Inhibitory Activity of Catechin Metabolites Produced by Intestinal Microbiota on Proliferation of HeLa Cells

Abstract

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...

Epigallocatechin gallate inhibits cell growth and regulates miRNA expression in cervical carcinoma cell lines infected with different high‑risk human papillomavirus subtypes

“…Catechin hydrate was reaveled to demonstrate inhibitory activity on SiHa cell proliferation by mediating apoptosis compared with cells without treatment (44). A recent study indicated that catechinmetabolites EGCM7, and EGC-M9, produced from EGCG, inhibit the proliferation of the HeLa (HPV16/18+) cell lines; however, the inhibitory mechanisms of catechin metabolites, produced by intestinal microbiota against cervical cancer cells, have not been clarified (45). However, the mechanism underlying cell cycle arrest and apoptosis induction mediated by EGCG remains to be elucidated.…”

Effects of Microbial Metabolites of (−)-Epigallocatechin Gallate on Glucose Uptake in L6 Skeletal Muscle Cell and Glucose Tolerance in ICR Mice

“…The following catechin metabolites were prepared using the methods we reported previously. 13,14,25) Abbreviation of EGCG metabolites were defined as follows: Cell Culture Rat L6 myoblast cells were purchased from Sumitomo Dainippon Pharma Co., Ltd. (Osaka, Japan). L6 myoblast cells were cultured in Eagle's minimum essential medium (MEM; Nissui Pharma Co., Ltd., Japan) containing 10% heat-inactivated fetal bovine serum (FBS; Sigma-Aldrich Japan Co.…”

“…23) Furthermore, EGCG improved glucose uptake by increasing GLUT4 translocation in dexamethasone-induced insulin resistant L6 muscle cells through the activation of both AMP-activated protein kinase (AMPK) and phosphatidylinositol 3 kinase (PI3K)/Akt pathways. 24) However, we know of no report concerning glucose uptake ability of EGCG microbial metabolites into skeletal muscle and their antidiabetic effect.…”

Blood–Brain Barrier Permeability of Green Tea Catechin Metabolites and their Neuritogenic Activity in Human Neuroblastoma SH‐SY5Y Cells

“…The production of nitric oxide was inhibited by 5‐(3′,4′,5′‐trihydroxyphenyl)‐γ‐valerolactone . Catechin metabolites, such as 1‐(3,4,5‐trihydroxyphenyl)‐3‐(2,4,6‐trihydroxyphenyl) propan‐2‐ol, 4‐hydroxy‐5‐(3,4,5‐trihydroxyphenyl) valeric acid, and 5‐(3,4,5‐trihydroxyphenyl) valeric acid showed inhibitory activity on HeLa cell proliferation, unlike the control . In addition to these studies, how differences in intestinal microbiota affect metabolism needs to be investigated.…”

“…propan-2-ol, 4-hydroxy-5-(3,4,5-trihydroxyphenyl) valeric acid, and 5-(3,4,5-trihydroxyphenyl) valeric acid showed inhibitory activity on HeLa cell proliferation, unlike the control. [20] In addition to these studies, how differences in intestinal microbiota affect metabolism needs to be investigated.…”