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.
↵ 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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