinks before the compounds within them are advocated for clinical use. The green tea-derived molecules should be treated with the same level of care and caution as any other novel pharmaceutical compounds.

Andrew Scott is a writer and lecturer based in Perth, UK