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Research ArticleArticle

Cytoprotective Effect of 20(S)-Rg3 on Benzo[a]pyrene-Induced DNA Damage

Po Ying Poon, Hoi Hin Kwok, Patrick Y. K. Yue, Mildred S. M. Yang, Nai Ki Mak, Chris K. C. Wong and Ricky N. S. Wong
Drug Metabolism and Disposition January 2012, 40 (1) 120-129; DOI: https://doi.org/10.1124/dmd.111.039503
Po Ying Poon
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Hoi Hin Kwok
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Patrick Y. K. Yue
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Mildred S. M. Yang
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Nai Ki Mak
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Chris K. C. Wong
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Ricky N. S. Wong
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Abstract

Benzo[a]pyrene (BaP) is a polycyclic aromatic hydrocarbon ubiquitously existing in the environment. Its metabolites have been shown to cause DNA damage and cellular dysfunction in humans. Panax ginseng C.A. Meyer is a Chinese medicinal herb, and ginsenosides are the main active constituent of ginseng. Accumulating evidence had indicated that ginseng extract and ginsenosides possess cytoprotective effects. In this study, the protective effect of ginsenosides on BaP-induced DNA damage in human dermal fibroblasts (HDFs) and HepG2 cells was investigated. The genotoxic effect of BaP was measured by the comet assay. Results showed that tail moment was increased in BaP-treated cells, but cotreatment of ginsenoside 20(S)-Rg3 can significantly decrease BaP-induced DNA damage. A downstream mechanistic study revealed that 20(S)-Rg3 increased the gene expression of an important phase II detoxifying enzyme NAD(P)H:quinine oxidoreductase 1. The effect was also associated with the activation of protein kinase B (Akt) and nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). These results indicated that 20(S)-Rg3 might protect HDFs from BaP-induced DNA damage through the activation of the phosphatidylinositol 3-kinase/Akt/Nrf2 pathway. Our results also demonstrated that 20(S)-Rg3 is a functional ligand of pregnane X receptor (PXR), a nuclear receptor that mediates the induction of drug clearance pathways. Subsequent knockdown of PXR expression by small interfering RNA confirmed the involvement of PXR on the protective effects of 20(S)-Rg3 against BaP-induced DNA damage. In summary, ginsenoside 20(S)-Rg3 can protect against BaP-induced genotoxicity in human cells, suggesting that ginseng may serve as a natural cytoprotective agent against environmental carcinogens.

Footnotes

  • This work was supported in part by the Central Allocation Group of the Research Grant Council, Hong Kong SAR [Grant HKBU 1/06C].

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

    http://dx.doi.org/10.1124/dmd.111.039503.

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

  • ABBREVIATIONS:

    BaP
    benzo[a]pyrene
    Nrf2
    nuclear factor erythroid 2-related factor 2
    Erk
    extracellular signal-regulated kinase
    NQO1
    NAD(P)H:quinine oxidoreductase 1
    PXR
    pregnane X receptor
    GST
    glutathione transferase
    UGT
    UDP-glucuronyltransferase
    PI3K
    phosphatidylinositol 3-kinase
    DMEM
    Dulbecco's modified Eagle's medium
    PBS
    phosphate-buffered saline
    DMSO
    dimethyl sulfoxide
    DAPI
    4,6-diamidino-2-phenylindole dihydrochloride
    LY294002
    2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride
    SR12813
    tetraethyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethenyl-1,1-bisphosphonate
    MTT
    3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl-tetrazolium bromide
    HDF
    human dermal fibroblast
    TUNEL
    terminal deoxynucleotidyl transferase dUTP nick-end labeling
    PCR
    polymerase chain reaction
    FRET
    fluorescence resonance energy transfer
    siRNA
    small interfering RNA
    siPXR
    siRNA targeting human PXR
    DME
    drug-metabolizing enzyme
    SULT
    sulfotransferase.

  • Received March 14, 2011.
  • Accepted September 28, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (1)
Drug Metabolism and Disposition
Vol. 40, Issue 1
1 Jan 2012
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Research ArticleArticle

CYTOPROTECTIVE EFFECT OF 20(S)-Rg3 ON BaP-INDUCED DNA DAMAGE

Po Ying Poon, Hoi Hin Kwok, Patrick Y. K. Yue, Mildred S. M. Yang, Nai Ki Mak, Chris K. C. Wong and Ricky N. S. Wong
Drug Metabolism and Disposition January 1, 2012, 40 (1) 120-129; DOI: https://doi.org/10.1124/dmd.111.039503

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Research ArticleArticle

CYTOPROTECTIVE EFFECT OF 20(S)-Rg3 ON BaP-INDUCED DNA DAMAGE

Po Ying Poon, Hoi Hin Kwok, Patrick Y. K. Yue, Mildred S. M. Yang, Nai Ki Mak, Chris K. C. Wong and Ricky N. S. Wong
Drug Metabolism and Disposition January 1, 2012, 40 (1) 120-129; DOI: https://doi.org/10.1124/dmd.111.039503
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