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Received for publication December 12, 2003.
Revised February 10, 2004.
Accepted for publication February 19, 2004.
Sulforaphane (SUL) is one of the isothiocyanates (ITCs) class of cancer chemopreventive compounds, which 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 utilized 5,000 (5K)-oligonucleotide microarrays 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 µmole SUL. The plasma concentration appeared at 1 hr and peaked around 20 µM at 4 hr after dosing and declined with a half-life of about 2.2 hr. 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 2-4 hrs after SUL dosing. The second cluster of genes is the glutathione S-transferase (GST-A3)-like genes, which include aflatoxin B1 aldehyde reductase and aldehyde oxidase. These genes are increased slightly by 4 hrs and peaked at 12 hrs. Real-time PCR were 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 MAPK 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.
Key words:
MAPK, Sulforaphane, gene expression, microarray, pharmacokinetics, real-time PCR
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