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The Antifolate Activity of Tea Catechins

¹ Grupo de Investigación de Enzimología, Departamento de Bioquímica y Biología Molecular A, Facultad de Biología, Universidad de Murcia; ² Servicio de Análisis Clínicos, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain; and ³ Computational Biology Group and ⁴ Department of Biological Chemistry, John Innes Centre, Norwich, United Kingdom

Requests for reprints: José Neptuno Rodríguez-López, Grupo de Investigación de Enzimología, Departamento de Bioquímica y Biología Molecular A, Facultad de Biología, Universidad de Murcia, E-30100 Espinardo, Murcia, Spain. Phone: 34-968398284; Fax: 34-968364147; E-mail: neptuno{at}um.es.

A naturally occurring gallated polyphenol isolated from green tea leaves, (–)-epigallocatechin gallate (EGCG), has been shown to be an inhibitor of dihydrofolate reductase (DHFR) activity in vitro at concentrations found in the serum and tissues of green tea drinkers (0.1-1.0 µmol/L). These data provide the first evidence that the prophylactic effect of green tea drinking on certain forms of cancer, suggested by epidemiologic studies, is due to the inhibition of DHFR by EGCG and could also explain why tea extracts have been traditionally used in "alternative medicine" as anticarcinogenic/antibiotic agents or in the treatment of conditions such as psoriasis. EGCG exhibited kinetics characteristic of a slow, tight-binding inhibitor of 7,8-dihydrofolate reduction with bovine liver DHFR (K_I = 0.109 µmol/L), but of a classic, reversible, competitive inhibitor with chicken liver DHFR (K_I = 10.3 µmol/L). Structural modeling showed that EGCG can bind to human DHFR at the same site and in a similar orientation to that observed for some structurally characterized DHFR inhibitor complexes. The responses of lymphoma cells to EGCG and known antifolates were similar, that is, a dose-dependent inhibition of cell growth (IC₅₀ = 20 µmol/L for EGCG), G₀-G₁ phase arrest of the cell cycle, and induction of apoptosis. Folate depletion increased the sensitivity of these cell lines to antifolates and EGCG. These effects were attenuated by growing the cells in a medium containing hypoxanthine-thymidine, consistent with DHFR being the site of action for EGCG.

Key Words: green tea • catechins • dihydrofolate reductase • EGCG • antifolates

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