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Research ArticleArticle

Identification of the ortho-Benzoquinone Intermediate of 5-O-Caffeoylquinic Acid In Vitro and In Vivo: Comparison of Bioactivation under Normal and Pathological Situations

Cen Xie, Dafang Zhong and Xiaoyan Chen
Drug Metabolism and Disposition August 2012, 40 (8) 1628-1640; DOI: https://doi.org/10.1124/dmd.112.045641
Cen Xie
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Dafang Zhong
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Xiaoyan Chen
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Abstract

5-O-Caffeoylquinic acid (5-CQA) is one of the major bioactive ingredients in some Chinese herbal injections. Occasional anaphylaxis has been reported for these injections during their clinical use, possibly caused by reactive metabolites of 5-CQA. This study aimed at characterizing the bioactivation pathway(s) of 5-CQA and the metabolic enzyme(s) involved. After incubating 5-CQA with GSH and NADPH-supplemented human liver microsomes, two types of GSH conjugates were characterized: one was M1-1 from the 1,4-addition of GSH to ortho-benzoquinone intermediate; the other was M2-1 and M2-2 from the 1,4-addition of GSH directly to the α,β-unsaturated carbonyl group of the parent. The formation of M1-1 was cytochrome P450 (P450)-mediated, with 3A4 and 2E1 as the principal catalyzing enzymes, whereas the formation of M2-1 and M2-2 was independent of NADPH and could be accelerated by cytosolic glutathione transferase. In the presence of cumene hydroperoxide, M1-1 formation increased 6-fold, indicating that 5-CQA can also be bioactivated by P450 peroxidase under oxidizing conditions. Furthermore, M1-1 could be formed by myeloperoxidase in activated human leukocytes, implying that 5-CQA bioactivation is more likely to occur under inflammatory conditions. This finding was supported by experiments on lipopolysaccharide-induced inflammatory rats, where a greater amount of M1-1 was detected. In S-adenosyl methionine- and GSH-supplemented human S9 incubations, M1-1 formation decreased by 80% but increased after tolcapone-inhibited catechol-O-methyltransferase (COMT) activity. In summary, the high reactivities of the ortho-benzoquinone metabolite and α,β-unsaturated carbonyl group of 5-CQA to nucleophiles have been demonstrated. Different pathological situations and COMT activities in patients may alter the bioactivation extent of 5-CQA.

Footnotes

  • This work was supported by the National Natural Science Foundation of China [Grant 81173115]; and the National Basic Research Program of China [Grant 2009CB930300].

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    http://dx.doi.org/10.1124/dmd.112.045641.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    5-CQA
    5-O-caffeoylquinic acid
    P450
    cytochrome P450
    HLM
    human liver microsomes
    3-CQA
    3-O-caffeoylquinic acid
    4-CQA
    4-O-caffeoylquinic acid
    CHP
    cumene hydroperoxide
    MPO
    myeloperoxidase
    PMA
    phorbol 12-myristate 13-acetate
    SAM
    S-adenosyl-methionine
    ABT
    1-aminobenzotriazole
    LPS
    lipopolysaccharides
    HPLC
    high-performance liquid chromatography
    UPLC
    ultraperformance liquid chromatography
    Q-TOF
    quadrupole time-of-flight
    MS
    mass spectrometry
    ES
    electrospray ionization
    CE
    collision energy
    PBS
    phosphate-buffered saline
    7′-SG-5-CQA
    7′-S-glutathionyl-5-O-caffeoylquinic acid
    COMT
    catechol-O-methyltransferase
    2′-SG-5-CQA
    2′-S-glutathionyl-5-O-caffeoylquinic acid
    GST
    glutathione transferase
    5-FQA
    5-O-feruloylquinic acid
    5-iFQA
    5-O-isoferuloylquinic acid
    4-FQA
    4-O-feruloylquinic acid.

  • Received March 12, 2012.
  • Accepted May 2, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (8)
Drug Metabolism and Disposition
Vol. 40, Issue 8
1 Aug 2012
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Research ArticleArticle

BIOACTIVATION OF 5-O-CAFFEOYLQUINIC ACID

Cen Xie, Dafang Zhong and Xiaoyan Chen
Drug Metabolism and Disposition August 1, 2012, 40 (8) 1628-1640; DOI: https://doi.org/10.1124/dmd.112.045641

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Research ArticleArticle

BIOACTIVATION OF 5-O-CAFFEOYLQUINIC ACID

Cen Xie, Dafang Zhong and Xiaoyan Chen
Drug Metabolism and Disposition August 1, 2012, 40 (8) 1628-1640; DOI: https://doi.org/10.1124/dmd.112.045641
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