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Research ArticleArticle

Enzymology of Methylation of Tea Catechins and Inhibition of Catechol-O-methyltransferase by (−)-Epigallocatechin Gallate

Hong Lu, Xiaofeng Meng and Chung S. Yang
Drug Metabolism and Disposition May 2003, 31 (5) 572-579; DOI: https://doi.org/10.1124/dmd.31.5.572
Hong Lu
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Xiaofeng Meng
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Chung S. Yang
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Abstract

(−)-Epigallocatechin gallate (EGCG) and (−)-epigallocatechin (EGC) are the major polyphenolic constituents in green tea. In this study, we characterized the enzymology of cytosolic catechol-O-methyltransferase (COMT)-catalyzed methylation of EGCG and EGC in humans, mice, and rats. At 1 μM, EGCG was readily methylated by liver cytosolic COMT to 4"-O-methyl-EGCG and then to 4′,4"-di-O-methyl-EGCG; EGC was methylated to 4′-O-methyl-EGC. The Km andVmax values for EGC methylation were higher than EGCG; for example, with human liver cytosol, theKm were 4.0 versus 0.16 μM andVmax were 1.28 versus 0.16 nmol/mg/min. Rat liver cytosol had higher COMT activity than that of humans or mice. The small intestine had lower specific activity than the liver in the methylation of EGCG and EGC. Glucuronidation on the B-ring or thed-ring of EGCG greatly inhibited the methylation on the same ring, but glucuronidation on the A-ring of EGCG or EGC did not affect their methylation. Using EGC and 3,4-dihydroxy-l-phenylalanine as substrates, EGCG, 4"-O-methyl-EGCG, and 4′,4"-di-O-methyl-EGCG were all potent inhibitors (IC50 ∼0.2 μM) of COMT. The COMT-inhibiting activity of (−)-EGCG-3′-O-glucuronide was similar to EGCG, but (−)-EGCG-4"-O-glucuronide was less potent. The present work provides basic information on the methylation of EGCG and suggests that EGCG may inhibit COMT-catalyzed methylation of endogenous and exogenous compounds.

Footnotes

  • This work was supported by National Institutes of Health Grants CA 56673 and CA88961.

  • Abbreviations used are::
    EGCG
    (−)-epigallocatechin gallate
    EGC
    (−)-epigallocatechin
    ECG
    (−)-epicatechin gallate
    EGCG-7-Gluc
    (−)-EGCG-7-O-glucuronide (similar abbreviations for other glucuronides)
    4′-MeEGC
    4′-O-methyl-(−)-epigallocatechin
    4"-MeEGCG
    4"-O-methyl-(−)-epigallocatechin gallate
    4′,4"-DiMeEGCG
    4′,4"-di-O-methyl-epigallocatechin gallate
    COMT
    catechol-O-methyltransferase
    SAM
    S-adenosylmethionine
    l-DOPA
    3,4-dihydroxy-l-phenylalanine
    3-MeDOPA
    l-3-O-methyl-DOPA
    UDPGA
    UGP-glucuronic acid
    LC/MS/MS
    liquid chromatographic tandem mass spectrometric method
    HPLC
    high-performance liquid chromatography
    EGCG-4"-Gluc
    (−)-EGCG-4"-O-glucuronide
    EGCG-3"-Gluc
    (−)-EGCG-3"-O-glucuronide
    EGCG-3′-Gluc
    (−)-EGCG-3′-O-glucuronide
    EGC-3′-Gluc
    (−)-EGC-3′-O-glucuronide
    EGC-7-Gluc
    (−)-EGC-7-O-glucuronide
    • Received October 15, 2002.
    • Accepted February 3, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (5)
Drug Metabolism and Disposition
Vol. 31, Issue 5
1 May 2003
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Research ArticleArticle

Enzymology of Methylation of Tea Catechins and Inhibition of Catechol-O-methyltransferase by (−)-Epigallocatechin Gallate

Hong Lu, Xiaofeng Meng and Chung S. Yang
Drug Metabolism and Disposition May 1, 2003, 31 (5) 572-579; DOI: https://doi.org/10.1124/dmd.31.5.572

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Research ArticleArticle

Enzymology of Methylation of Tea Catechins and Inhibition of Catechol-O-methyltransferase by (−)-Epigallocatechin Gallate

Hong Lu, Xiaofeng Meng and Chung S. Yang
Drug Metabolism and Disposition May 1, 2003, 31 (5) 572-579; DOI: https://doi.org/10.1124/dmd.31.5.572
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