Using a primary hepatocyte culture in which the mouse Cyp2b10 gene transcription is activated by phenobarbital (PB)-type inducers, we examined the cellular signalling mechanisms associated with PB induction. Low nanomolar concentrations of protein serine/threonine phosphatase inhibitors okadaic acid (OA) and calyculin A blocked the induction of CYP2B10 mRNA. Nuclear run-on assays indicated that OA suppressed Cyp2b10 gene transcription. Pretreatment of the cells with an inhibitor of Ca2+/calmodulin-dependent protein kinases {1-[N,O-bis-(5-isoquinolinesulphonyl)-N-methyl-l-tyrosyl]-4-phenylpiperazine (KN-62)} or with a flavonoid, naringin, were completely or partly protective respectively against the OA-mediated suppression of CYP2B10 mRNA. Several other established modulators of protein kinase activities did not greatly affect the induction of CYP2B10 mRNA, nor could they prevent the suppressive effect of OA. Our results indicate that specific protein phosphorylation-dephosphorylation is required for the induction of Cyp2b10 gene expression, which is modulated through multiple endogenous and exogenous signals.
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March 1998
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Research Article|
March 01 1998
Protein serine/threonine phosphatase inhibitors suppress phenobarbital-induced Cyp2b10 gene transcription in mouse primary hepatocytes Available to Purchase
Paavo HONKAKOSKI;
Paavo HONKAKOSKI
1
*Department of Pharmaceutics, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland
†Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, NIEHS, National Institutes of Health, P.O. Box 12233, Research Triangle Park, NC 27709, U.S.A.
1To whom correspondence should be addressed.
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Masahiko NEGISHI
Masahiko NEGISHI
†Pharmacogenetics Section, Laboratory of Reproductive and Developmental Toxicology, NIEHS, National Institutes of Health, P.O. Box 12233, Research Triangle Park, NC 27709, U.S.A.
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Publisher: Portland Press Ltd
Received:
September 22 1997
Revision Received:
October 29 1997
Accepted:
November 20 1997
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 1998
1998
Biochem J (1998) 330 (2): 889–895.
Article history
Received:
September 22 1997
Revision Received:
October 29 1997
Accepted:
November 20 1997
Citation
Paavo HONKAKOSKI, Masahiko NEGISHI; Protein serine/threonine phosphatase inhibitors suppress phenobarbital-induced Cyp2b10 gene transcription in mouse primary hepatocytes. Biochem J 1 March 1998; 330 (2): 889–895. doi: https://doi.org/10.1042/bj3300889
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