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Identification of the Catechin Uptake Transporter Responsible for Intestinal Absorption of Epigallocatechin Gallate in Mice.
Ishii S
,
Kitazawa H
,
Mori T
,
Kirino A
,
Nakamura S
,
Osaki N
,
Shimotoyodome A
,
Tamai I
.
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Many studies have shown that epigallocatechin gallate (EGCg) contribute to the health benefits of green tea, although its bioavailability is usually low. However, the mechanism underlying its intestinal absorption remains unclear. In human subjects, it has been reported that the bioavailability of EGCg increases after repeated oral catechin intake. We hypothesized that a certain uptake transporter was involved in this increase, and investigated a novel EGCg transporter. We first confirmed the increase in EGCg bioavailability in mice fed the catechin diet for two weeks. Then, in situ intestinal catechin infusion exhibited that the absorption of EGCg in the ileum was selectively increased in mice fed the catechin diet. A comprehensive analysis of plasma membrane proteins revealed 10 candidates for EGCg transporter, which were selectively increased in the ileum. EGCg uptake by a Xenopus laevis oocyte expressed with respective transporter revealed that oocytes microinjected with DTDST cRNA exhibited significantly higher EGCg uptake. Furthermore, uptake of EGCg by CHO-K1 cells stably expressing DTDST was significantly higher than that by mock cells, which was nullified by treating with a DTDST inhibitor. In conclusion, this study identified DTDST as a novel intestinal EGCg transporter that is upregulated after repeated oral catechin intake.
Figure 1. Plasma concentration of (a) epigallocatechin gallate (EGCg), (b) epicatechin gallate (ECg), (c) epigallocatechin (EGC), and (d) epicatechin (EC) after oral catechin administration (catechin group, ●; control group, □; n = 5/group). Two-factor repeated measures ANOVA was used to evaluate the group-by-time interaction and the P value for this test is shown in the upper-right of each panel. Data are presented as mean ± SD. Significant differences as determined by Student’s t-test are indicated by *(P < 0.05) and **(P < 0.01).
Figure 2. Plasma concentrations of epigallocatechin gallate (EGCg) after in situ catechin infusion into (a) the pylorus, (b) jejunum, (c) ileum, or (d) cecum (catechin group, ●; control group, □; n = 3–6/group). Two-factor repeated measures ANOVA was used to evaluate the group-by-time interaction and the P value for this test is shown in the upper-right of each panel. The area under the curve is shown for (e) the pylorus, (f) jejunum, (g) ileum, and (h) cecum. Data are presented as mean ± SD. Significant differences as determined by Student’s t-test are indicated by *(P < 0.05).
Figure 3. Time-course data of epigallocatechin gallate (EGCg) uptake by Xenopus laevis oocytes microinjected with diastrophic dysplasia sulfate transporter (DTDST) cRNA (●), zinc transporter 14 (ZIP14) cRNA (▲) or water (□) (n = 6–8/group) incubated with 500 μM EGCg. Linear approximation was performed and the line is shown. Two-factor repeated measures ANOVA was used to evaluate the group-by-time interaction and the P values are shown in the upper-left of the panel. Data are presented as mean ± SD. Significant differences as determined by Student’s t-test are indicated by **(P < 0.01).
Figure 4. (a) Time-course data of epigallocatechin gallate (EGCg) uptake by CHO-K1 cells stably expressing diastrophic dysplasia sulfate transporter (DTDST; ●) or mock cells (□) (n = 4/group) incubated with 500 μM EGCg. Linear approximation was performed and the line is shown. Two-factor repeated measures ANOVA was used to evaluate the group-by-time interaction and the P value is shown in the upper-left of the panel. Data are presented as mean ± SD. Significant differences as determined by means of Student’s t-test are indicated by *(P < 0.05) and **(P < 0.01). (b) EGCg uptake by CHO-K1 cells stably expressing DTDST or mock cells after treatment with the DTDST inhibitor 4,4′-diisothiocyano-2,2′-stilbenedisulfonic acid (DIDS) or vehicle (n = 3/group) incubated with 500 μM EGCg for 30 min. Data are presented as mean ± SD. Significant differences as determined by Student’s t-test are indicated by *(P < 0.05). (c) Kinetics of EGCg uptake mediated by DTDST after subtracting the values obtained with mock cells (n = 4). CHO-K1 cells stably expressing DTDST or mock cells were incubated with EGCg at concentrations ranging from 1 to 1000 μM for 30 min. Data are presented as mean ± SD. The kinetic parameters were obtained by fitting the data to the Michaelis–Menten equation in the enzyme kinetics module of GraphPad Prism software Version 6.0.
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