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First published on April 11, 2006; DOI: 10.1124/mol.105.018622

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Received for publication September 9, 2005.
Revised April 11, 2006.
Accepted for publication April 11, 2006.

Chemical inducers of rodent GSTs down-regulate human GSTA1 transcription through a mechanism involving variant hepatic nuclear factor 1-C

Laura Romero 1, Lorraine Ng 1, Gordon M Kirby 1*

1 University of Guelph

* Address correspondence to: E-mail: gkirby{at}uoguelph.ca

Abstract

The regulation of human GSTA1 by chemical inducers of rodent GSTs and the regulatory role of hepatic nuclear factor 1 (HNF1) was investigated in Caco-2 cells. Treatment of pre-confluent and confluent cells with 12-O-tetradecanoyl phorbol-13-acetate (TPA), 3-methylcholanthrene (3-MC), 2-tert-butyl-4-hydroxy-anisol (BHA) and phenobarbital (PB) reduced GSTA1 mRNA levels in pre-confluent and confluent cells. Constitutive levels of GSTA1 and HNF-1{alpha} mRNA were elevated 6.25 and 50 fold, respectively, in post-confluent cells compared to pre-confluent cells. Overexpression of HNF1{alpha} in cells transfected with a GSTA1 promoter-luciferase construct (pGSTA1-1591-luc) resulted in dose-related increases in reporter activity not observed when an HNF1 response element (HRE) in the proximal promoter was mutated (pGSTA1-{Delta}HNF1-luc). TPA, 3-MC, BHA and PB reduced HNF1{alpha} mRNA levels in pre-confluent and confluent cells and caused marked reductions in luciferase activity in pGSTA1-1591-luc transfectants. Transcriptional repression was abrogated with pGSTA1-{Delta}HNF1-luc and with truncated constructs that eliminated a functional HRE. Moreover, co-transfection of pHNF1{alpha} with pGSTA1-1591-luc partially prevented the reduction in luciferase activity by rodent GST inducers. Immunoblot analysis of DNA binding studies indicate that vHNF1-C binding to HRE is increased in preconfluent cells treated with 3-MC, BHA and PB. Also, overexpression of vHNF1-C repressed GSTA1 transcriptional activity in luciferase reporter assays. Finally, treatment with 3-MC, BHA and PB increased vHNF1-C mRNA levels in pre-confluent cells. These data demonstrate that repression of human GSTA1 transcription by chemical inducers of rodent GSTs occurs, in part, through a mechanism involving the repressive action of vHNF1-C.


Key words: Glutathione S-transferases, Regulation - transcriptional


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L. Ng, K. Nichols, K. O'Rourke, A. Maslen, and G. M. Kirby
Repression of Human GSTA1 by Interleukin-1beta Is Mediated by Variant Hepatic Nuclear Factor-1C
Mol. Pharmacol., January 1, 2007; 71(1): 201 - 208.
[Abstract] [Full Text] [PDF]


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