Many people around the world drink green tea in hopes of warding off cancer, heart disease and immune system ailments, but people who take supplements made from concentrated tea extract with the goal of multiplying those benefits should think twice.

A study completed by University of Mississippi researchers indicates that extremely high doses of green tea extract actually may activate – rather than shut down – genetic mechanisms that help certain tumors survive and grow.

“Drinking green tea still is good for you,” said Yu-Dong Zhou, a molecular biologist at the university’s National Center for Natural Products Research. “There are thousands of years of evidence on that, but the idea of taking the equivalent of hundreds of cups of tea a day is something that needs to be looked at carefully.”

Zhou is principal investigator on a study that examined the effect of high doses of the active ingredients in green tea extract on hypoxia-inducible factor-1, or HIF-1, a key regulator of how tumor cells adapt to low-oxygen conditions. The results were published in a recent issue of the Journal of Natural Products.

Green tea is a popular beverage throughout much of the world and has been used medicinally for centuries in China and India. In areas where people drink a lot of green tea, there is a lower incidence of heart disease and some cancers.

In recent years, several manufacturers have produced dietary supplements containing concentrated extracts of green tea’s active ingredients.

The compounds are not toxic in large doses, but high concentrations may not necessarily be healthful, explained Dale Nagle, associate professor of pharmacognosy in the UM School of Pharmacy who worked with Zhou on the project. Many commercial supplements provide far more of the active compounds than a person could obtain by simply drinking tea.

“Nearly all the evidence of the beneficial effects of green tea comes from studies on populations who consume green tea, not tea extract in the form of powder, concentrates or pills,” Nagle explained. “There is no direct evidence that taking reasonable quantities of these green tea products is toxic. But the issue here is whether these extremely high doses are really beneficial.

“The fact that the green tea ingredient known as ECG activates HIF-1 – which can have different effects depending on the type of tumor – means it may not have the desired effect that people think they’re getting.”

The active compounds in green tea could actually serve dual functions, inhibiting HIF-1 at low concentrations and activating it at higher doses, Zhou said.

“At low concentrations, it doesn’t seem to have this potentially negative effect as we saw in the lab,” she said. “A lot more study needs to be done to see what the outcome will be in people who take high doses of these compounds.”

“In theory, this effect on HIF-1 could suppress some early forms of tumors but may actually help other tumors – especially some of the more aggressive ones – survive and grow,” Nagle said.

Zhou began studying green tea compounds more than three years ago, originally because they are touted as having antioxidant properties.

“We ran the experiment looking for one thing and found something totally different,” she said.

The project was funded initially by the UM Office of Research and Sponsored Programs through its Faculty Research Fellows program. Additional support for this research has come from the Department of Defense’s Breast Cancer Research Program and the National Cancer Institute.

Cautioning that the results are preliminary – the study was performed using cultured cells in test tubes – Zhou noted that taking extremely high doses of any dietary supplement is worrisome to researchers.

“We can’t really tell people for sure what will happen when they take these high doses,” she said. “Our best advice is to be careful. This needs to be studied carefully, and it will take time to determine what the actual overall effects are.”

Other researchers who participated in this project include Scott Baerson, a U.S. Department of Agriculture molecular biologist stationed at the natural products center, NCNPR research scientists Xing-Cong Li and Ameeta Agarwal, and Daneel Ferreira, chair of pharmacognosy in the School of Pharmacy. Two former members of the Zhou/Nagle research group, Yong-Pil Kim and Tyler Hodges, also contributed to this study.

Tests by UK and Spanish researchers showed polyphenol EGCG taken from green tea leaves inhibits cancer cell growth.

The effect was seen even at low concentrations, equivalent to drinking two or three cups of green tea a day.

However, the study, published in Cancer Research, also found high concentrations of the chemical may increase the risk of birth defects.

We may be able to develop new anti-cancer drugs based on the structure of the EGCG molecule
Professor Roger Thorneley

Previous research has suggested that drinking green tea helps to cut the risk of certain forms of cancer.

The latest study found that EGCG binds to a key enzyme - dihydrofolate reductase (DHFR) - that is targeted by established anti-cancer drugs.

This stops the enzyme from triggering the manufacture of new DNA in tumour cells.

It appears to work in the same way as the cancer drug methotrexate - but in practice would probably have fewer side effects.

Drug development

Professor Roger Thorneley, from the John Innes Centre in Norwich, conducted the research with team from the University of Murcia in Spain.

He said: "This is a very exciting discovery. For the first time we have a clear scientific explanation of why EGCG inhibits the growth of cancer cells at concentrations which are found in the blood of people who drink two or three cups of green tea a day.

"We have identified the enzyme in tumour cells that EGCG targets and understand how it stops this enzyme from making DNA.

"This means we may be able to develop new anti-cancer drugs based on the structure of the EGCG molecule."

Fellow researcher Dr Jose Neptuno Rodriguez-Lopez said: "We decided to look at EGCG because we recognised that its structure is very similar to that of the successful anti-cancer drug methotrexate.

"We discovered that EGCG can kill cancer cells in the same way as methotrexate.

"However, because EGCG binds to the target enzyme less tightly than methotrexate, it should have decreased side effects on healthy cells."

Fewer side effects

Dr Rodriguez-Lopez said the researchers were now using EGCG as the starting point to design and develop effective new anti-cancer drugs that kill tumour cells but inflict less damage on healthy cells.

Previous studies have also linked high levels of green tea consumption around the time of conception and during pregnancy with an increased incidence of neural tube defects such as spina bifida.

These defects are associated with a lack of the key nutrient folic acid.

The scientists said EGCG in green tea would be expected to cause a significant drop in folic acid levels.

GREEN TEA DANGER FOR PREGNANT MOTHERS

Warning: Green tea may cause birth defects. Pregnant women who drink green tea increase the risk of birth defects such as spina bifida, experts say. The chemical extracted from the tea also inhibits the growth of cancer cells and may pro vide the starting point for a new family of anti-cancer drugs, scientists say.

Studies have already shown that people who drink green tea are less likely to suffer certain forms of cancer. The new study provides an explanationfor the beverage's anti-cancer effect. The effect was seen even at low concentrations equivalent to drinking two or three cups of green tea a day.

Drop in folic acid levels

Scientists found that polyphenol EGCG binds to the enzyme dihydrofolate reductase (DHFR) which is already an established target for chemotherapy drugs. DHFR is also implicated in birth defects.The green tea compound stops DHFR promoting DNA synthesis in tumour cells. It appears to work in the same way as the cancer drug methotrexate, but in practice would probably have fewer side effects.Studies have linked high levels of green tea consumption around the time of conception and during pregnancy with an increased incidents of spina bifida and anencephaly, a birth defect that results in the absence of part of the brain and skull. Both are 'neural tube' disorders associated with folic acid deficiency. The scientists said EGCG in green tea would be expected to cause a significant drop in folic acid levels.