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Chemical Inducers of Rodent Glutathione S-Transferases Down-Regulate Human GSTA1 Transcription through a Mechanism Involving Variant Hepatic Nuclear Factor 1-C

Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada

The regulation of human GSTA1 by chemical inducers of rodent glutathione S-transferases (GSTs) and the regulatory role of hepatic nuclear factor (HNF) 1 was investigated in Caco-2 cells. Treatment of preconfluent and confluent cells with 12-O-tetra-decanoyl phorbol-13-acetate (TPA), 3-methylcholanthrene (3-MC), 2-tert-butyl-4-hydroxy-anisol (BHA), and phenobarbital (PB) reduced GSTA1 mRNA levels in preconfluent and confluent cells. Constitutive levels of GSTA1 and HNF1 mRNA were elevated 6.25- and 50-fold, respectively, in postconfluent cells compared with preconfluent cells. Overexpression of HNF1 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-HNF1-luc). TPA, 3-MC, BHA, and PB reduced HNF1 mRNA levels in preconfluent and confluent cells and caused marked reductions in luciferase activity in pGSTA1-1591-luc transfectants. Transcriptional repression was abrogated with pGSTA1-HNF1-luc and with truncated constructs that eliminated a functional HRE. Moreover, cotransfection of pHNF1 with pGSTA1-1591-luc partially prevented the reduction in luciferase activity by rodent GST inducers. Immunoblot analysis of DNA binding studies indicate that variant (v)HNF1-C binding to HRE is increased in preconfluent cells treated with 3-MC, BHA, and PB. In addition, 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 preconfluent 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.

Address correspondence to: Dr. Gordon M. Kirby, Department of Biomedical Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1. E-mail: gkirby{at}uoguelph.ca

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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]