Peroxisome proliferators do not activate the transcription factors AP-1, early growth response-1, or heat shock factors 1 and 2 in rats or hamsters.
Peroxisome proliferators (PPs) cause hepatomegaly, peroxisome proliferation, and hepatocarcinogenesis in rats and mice, whereas hamsters are less responsive to these compounds. PPs increase peroxisomal beta-oxidation and P4504A subfamily activity, which have been hypothesized to result in oxidative stress. Work in our laboratory indicated that differential modulation of the redox-sensitive transcription factor NF-kappaB may contribute to the resulting difference in species susceptibility following PP administration. Therefore, we hypothesized that other redox-sensitive transcription factors such as AP-1, early growth response gene 1 (Egr-1), and heat-shock factors 1 and 2 (HSF1/2) may also be alternatively activated in differentially susceptible species. Accordingly, we measured the activation of these transcription factors using gel mobility shift assays, with hepatic nuclear extracts derived from rats and Syrian hamsters fed two doses of three peroxisome proliferators (dibutyl-phthalate [DBP], gemfibrozil and Wy-14,643) for 6, 34, or 90 days. Although changes were observed at various time points, no consistent, dose-responsive changes were observed in the DNA binding activities of these transcription factors following PP treatment. The lack of increased binding of AP-1, Egr-1, and HSFs suggests that these factors are not involved in increased cell proliferation following PP administration, although we cannot rule out that these factors are activated at earlier time points than those examined in this study.
O'Brien
Michelle L
ML
Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky 40506, USA.
Cunningham
Michael L
ML
Spear
Brett T
BT
Glauert
Howard P
HP
D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D015342:DNA Probes; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051766:Early Growth Response Protein 1; D024202:Electrophoretic Mobility Shift Assay; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000378:metabolism*; D017874:Immediate-Early Proteins; D008297:Male; D008647:Mesocricetus; D009687:Nuclear Proteins / Q000378:metabolism; D020025:Peroxisome Proliferators / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
D015342:DNA Probes; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C000619709:Hsf1 protein, rat; D017874:Immediate-Early Proteins; D009687:Nuclear Proteins; D020025:Peroxisome Proliferators; D018808:Transcription Factor AP-1; D014157:Transcription Factors; C070389:HSF2 protein, human; D004247:DNA