Eleven kinds of catechin metabolites produced from ( )-epigallocatechin (EGC) and ( )-epigallocatechin gallate (EGCg) by intestinal microbiota were evaluated for inhibitory activity on the proliferation of HeLa cells, which are human cervical cancer cells. Among the catechin metabolites, 1-(3,4,5-trihydroxyphenyl)-3-(2,4,6-trihydroxyphenyl)propan-2-ol (EGC-M2), 4-hydroxy-5-(3,4,5-trihydroxyphenyl)valeric acid (EGC-M7), and 5-(3,4,5-trihydroxyphenyl)valeric acid (EGC-M9) were found to show inhibitory activity on HeLa cell proliferation as compared with control. The results suggested that three adjacent hydroxyl groups in the phenyl moiety may play an important role in the inhibitory activity. In addition, the inhibitory activity was also examined with four ( )-epicatechin (EC) metabolites possessing two adjacent hydroxyl groups in the phenyl moiety. Only 5-(3,4-dihydroxyphenyl)valeric acid (EC-M9) showed inhibitory activity and therefore valeric acid moiety likely contributes to the inhibitory activity. EGC-M9 showed the strongest inhibitory activity with IC 50 of 5.58 µM. Thus, in this study it was found for the first time that several catechin metabolites derived from EGC, EGCg, and EC inhibit the proliferation of cervical cancer cells.Key words epigallocatechin gallate; metabolite; cervical cancer; catechin; 5-(3,4,5-trihydroxyphenyl)valeric acid; HeLa cell Tea catechins are natural constituents which have various physiological functions such as antioxidative, 1,2) blood glucose-lowering, 3) hypotensive, 4,5) and anticancer activities. 6)However, it has been reported that the absorption rate of a major tea catechin, (−)-epigallocatechin gallate (EGCg), was 0.1 to 1.6% of the oral dose in rats. 7) We also estimated the bioavailability of EGCg including its conjugated forms to be 0.26% after oral dosage of [4-3 H] EGCg in rats. 8) In humans, the bioavailability of tea catechins has been reported to be less than 4%. 9) Thus, intact tea catechins have been regarded as being poorly absorbed in the body. On the other hand, tea catechins are recognized to be metabolized by intestinal microbiota after reaching the colon. [10][11][12][13] The metabolites such as 5-hydroxyphenyl-γ-valerolactones, 4-hydroxy-5-hydroxyphenyl valeric acids, and 3-hydroxyphenyl propionic acids were absorbed into the body and were detected in urine.14-18) Particularly, 5-hydroxyphenyl-γ-valerolactones were recognized to be dominant urinary metabolites in rats and human urine and their excretion amounts reached 6-39% of the ingested catechins. 8,9,19) Catechin metabolites have been reported to show bioactivities such as antioxidative, anti-inflammatory, anti-thrombotic, and blood pressure lowering activities. 18,20,21) Kim et al. recently showed that 5-(3,5-dihydroxyphenyl)-γ-valerolactone, one of the major metabolites of EGCg, increased the activity of CD4+ T cells and enhanced the cytotoxic activity of natural killer cells. 22) Thus, it is expected catechin metabolites may exhibit additional biological activities. With regard to anticancer e...

Glucose uptake ability into L6 skeletal muscle cell was examined with eleven kinds of ring fission metabolites of ()-epigallocatechin gallate (EGCG) produced by intestinal bacteria. The metabolites 5-(3,5-dihydroxyphenyl)-γ-valerolactone (EGC-M5), 4-hydroxy-5-(3,4,5-trihydroxyphenyl)valeric acid (EGC-M6), 5-(3,4,5-trihydroxyphenyl)-γ-valerolactone (EGC-M7) and 5-(3-hydroxyphenyl)valeric acid (EGC-M11) have been found to promote uptake of glucose into L6 myotubes significantly. EGC-M5, which is one of the major ring fission metabolites of EGCG, was also found to have a promotive effect on glucose transporter 4 (GLUT4) translocation accompanied by phosphorylation of AMP-activated protein kinase (AMPK) signaling pathway in skeletal muscle both in vivo and in vitro. Furthermore, the effect of oral single dosage of EGC-M5 on glucose tolerance test with ICR mice was examined and significant suppression of hyperglycemia was observed. These data suggested that EGC-M5 has an antidiabetic effect in vivo.