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The effects of elevated intracellular cyclic adenosine
monophosphate (cAMP) in regulating phenobarbital (PB)-inducible gene
expression in primary rat hepatocyte cultures were investigated. Cells
were exposed to various concentrations (0.1-100 µM)
of cAMP analogs and/or activators of intracellular cAMP-dependent
pathways. Effects of these treatments were assessed either using a 1-h
pulse prior to PB (100 µM) exposure or in conjunction with
PB during a 24-h exposure period. PB-inducible responses were measured
in hepatocytes by hybridization to cytochrome P450 (CYP) CYP2B1,
CYP2B2, and CYP3A1 mRNAs. The cAMP analogs, 8-bromo-cAMP,
8-(4-chlorophenylthio)-cAMP, dibutyryl cAMP,and
(S
Volume 270,
Number 21,
Issue of May 26, pp. 12762-12773, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
)-5,6-DCl-cBiMPS
((S)-5,6-dichloro-1-
-D-ribofuranosylbenzimidazole
- 3 ` ,5 ` - monophosphorothioate), and the activators of
adenylate cyclase, forskolin and glucagon, dramatically inhibited
PB-mediated induction of CYP2B1 and CYP2B2 in a concentration-dependent
manner. A similar inhibition of PB-induced CYP3A1 mRNA levels was
effected by the cAMP analogs and glucagon. The phosphodiesterase
inhibitors isobutylmethylxanthine and RO 201724 potentiated the cAMP
responses. Increasing the concentration of PB (0.05-1.00
mM) did not alleviate the cAMP-mediated repression. A
requirement for protein kinase A (PKA) was demonstrated by the use of
(S)-cAMPS, a highly specific activator of PKA,
whereas the inactive diastereoisomer, (R)-cAMPS,
was ineffective in modulating PB induction. The response to cAMP was
specific since elevated intracellular cAMP levels did not perturb
-naphtholflavone-mediated induction of CYP1A1, CYP1A2, microsomal
epoxide hydrolase, or dexamethasone-mediated induction of CYP3A1 gene
expression. Nor did elevated intracellular cAMP modulate the
liver-selective albumin gene expression levels. The results of the
present study demonstrated striking inhibition of PB-mediated CYP gene
induction by cAMP and PKA activators, indicating a negative regulatory
role for the cAMP signal transduction pathway on PB gene induction.
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