Carcinogenesis, Vol 18, 2077-2083, Copyright © 1997 by Oxford University Press
WG Karam and BI Ghanayem
Peroxisome proliferators (PP) are known hepatocarcinogens in rats and mice.
We have investigated the ability of Wyeth-14 643 (Wy), a PP and potent
rodent carcinogen, to induce replicative DNA synthesis and to modulate the
levels of peroxisome proliferator activated receptor-alpha (PPAR alpha)
transcriptionally-dependent genes in primary rat hepatocyte (HPC) cultures
and hepatocyte/nonparenchymal cell (HPC/NPC) co-cultures maintained on
Matrigel. Four days after plating, cells were treated with Wy and
replicative DNA synthesis was quantitated using [3H]thymidine incorporation
and specific mRNA transcript levels were determined by
reverse-transcriptase polymerase chain reaction (RT-PCR). An increase in
HPC replicative DNA synthesis was detected at 48 h in both Wy-treated HPC
and HPC/NPC co-cultures relative to controls. This increase was
approximately 3- and 6-fold in HPC and HPC/NPC cultures respectively, and
was Wy concentration-dependent. The levels of PPAR alpha-transcriptionally
dependent genes [cytochrome P4504A1, acyl-CoA oxidase (AOxase), and
liver-fatty acid binding protein (L-FABP)] transcripts were determined as
indicators of PPAR alpha activation. These transcripts increased
dose-dependently at 48 h in HPC/NPC cultures up to 10 microM Wy. Similarly,
RT-PCR product levels were also increased in HPC cultures with 10 microM Wy
at 48 h. In conclusion, we have investigated the transcription of PPAR
alpha-dependent genes and HPC replicative DNA synthesis by Wy in HPC/NPC
co-cultures. Results of this work are clearly more reflective of the known
in vivo effects of PP and suggest that HPC/NPC co-cultures are more
appropriate than HPC cultures for such studies. The effect of PP on human
HPC/NPC co- cultures is currently being investigated in our laboratory in
an attempt to assess human risks to these chemicals more directly.
ARTICLES
Induction of replicative DNA synthesis and PPAR alpha-dependent gene transcription by Wy-14 643 in primary rat hepatocyte and non- parenchymal cell co-cultures
Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, RTP, NC 27709, USA.
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