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. 2019 Mar 26;24(6):1185.
doi: 10.3390/molecules24061185.

Effect of Stereochemical Configuration on the Transport and Metabolism of Catechins from Green Tea across Caco-2 Monolayers

Zeyi Ai  1 , Shuyuan Liu  2 , Fengfeng Qu  3 , Haojie Zhang  4 , Yuqiong Chen  5 , Dejiang Ni  6
Affiliations

Effect of Stereochemical Configuration on the Transport and Metabolism of Catechins from Green Tea across Caco-2 Monolayers

Zeyi Ai et al. Molecules. .

Abstract

The transcellular transport and metabolism of eight green tea catechins (GTCs) were studied in Caco-2 monolayers, with the aim of investigating the effect of cis⁻trans isomerism on the membrane permeability and biotransformation of GTCs. The results showed that the catechin stereochemistry significantly affects the efflux transport rather than the absorption transport in the Caco-2 monolayers. The trans catechins showed a better transcellular permeability than their corresponding cis (epi) catechins in the efflux transport, as the efflux amount of trans catechins were all significantly higher than that of the cis (epi) catechins at each concentration and each time point tested. Moreover, the relative contents of the (+)-catechin (C)-O-sulfate, (+)-gallocatechin (GC)-O-sulfate, (-)-catechin gallate (CG)-O-sulfate, and (-)-gallocatechin gallate (GCG)-O-sulfate in the efflux transport were 2.67, 16.08, 50.48, and 31.54 times higher than that of the (-)-epicatechin (EC)-O-sulfate, (-)-epigallocatechin (EGC)-O-sulfate, (-)-epicatechin gallate (ECG)-O-sulfate, and (-)-epigallocatechin gallate (EGCG)-O-sulfate, respectively. It indicated that more metabolites were observed after the transcellular efflux of trans catechins. Furthermore, after two hours of incubation, the GTCs could significantly increase the expression of multidrug resistance-associated protein 2 (MRP2) and breast cancer-resistance protein (BCRP), and decrease the expression of P-glycoprotein in the Caco-2 cells. The regulation of GTCs on P-glycoprotein, MRP2, and BCRP could also be significantly influenced by the chemical and dimensional structure. In a conclusion, catechin stereochemistry significantly affects the transport and metabolism of GTCs when refluxed in the Caco-2 monolayers.

Keywords: bidirectional transport; cis–trans catechins; efflux pumps; metabolism; stereochemical configuration.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Eight catechins (A); three dimensional structure of the C-ring between the cis–trans catechins (B); nomenclature of catechins (C).
Figure 2
Figure 2
Effects of concentration on the transport of trans catechins and cis (epi) catechins (A) C and EC, (B) CG and ECG, (C) GC and EGC, and (D) GCG and EGCG across Caco-2 cell monolayers in both directions. The apical (AP) to basolateral (BL) fluxes at concentrations from 200 μM to 400 μM are all linear for up to 2 h in a concentration-dependent manner, with relative independent Papp values, respectively (p > 0.05), while the BL to AP fluxes are increased with the increasing concentrations, with a saturation at concentrations higher than 300 μM for the corresponding Papp, which decreased with loading concentrations greater than 300 μM. Surges at 500 μmol/L were observed in the fluxes of eight catechins from both directions. Each value was the average of three different samples; the different lowercase letters in each line indicate a significant difference at a 0.05 level between the different concentrations; for cis–trans catechins, * and ** indicate significantly different at a 0.05 and 0.01 level respectively, While NS indicates not significant.
Figure 3
Figure 3
Effect of incubation the time on the efflux transport of trans catechins and cis (epi) catechins at 300 μM, across Caco-2 cell monolayers (A) C and EC, (B) CG and ECG, (C) GC and EGC, and (D) GCG and EGCG. The efflux amount of each catechin increased linearly with the incubation time. Each value was the average of three different samples; * and ** indicate significantly different at a 0.05 and 0.01 level between cis and trans catechins, respectively.
Figure 4
Figure 4
LC chromatograms of the samples taken from apical sides after loading C (line in red) and EC (line in blue) in the basolateral side, obtained by negative electrospray ionization (ESI)/MS interface extracted with (A) 369 [M − H]− and (B) 303 [M − H]−. The relative content of the catechin metabolites were measured as free-form equivalents, relative to the internal standard. Each value was the average of three different samples; * indicates significantly different at a 0.05 level. The mean values with the same lowercase letters indicate no significant difference at a 0.05 level.
Figure 5
Figure 5
LC chromatograms of the samples taken from apical sides after loading GC (line in red) and EGC (line in blue) in the basolateral side, obtained by negative ESI/MS interface extracted with (A) 385 [M − H]−, (B) 319 [M − H]−, and (C) 399 [M − H]−. The relative content of the catechin metabolites were measured as free-form equivalents, relative to the internal standard. Each value was the average of three different samples; ** indicates significantly different at a 0.01 level. The mean values with the same lowercase letters indicate no significant difference at a 0.05 level.
Figure 6
Figure 6
LC chromatograms of the samples taken from apical sides after loading CG (line in red) and ECG (line in blue) in the basolateral side, obtained by the negative ESI/MS interface extracted with (A) 521 [M − H]−, (B) 455 [M − H]−, and (C) 535 [M − H]−. The relative content of the catechin metabolites were measured as free-form equivalents, relative to the internal standard. Each value was the average of three different samples; ** indicates significantly different at a 0.01 level. Mean values with the same lowercase letters indicate no significant difference at a 0.05 level.
Figure 7
Figure 7
LC chromatograms of the samples taken from apical sides after loading GCG (line in red) and EGCG (line in blue) in the basolateral side, obtained by negative ESI/MS interface extracted with (A) 537 [M − H]−, (B) 471 [M − H]−, and (C) 551 [M − H]−. The relative content of the catechin metabolites were measured as free-form equivalents, relative to the internal standard. Each value was the average of three different samples; Mean values with the same lowercase letters indicate no significant difference at a 0.05 level.
Figure 8
Figure 8
LC chromatograms of the samples taken from apical sides (line in red) and from the basolateral side (line in blue) after loading C and EC in the corresponding donor side, obtained by negative ESI/MS interface extracted with m/z (A) 369 [M − H]−, (B) 303 [M − H]−, (C) 369 [M − H]−, and (D) 303 [M − H]−. Each value was the average of three different samples; ** indicates significantly different at a 0.01 level.
Figure 9
Figure 9
The mRNA level and protein expression of P-glycoprotein (A), MRP2 (B), and BCRP (C) in Caco-2 cells after treatment with C, EC, CG, ECG, GC, EGC, GCG, and EGCG for 2 h. Each value was the average of three different samples; mean values with the same lowercase letters indicate no significant difference at a 0.05 level.
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