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J. Biol. Chem., Vol. 277, Issue 27, 24780-24787, July 5, 2002
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From Oltipraz, a synthetic derivative of the
cruciferous vegetable product 1,2-dithiole-3-thione, is considered as
one of the most potent chemoprotectants. It modulates both cytochrome
P-450 (CYP) and glutathione S-transferase expression
and activities in rat tissues. Its effects, however, are variable
according to the enzyme, tissue, and species. We show here that, as
previously found in rat lung and kidney, CYP1A1 is inducible by
oltipraz in both rat intestine and Caco-2 cells, a cell line originated
from a human colon adenocarcinoma. In these cells, a 50 µM oltipraz treatment increased CYP1A1 mRNA
(~30-fold), protein and activity. mRNA level was augmented as
early as 2 h after the beginning of treatment, suggesting a
transcriptional activation, and was maximal between 8 and 12 h.
Transient transfection of Caco-2 cells with constructs containing
different sizes of the 5'-flanking region of the
CYP1A1 gene upstream of the luciferase reporter gene
showed an increase in luciferase activity in oltipraz-treated cells,
which correlates with the presence of the xenobiotic responsive element
(XRE). Furthermore we demonstrated that resveratrol, an antagonist of the aryl hydrocarbon (Ah) receptor, inhibited the induction of both
CYP1A1 promoter activity and mRNA by oltipraz,
supporting the involvement of the Ah receptor in this induction. In an
attempt to further characterize the mechanism of CYP1A1
induction, we showed a rapid increase in intracellular calcium
concentration upon treatment of Caco-2 cells with oltipraz. Moreover,
the effect of this compound on CYP1A1 was strongly abolished in the
presence of BAPTA-AM, a well known chelator of intracellular calcium,
and 2-aminoethyl diphenylborate, an inhibitor of store-operated calcium channels. These results bring the first demonstration that oltipraz activates transcription of the CYP1A1 gene through the Ah
receptor-XRE pathway in Caco-2 cells and that CYP1A1
induction relies upon an increase of intracellular calcium concentration.
Transcriptional Induction of CYP1A1 by Oltipraz in
Human Caco-2 Cells Is Aryl Hydrocarbon Receptor- and
Calcium-dependent*
§,,,,,,, and¶
INSERM U456, Université de Rennes 1, 2 Avenue du Pr. Léon Bernard, 35043 Rennes, France and
§ Biopredic, 14-18 rue Jean Pecker, 35000 Rennes,
France
*
This work was supported in part by the Institut National de
la Santé et de la Recherche Médicale and the Association
pour la Recherche sur le Cancer.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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