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. 2022 Jul 13;70(27):8264-8273.
doi: 10.1021/acs.jafc.2c02150. Epub 2022 Jul 5.

4″-Sulfation Is the Major Metabolic Pathway of Epigallocatechin-3-gallate in Humans: Characterization of Metabolites, Enzymatic Analysis, and Pharmacokinetic Profiling

Akane Hayashi  1 , Shimpei Terasaka  1 , Yuko Nukada  1 , Akiyo Kameyama  1 , Masayuki Yamane  1 , Ryuta Shioi  2 , Masazumi Iwashita  2 , Kohjiro Hashizume  2 , Osamu Morita  1
Affiliations

4″-Sulfation Is the Major Metabolic Pathway of Epigallocatechin-3-gallate in Humans: Characterization of Metabolites, Enzymatic Analysis, and Pharmacokinetic Profiling

Akane Hayashi et al. J Agric Food Chem. .

Abstract

Epigallocatechin-3-gallate (EGCG), a major green tea polyphenol, has beneficial effects on human health. This study aimed to elucidate the detailed EGCG sulfation process to better understand its phase II metabolism, a process required to maximize its health benefits. Results show that kinetic activity of sulfation in the human liver and intestinal cytosol is 2-fold and 60- to 300-fold higher than that of methylation and glucuronidation, respectively, suggesting sulfation as the key metabolic pathway. Moreover, SULT1A1 and SULT1A3 are responsible for sulfation in the liver and intestine, respectively. Additionally, our human ingestion study revealed that the concentration of EGCG-4″-sulfate in human plasma (Cmax: 177.9 nmol·L-1, AUC: 715.2 nmol·h·L-1) is equivalent to free EGCG (Cmax: 233.5 nmol·L-1, AUC: 664.1 nmol·h·L-1), suggesting that EGCG-4″-sulfate is the key metabolite. These findings indicate that sulfation is a crucial factor for improving EGCG bioavailability, while also advancing the understanding of the bioactivity and toxicity of EGCG.

Keywords: bioavailability; epigallocatechin-3-gallate; metabolism; pharmacokinetics; sulfation.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Chemical structure of EGCG.
Figure 2
Figure 2
Representative LC–MS/MS extracted ion chromatogram of EGCG-sulfates generated by human cytosol or standards. EGCG was incubated with HLC, small intestinal cytosol (HIC), and 3′-phosphoadenosine-5′-phosphosulfate (PAPS). The supernatants and authentic standards were analyzed by LC–MS/MS operated in full-scan mode. Analyses were carried out using the extracted ion chromatogram (XIC) of the m/z 537.03445 ion with a 0.002 Da window. RT means retention time.
Figure 3
Figure 3
Concentration-dependent sulfation, methylation, and glucuronidation of EGCG by human liver or small intestinal fractions. Various concentrations of EGCG were incubated with (A) HLC and PAPS, (B) human small intestinal cytosol and PAPS, (C) HLC and S-adenosyl methionine (SAM), (D) human small intestinal cytosol and SAM, (E) human liver microsomes and uridine 5′-diphosphoglucuronic acid (UDPGA), and (F) human small intestinal microsomes and UDPGA. Data are presented as the mean ± SD of three independent experiments. The kinetic curve at lower or higher concentrations is shown in Figure S4.
Figure 4
Figure 4
Concentration-dependent sulfation of EGCG by SULT1A1, SULT1A3, and SULT1E1. Different concentrations of EGCG were incubated with (A) SULT1A1, (B) SULT1A3, and (C) SULT1E1. EGCG-4″-sulfate formation was quantified using LC–MS. (D) Rate of sulfation of each SULT was compared at EGCG concentrations <3 μM. Data are presented as the mean ± SD of three independent experiments. The kinetic curve at the lower concentrations is shown in Figure S5.
Figure 5
Figure 5
EGCG metabolite profile in human plasma after oral ingestion of catechin-rich tea. (A) Representative extracted ion chromatogram of EGCG metabolites from human plasma collected 2 h after ingestion of 615 mg of extracted catechin (135 mg of EGCG). Each chromatogram represents the detection of EGCG or its metabolites: m/z 457 for free (E)GCG, m/z 537 for (E)GCG-sulfate, m/z 471 for (E)GCG-methyl, m/z 551 for (E)GCG-methyl-sulfate, m/z 633 for (E)GCG-glucuronide, and m/z 565 for (E)GCg-dimethyl-sulfate. (B) MS/MS spectrum of EGCG-sulfate. (C) MS/MS spectrum of (E)GCg-diMe-sulfate.
Figure 6
Figure 6
Time-concentration curve of EGCG, EGCG-4″-sulfate, and EGCG-4″-glucuronide in human plasma. Concentrations of EGCG, EGCG-4″-sulfate, and EGCG-4″-glucuronide in human plasma over 6 h after the ingestion of EGCG were determined by LC–MS/MS. The values for each point are presented as the mean ± SD of 10 volunteers.
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