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Research ArticleArticle

Metabolism of [6]-Shogaol in Mice and in Cancer Cells

Huadong Chen, Lishuang Lv, Dominique Soroka, Renaud F. Warin, Tiffany A. Parks, Yuhui Hu, Yingdong Zhu, Xiaoxin Chen and Shengmin Sang
Drug Metabolism and Disposition April 2012, 40 (4) 742-753; DOI: https://doi.org/10.1124/dmd.111.043331
Huadong Chen
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Lishuang Lv
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Dominique Soroka
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Renaud F. Warin
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Tiffany A. Parks
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Yuhui Hu
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Yingdong Zhu
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Xiaoxin Chen
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Shengmin Sang
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Abstract

Ginger has received extensive attention because of its antioxidant, anti-inflammatory, and antitumor activities. However, the metabolic fate of its major components is still unclear. In the present study, the metabolism of [6]-shogaol, one of the major active components in ginger, was examined for the first time in mice and in cancer cells. Thirteen metabolites were detected and identified, seven of which were purified from fecal samples collected from [6]-shogaol-treated mice. Their structures were elucidated as 1-(4′-hydroxy-3′-methoxyphenyl)-4-decen-3-ol (M6), 5-methoxy-1-(4′-hydroxy-3′-methoxyphenyl)-decan-3-one (M7), 3′,4′-dihydroxyphenyl-decan-3-one (M8), 1-(4′-hydroxy-3′-methoxyphenyl)-decan-3-ol (M9), 5-methylthio-1-(4′-hydroxy-3′-methoxyphenyl)-decan-3-one (M10), 1-(4′-hydroxy-3′-methoxyphenyl)-decan-3-one (M11), and 5-methylthio-1-(4′-hydroxy-3′-methoxyphenyl)-decan-3-ol (M12) on the basis of detailed analysis of their 1H, 13C, and two-dimensional NMR data. The rest of the metabolites were identified as 5-cysteinyl-M6 (M1), 5-cysteinyl-[6]-shogaol (M2), 5-cysteinylglycinyl-M6 (M3), 5-N-acetylcysteinyl-M6 (M4), 5-N-acetylcysteinyl-[6]-shogaol (M5), and 5-glutathiol-[6]-shogaol (M13) by analysis of the MSn (n = 1–3) spectra and comparison to authentic standards. Among the metabolites, M1 through M5, M10, M12, and M13 were identified as the thiol conjugates of [6]-shogaol and its metabolite M6. M9 and M11 were identified as the major metabolites in four different cancer cell lines (HCT-116, HT-29, H-1299, and CL-13), and M13 was detected as a major metabolite in HCT-116 human colon cancer cells. We further showed that M9 and M11 are bioactive compounds that can inhibit cancer cell growth and induce apoptosis in human cancer cells. Our results suggest that 1) [6]-shogaol is extensively metabolized in these two models, 2) its metabolites are bioactive compounds, and 3) the mercapturic acid pathway is one of the major biotransformation pathways of [6]-shogaol.

Footnotes

  • This work was supported by the National Institutes of Health National Cancer Institute [Grant CA138277]; and the National Institutes of Health National Cancer Institute and Office of Dietary Supplements [Grant CA138277S1].

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

    http://dx.doi.org/10.1124/dmd.111.043331.

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

  • ABBREVIATIONS:

    TLC
    thin-layer chromatography
    HPLC
    high-performance liquid chromatography
    LC/MS
    liquid chromatography/mass spectrometry
    LC/MS/MS
    liquid chromatography/tandem mass spectrometry
    MS
    mass spectrometry
    ESI
    electrospray ionization
    ESI-MS
    electrospray ionization-mass spectrometry
    CC
    column chromatography
    PBS
    phosphate-buffered saline
    H-ESI
    heated electrospray ionization
    2D
    two dimensional
    ECD
    electrochemical detector
    DMSO
    dimethyl sulfoxide
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
    TUNEL
    terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling
    HMBC
    heteronuclear multiple-bond correlation
    LTB4 12-HD/PGR
    leukotriene B4 12-hydroxydehydrogenase/15-oxo-prostaglandin 13-reductase
    SFN
    sulforphane
    Nrf2
    nuclear factor-E2-related factor 2
    KEAP1
    Kelch-like ECH-associated protein 1.

  • Received October 14, 2011.
  • Accepted January 13, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (4)
Drug Metabolism and Disposition
Vol. 40, Issue 4
1 Apr 2012
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Research ArticleArticle

METABOLISM OF [6]-SHOGAOL

Huadong Chen, Lishuang Lv, Dominique Soroka, Renaud F. Warin, Tiffany A. Parks, Yuhui Hu, Yingdong Zhu, Xiaoxin Chen and Shengmin Sang
Drug Metabolism and Disposition April 1, 2012, 40 (4) 742-753; DOI: https://doi.org/10.1124/dmd.111.043331

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Research ArticleArticle

METABOLISM OF [6]-SHOGAOL

Huadong Chen, Lishuang Lv, Dominique Soroka, Renaud F. Warin, Tiffany A. Parks, Yuhui Hu, Yingdong Zhu, Xiaoxin Chen and Shengmin Sang
Drug Metabolism and Disposition April 1, 2012, 40 (4) 742-753; DOI: https://doi.org/10.1124/dmd.111.043331
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