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Vol. 282, Issue 2, 1122-1129, 1997
Department of Environmental Health, University of Washington,
Seattle, Washington
We have previously demonstrated that specific activation of a
cAMP-dependent protein kinase A (PKA) pathway resulted in complete repression of phenobarbital (PB)-inducible CYP gene expression in
primary rat hepatocyte cultures. In the current investigation, we
examined the role of protein phosphatase pathways as potential co-regulators of this repressive response. Primary rat hepatocytes were
treated with increasing concentrations (0.1-25 nM) of okadaic acid, a
potent inhibitor of serine/threonine-specific protein phosphatases PP1
and PP2A. PB induction responses were assessed by use of specific
hybridization probes to CYP2B1 and CYP2B2 mRNAs. Okadaic acid
completely inhibited the PB induction process in a
concentration-dependent manner (IC50, ~1.5-2
nM). Similar repression was obtained with low concentrations of other
highly specific phosphatase inhibitors, tautomycin and calyculin A. In
contrast, exposure of hepatocytes to 1-nor-okadaone or okadaol,
negative analogs of okadaic acid largely devoid of phosphatase
inhibitory activity, was without effect on the PB induction process. At
similar concentrations, okadaic acid produced only comparatively weak modulation of the 
-naphthoflavone-inducible CYP1A1 gene expression pathway. In additional experiments, hepatocytes were treated with suboptimal concentrations of PKA activators together with phosphatase inhibitors. Okadaic acid markedly potentiated the repressive effects of
dibutyryl-cAMP on the PB induction process. Together, these results
indicate that both PKA and protein phosphatase (PP1 and/or PP2A)
pathways exert potent and complementary control of the intracellular processes modulating the signaling of PB in cultured primary rat hepatocytes.
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