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. 2023 Sep 17;15(18):4021.
doi: 10.3390/nu15184021.

Gallation and B-Ring Dihydroxylation Increase Green Tea Catechin Residence Time in Plasma by Differentially Affecting Tissue-Specific Trafficking: Compartmental Model of Catechin Kinetics in Healthy Adults

Joanna K Hodges  1   2 , Geoffrey Y Sasaki  1 , Yael Vodovotz  3 , Richard S Bruno  1
Affiliations

Gallation and B-Ring Dihydroxylation Increase Green Tea Catechin Residence Time in Plasma by Differentially Affecting Tissue-Specific Trafficking: Compartmental Model of Catechin Kinetics in Healthy Adults

Joanna K Hodges et al. Nutrients. .

Abstract

Catechins in green tea extract (GTE) (epigallocatechin gallate (EGCG), epigallocatechin (EGC), epicatechin (EC), epicatechin gallate (ECG)) vary in bioactivity. We developed a physiologically relevant mathematical model of catechin metabolism to test the hypothesis that fractional catabolic rates of catechins would be differentially affected by their structural attributes. Pharmacokinetic data of plasma and urine catechin concentrations were used from healthy adults (n = 19) who ingested confections containing 0.5 g GTE (290 mg EGCG, 87 mg EGC, 39 mg EC, 28 mg ECG). A 7-compartmental model of catechin metabolism comprised of the gastrointestinal tract (stomach, small and large intestine), liver, plasma, extravascular tissues, and kidneys was developed using a mean fraction dose of EGCG, ECG, EGC, and EC. Fitting was by iterative least squares regression analysis, and goodness of fit was ascertained by the estimated variability of parameters (FSD < 0.5). The interaction of gallation and B-ring dihydroxylation most greatly extended plasma residence time such that EGC > EC = EGCG > EGC. The interaction between gallation and B-ring dihydroxylation accelerated the transfer from the upper gastrointestinal tract to the small intestine but delayed subsequent transfers from the small intestine through the liver to plasma and from kidneys to urine. Gallation and B-ring dihydroxylation independently delayed the transfer from plasma to extravascular tissues, except the uptake to kidneys, which was slowed by gallation only. This multi-compartment model, to be validated in a future study, suggests that gallation and B-ring dihydroxylation affect catechin catabolism in a tissue-specific manner and thus their potential bioactivity.

Keywords: bioavailability; catechins; green tea; human; mathematical modeling; metabolism.

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Conflict of interest statement

R.S.B. serves on the scientific advisory boards of Gem Health, Inc. (Venice, CA, USA) and Opsis Health (Golden, CO, USA) and has received honorarium from several agencies and industry groups within the past 5 years to conduct scientific reviews or provide scientific expertise related to the broad field of nutrition (Egg Nutrition Center, Alliance for Potato Research and Education, Dairy Management Inc., Abyrx, Pennsylvania Department of Public Health, and BIO-CAT Microbials, LLC). None of the other authors have any conflict of interest.

Figures

Figure 1
Figure 1
Chemical structures of major catechins present in green tea. Epigallocatechin gallate (EGCG) and epicatechin gallate (ECG) contain a gallate group (red circle), whereas EGCG and epigallocatechin (EGC) are trihydroxylated on the B-ring (green circle) compared with ECG and epicatechin (EC) that are dihydroxylated (blue circle indicates the site of the missing hydroxyl group).
Figure 2
Figure 2
Study Design. Healthy adults completed a pharmacokinetics study in which they ingested a gelatin-based confection containing green tea extract (445 mg total catechins; 290 mg epigallocatechin gallate, 87 mg epigallocatechin, 39 mg epicatechin, 28 mg epicatechin gallate). Blood samples were collected at timed intervals for 12 h and urine was collected for 24 h. Analyzed catechins were used to construct a multi-compartment model of tissue and plasma transfer of catechins.
Figure 3
Figure 3
Structure of the multi-compartment model. Seven body compartments, including the upper GI tract, small and large intestine, liver, plasma, extravascular tissues, and kidneys, were required to obtain the best model fit to the observed data. The asterisk indicates the site of catechin introduction to the physiological system. U(1) indicates any introduction of dietary catechins, which was negligible due to dietary restriction. The triangles indicate the sites of biospecimen sampling. Abbreviations: GI, gastrointestinal; Sm, small; Lg, large; Cum, cumulative.
Figure 4
Figure 4
Mean fraction of the catechin dose in plasma (A) and urine (B) over time. Gallated catechins showed less steep terminal slopes in plasma and a lower fraction of dose in urine compared with the non-gallated catechins. Symbols represent the observed data (n = 19), and lines represent the model prediction.
Figure 5
Figure 5
FCR and residence times of catechins in plasma from healthy adults who ingested a green tea extract-containing confection. (A) Catechin FCR was affected by an interaction between the degree of hydroxylation and the presence of a gallate group. While trihydroxylated and non-gallated catechins had greater FCR, their structural combination potentiated the FCR such that ECG > EGCG = EC > ECG. (B) The degree of hydroxylation and presence of a gallate group interacted significantly such that dihydroxylation and gallation most greatly increased residence time of catechins: ECG > EC = EGCG > EGC. Data (means ± SE, n = 19 subjects) were analyzed by two-way ANOVA with Tukey’s post-hoc test. Group means not sharing a common letter are different from each other (p < 0.05) such that a > b > c. Abbreviations: EC, epicatechin; ECG, epicatechin gallate; EGC, epigallocatechin; EGCG, epigallocatechin gallate; FCR, fractional catabolic rate; GAL, gallated; OH, degree of hydroxylation.
Figure 6
Figure 6
Fractional transfer rates of catechins between body pools from healthy adults who ingested a green tea extract-containing confection. (A) The degree of hydroxylation and presence of a gallate group interacted such that dihydroxylated and gallated ECG had a higher fractional transfer rate from upper GI tract to small intestine. (B) The degree of hydroxylation and presence of a gallate group interacted such that gallation slowed down the fractional transfer from small intestine to liver but only for the dihydroxylated catechin ECG. (C) The degree of hydroxylation and presence of a gallate group interacted such that combination of gallation and B-ring dihydroxylation most greatly attenuated the fractional transfer rate of catechins from liver to plasma: EGC > EC > EGCG = ECG. (D) Presence of a gallate group, but not hydroxylation, decreased the fractional transfer rate from plasma to kidneys: EGC = EC > EGCG = ECG. (E) Gallation and dihydroxylation independently decreased the fractional transfer rate from plasma to extravascular tissues: EGC > EGCG > EC > ECG. (F) The effect of hydroxylation and gallation on the fractional transfer from kidneys to urine was identical to that found on the transfer from small intestine to liver. Data (means ± SE, n = 19 subjects) were analyzed by two-way ANOVA with Tukey’s post-hoc test. Group means not sharing a common letter are different from each other (p < 0.05) such that a > b > c. Abbreviations: EC, epicatechin; ECG, epicatechin gallate; EGC, epigallocatechin; EGCG, epigallocatechin gallate; FCR, fractional catabolic rate; GAL, gallated; OH, degree of hydroxylation.
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