Activation of transcription factors by drugs inducing oxidative stress in rat liver.
Chemically induced oxidative stress of the liver associates with gene reprogramming and activation of some transcription factors (TFs), in particular nuclear factor-kappaB (NF-kappaB). We have now investigated other TFs, such as activator protein-1 (AP-1) and hypoxia inducible factor-1 (HIF-1) that we had shown to be activated in rat liver during heat shock, ischemia or post-ischemic reperfusion, and signal transducer and activator of transcription (STAT), CCAAT/enhancer binding protein (C/EBP) and hepatocyte nuclear factor-1 (HNF-1), which may be involved in the response of the liver to injury. The expression of target genes, containing consensus sequences for these TFs was assessed by Northern and Western blot analysis. The rats were treated with buthionine-sulfoximine, nitrofurantoin (NF) or phorone (Ph), which cause liver oxidative stress with different mechanisms. All these agents activated AP-1, known to depend on redox state, HIF-1, initially described as an hypoxia-responsive TF, and STAT3, generally connected to the response to cytokines. HNF-1 a constitutive TF associated with liver-specific gene expression was not affected. The composition of AP-1 was slightly different according to the drug used for treatment. The levels of the mRNAs for heme oxygenase-1 (HO-1), Aldolase A and alpha(1)-acid glycoprotein as well as the corresponding proteins increased after the treatments, thus, indicating that the activation of the TFs was functional. These observations suggest that the treatment of rats with drugs inducing oxidative stress causes a broad spectrum of changes in gene expression with features common to stresses generally considered as separate entities.
Tacchini
Lorenza
L
Istituto di Patologia Generale dell'Universita' degli Studi di Milano, Centro di Studio sulla Patologia Cellulare del CNR, Via Mangiagalli 31, I-20133, Milan, Italy.
Fusar-Poli
Daniela
D
Bernelli-Zazzera
Aldo
A
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D004268:DNA-Binding Proteins; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D000255:Adenosine Triphosphate; D004247:DNA; D005978:Glutathione