1: Toxicol Sci. 2002 Sep;69(1):139-48. 

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.

O'Brien ML, Cunningham ML, Spear BT, Glauert HP.

Graduate Center for Toxicology, University of Kentucky, Lexington, Kentucky
40506, USA.

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.

PMID: 12215668 [PubMed - indexed for MEDLINE]


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