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Scientific studies related to EGCG (1)
There remain several major challenges to interpret the clinical relevance of the hundreds of studies that examine the effects of EGCG on various in vitro disease-related molecular targets and in vivo models for potential health benefits. The overwhelming majority of in vitro studies find that EGCG inhibits a vast array of biomedically relevant molecular targets and disease-related cellular processes at relatively high concentrations (reviewed in: Boik, 2001, Doss et al., 2005, Adhami et al., 2003, Haslam, 1996, Khan et al., 2006, Conney, 2003). These include in vitro anticancer molecular targets and tumor cell cytotoxicity studies conducted at test concentrations that typically range from about 10 to 1000 μM. By contrast, a relatively small number of studies have shown that EGCG can inhibit certain biomedically important molecular targets such as DNA methyltransferases (Lee et al., 2005), squalene epoxidase (Abe et al., 2000), antiapoptotic Bcl-2 proteins (Leone et al., 2003), and vascular endothelial growth factor receptor (VEGFR) signaling (Lamy et al., 2002) at sub-micromolar concentrations.
Pharmacokinetic studies conducted in humans indicate that the physiologically relevant serum concentrations of EGCG may be in the high nanomolar range (Henning et al., 2004, Chow et al., 2003, Ullmann et al., 2003). Therefore, high micromolar concentrations are unlikely to be established in the bloodstream of individuals that simply drink green tea or ingest only two to three 200 mg capsules of green tea extract (GTE) each day. Yet, epidemiological studies continue to suggest that there may be significant health benefits associated with drinking green tea (Bushman, 1998). This is further supported by animal studies that indicate the consumption of green tea and green tea products with high levels of EGCG and other catechins may have a significant effect on the prevention of tumors, cardiovascular disease, and other medical conditions.
Meanwhile, considerable speculation has arisen to “fit” the results from in vitro studies that demonstrate the activities of EGCG on most of the molecular-targets and the tumor cell cytotoxic effects exerted by EGCG and GTE at concentrations that are far above the physiologically relevant range. This apparent discrepancy has brought forth a number of possible explanations. It has been suggested that the effects of EGCG may be more synergistic when combined with other catechins than previously thought (Suganuma et al., 1999). It is also believed that EGCG (and other tea catechins) may be metabolically activated to form more potent and effective bioactive compounds.
Others speculate that EGCG may accumulate in tissues over time to produce cellular concentrations that are much higher than those have been observed in clinical serum samples. Alternatively, the simplest explanation is that the effects of EGCG on many of its reported molecular targets are merely high-concentration effects or experimental artifacts that reflect the propensity of catechins and other polyphenolic substances to chelate metals and bind proteins in a nonselective manner (reviewed in Haslam, 1996). This is the main reason that the high-throughput pharmaceutical screening community has considered polyphenols and other tannins to be “nuisance” compounds that must either be removed from test samples or dereplicated prior to extensive evaluation in protein-based bioassay systems (i.e., enzyme or receptor) (Cardellina et al., 1993). If this is the case, only a relatively small number of the numerous molecular mechanistic studies reported for EGCG and other green tea products actually reflect physiologically relevant processes.