TY - JOUR T1 - Chemical Inducers of Rodent Glutathione <em>S</em>-Transferases Down-Regulate Human <em>GSTA1</em> Transcription through a Mechanism Involving Variant Hepatic Nuclear Factor 1-C JF - Molecular Pharmacology JO - Mol Pharmacol SP - 277 LP - 286 DO - 10.1124/mol.105.018622 VL - 70 IS - 1 AU - Laura Romero AU - Lorraine Ng AU - Gordon M. Kirby Y1 - 2006/07/01 UR - http://molpharm.aspetjournals.org/content/70/1/277.abstract N2 - 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 HNF1α mRNA were elevated 6.25- and 50-fold, respectively, in postconfluent cells compared with preconfluent cells. Overexpression of HNF1α 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-ΔHNF1-luc). TPA, 3-MC, BHA, and PB reduced HNF1α 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-ΔHNF1-luc and with truncated constructs that eliminated a functional HRE. Moreover, cotransfection of pHNF1α 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. ER -