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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

In Vivo Pharmacokinetics and Regulation of Gene Expression Profiles by Isothiocyanate Sulforaphane in the Rat

Rong Hu, Vidya Hebbar, Bok-Ryang Kim, Chi Chen, Bozena Winnik, Brian Buckley, Patricia Soteropoulos, Peter Tolias, Ronald P. Hart and A.-N. Tony Kong
Journal of Pharmacology and Experimental Therapeutics July 2004, 310 (1) 263-271; DOI: https://doi.org/10.1124/jpet.103.064261
Rong Hu
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Vidya Hebbar
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Bok-Ryang Kim
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Chi Chen
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Bozena Winnik
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Brian Buckley
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Patricia Soteropoulos
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Peter Tolias
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Ronald P. Hart
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A.-N. Tony Kong
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Abstract

Sulforaphane (SUL) is one member of the isothiocyanate class of cancer chemopreventive compounds that has been shown to be effective in blocking initiation and progression of carcinogenesis. Previously, many studies have shown that SUL can potently induce phase II detoxifying enzymes, which contributes to its chemopreventive functions. In this study, we used 4967 oligonucleotides microarray to assess the genes that are modulated by SUL in in vivo rat livers, as well as time course of expression of these genes. The pharmacokinetics of SUL was assessed after oral dose of 50 μmol of SUL. The plasma concentration occurred at 1 h and peaked around 20 μM at 4 h after dosing and declined with a half-life of about 2.2 h. Analysis of the gene expression data found various clusters of genes that are important in cellular defense mechanisms and cell cycle regulation. The most robust cluster of genes is the metallothionein-like genes (MT-1/2 and MT-1a), which are increased up to 10-fold by 2 to 4 h after SUL dosing. The second cluster of genes is the glutathione S-transferase-A3-like genes, which include aflatoxin B1 aldehyde reductase and aldehyde oxidase. These genes are increased slightly by 4 h and peaked at 12 h. Real-time polymerase chain reaction was performed to authenticate the mRNA expression of some of these genes. In summary, this in vivo study of SUL provides the first clue as to the plasma concentrations of SUL, in vivo mitogen-activated protein kinase activations in rat livers, as well as what other genes are modulated in addition to phase II detoxifying genes. The results from this study may yield better insights for its chemopreventive functions.

Footnotes

  • This work was supported by the National Institutes of Health Grant R01-CA73674.

  • DOI: 10.1124/jpet.103.064261.

  • ABBREVIATIONS: SUL, sulforaphane; ITC, isothiocyanate; GST, glutathione S-transferase; ARE, antioxidant response element; MAPK, mitogen-activated protein kinase; LC/MS, liquid chromatography/mass spectrometry; Cp, plasma drug concentration(s); ERK, extracellular signal-regulated kinase; JNK, c-Jun NH2-terminal kinase; SSC, standard saline citrate; PCR, polymerase chain reaction; MT, metallothionein; ABAR, aflatoxin B1 aldehyde reductase; pb, phenobarbital; RT-PCR, reverse transcription-polymerase chain reaction; ARE, antioxidant response element; UGT, uridine diphosphate glucuronosyltransferase.

  • ↵1 These authors contributed equally to this work.

    • Received December 12, 2003.
    • Accepted February 19, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 310 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 310, Issue 1
1 Jul 2004
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

In Vivo Pharmacokinetics and Regulation of Gene Expression Profiles by Isothiocyanate Sulforaphane in the Rat

Rong Hu, Vidya Hebbar, Bok-Ryang Kim, Chi Chen, Bozena Winnik, Brian Buckley, Patricia Soteropoulos, Peter Tolias, Ronald P. Hart and A.-N. Tony Kong
Journal of Pharmacology and Experimental Therapeutics July 1, 2004, 310 (1) 263-271; DOI: https://doi.org/10.1124/jpet.103.064261

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

In Vivo Pharmacokinetics and Regulation of Gene Expression Profiles by Isothiocyanate Sulforaphane in the Rat

Rong Hu, Vidya Hebbar, Bok-Ryang Kim, Chi Chen, Bozena Winnik, Brian Buckley, Patricia Soteropoulos, Peter Tolias, Ronald P. Hart and A.-N. Tony Kong
Journal of Pharmacology and Experimental Therapeutics July 1, 2004, 310 (1) 263-271; DOI: https://doi.org/10.1124/jpet.103.064261
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