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Carcinogenesis Advance Access originally published online on April 16, 2004
Carcinogenesis 2004 25(9):1629-1637; doi:10.1093/carcin/bgh169
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Carcinogenesis vol.25 no.9 © Oxford University Press 2004; all rights reserved.

ARTICLE

Interactions between sulforaphane and apigenin in the induction of UGT1A1 and GSTA1 in CaCo-2 cells

Vanda Svehlíková, Shuran Wang1, Jana Jakubíková2, Gary Williamson3, Richard Mithen and Yongping Bao4

Nutrition Division, Institute of Food Research, Norwich Research Park, Norwich NR4 7UA, UK
Present addresses: 1 Department of Nutrition and Food Hygiene, Harbin Medical University, Harbin 150001, P. R. China, 2 Department of Molecular Immunology, Cancer Research Institute, Vlarska 7, Bratislava, Slovak Republic and 3 Nestlé Research Center, PO Box 44, CH-1000 Lausanne 26, Switzerland

4 To whom correspondence should be addressed Email: yongping.bao{at}bbsrc.ac.uk

The isothiocyanate, sulforaphane and the flavonoid, apigenin modulate gene expression including phase II detoxifying enzymes, such as glutathione S-transferases (GST) and UDP-glucuronosyltransferases (UGT). Using undifferentiated CaCo-2 cells, we have examined the interactions between sulforaphane and apigenin in the regulation of UGT and GST expression. We show that apigenin induces UGT1A1 transcription (4-fold) but not GSTA1, and that sulforaphane induces both UGT1A1 (3.7-fold) and GSTA1 (2.8-fold) transcription in both dose- and time-dependent manners. The combination of sulforaphane and apigenin resulted in a synergistic induction of UGT1A1 mRNA up to 12-fold, although this interaction was not seen for GSTA1. Nuclear factor kappa B (NF-{kappa}B) mRNA was induced by apigenin and sulforaphane (2.5- and 2-fold, respectively). NF-{kappa}B translocation inhibitor SN50 and phosphatidylinositol 3-kinase (PI3) inhibitor LY294002 decreased the induction of GSTA1 by sulforaphane almost to baseline level. However, the MEK inhibitor PD98059 enhanced significantly the induction of GSTA1 by sulforaphane. This suggests that NF-{kappa}B and PI3-kinase signaling pathways play a role in GSTA1 gene expression. Conversely, the induction of UGT1A1 transcription by sulforaphane was totally abolished by PD98059, although PD98059 slightly enhanced (20%) the induction of UGT1A1 by apigenin implying that the induction of UGT1A1 by sulforaphane is mediated by MAPK/extracellular signal-regulated kinase kinase, whereas UGT1A1 induction by apigenin may be associated with NF-{kappa}B translocation since the NF-{kappa}B translocation inhibitor, SN50 enhanced the induction of UGT by apigenin. The results show that UGT1A1 and GSTA1 are regulated by sulforaphane through different signal transduction pathways and the differences in the mechanisms of modulation of UGT1A1 transcription by sulforaphane and apigenin resulted in a synergistic effect between these two compounds in the induction of UGT1A1.


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