Role for mitogen-activated protein kinases in phenobarbital-induced expression of cytochrome P450 2B in primary cultures of rat hepatocytes

Phenobarbital (PB) alters expression of numerous hepatic genes, including genes of cytochrome P450 2B1 and 2B2 (CYP2B). However, the intracellular mechanisms remain to be fully elucidated. The present study investigated the involvement of mitogen-activated protein kinases (MAPKs) in rat hepatocytes...

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Veröffentlicht in:Toxicology letters 2006-02, Vol.161 (1), p.61-72
Hauptverfasser: Joannard, Florence, Rissel, Mary, Gilot, David, Anderson, Alan, Orfila-Lefeuvre, Luz, Guillouzo, André, Atfi, Azzedine, Lagadic-Gossmann, Dominique
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container_end_page 72
container_issue 1
container_start_page 61
container_title Toxicology letters
container_volume 161
creator Joannard, Florence
Rissel, Mary
Gilot, David
Anderson, Alan
Orfila-Lefeuvre, Luz
Guillouzo, André
Atfi, Azzedine
Lagadic-Gossmann, Dominique
description Phenobarbital (PB) alters expression of numerous hepatic genes, including genes of cytochrome P450 2B1 and 2B2 (CYP2B). However, the intracellular mechanisms remain to be fully elucidated. The present study investigated the involvement of mitogen-activated protein kinases (MAPKs) in rat hepatocytes in primary culture. We showed that PB induced an early, dose-dependent activation of ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase) and p38 MAPKs. Regarding the PB (1 mM) induction of CYP2B mRNA expression, while chemically inhibiting JNK had no effect, specific inhibitors of the ERK (U0-126) and p38 (SB-203580) pathways up- and down-regulated this expression, respectively. However, although such a regulation was confirmed when testing the effect of a dominant negative mutant of the ERK pathway on the CYP2B2 enhancer-promoter activity, no such transcriptional role was found with the p38 pathway. Moreover, upon arrest of transcription, the stability of CYP2B mRNA remained unaffected by SB-203580. In conclusion, we show that the ERK pathway negatively regulates CYP2B2 enhancer-promoter activity and that, despite p38 activation upon PB exposure, the sensitivity of CYP2B mRNA expression to SB-203580 appears to be unrelated to this kinase.
doi_str_mv 10.1016/j.toxlet.2005.08.006
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In conclusion, we show that the ERK pathway negatively regulates CYP2B2 enhancer-promoter activity and that, despite p38 activation upon PB exposure, the sensitivity of CYP2B mRNA expression to SB-203580 appears to be unrelated to this kinase.</abstract><cop>Shannon</cop><cop>Amsterdam</cop><pub>Elsevier Ireland Ltd</pub><pmid>16154717</pmid><doi>10.1016/j.toxlet.2005.08.006</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-2646-671X</orcidid></addata></record>
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subjects Animals
Biological and medical sciences
Blotting, Northern
Butadienes
Butadienes - pharmacology
Cells, Cultured
Cytochrome P-450 CYP2B1
Cytochrome P-450 CYP2B1 - antagonists & inhibitors
Cytochrome P-450 CYP2B1 - biosynthesis
Cytochrome P-450 CYP2B1 - genetics
Cytochrome P450 2B
Dichlororibofuranosylbenzimidazole
Dichlororibofuranosylbenzimidazole - pharmacology
Dose-Response Relationship, Drug
Drug Synergism
Enzyme Activation
Enzyme Activation - drug effects
Enzyme Inhibitors
Enzyme Inhibitors - pharmacology
Gene Expression
Gene Expression - drug effects
Hepatocytes
Hepatocytes - cytology
Hepatocytes - drug effects
Hepatocytes - metabolism
Imidazoles
Imidazoles - pharmacology
Life Sciences
Liver
Luciferases, Firefly
Luciferases, Firefly - genetics
Luciferases, Firefly - metabolism
Male
Medical sciences
Mitogen-activated protein kinase
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 3 - genetics
Mitogen-Activated Protein Kinase 3 - metabolism
Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinases - genetics
Mitogen-Activated Protein Kinases - metabolism
Mutation
Nitriles
Nitriles - pharmacology
p38
p38 Mitogen-Activated Protein Kinases
p38 Mitogen-Activated Protein Kinases - genetics
p38 Mitogen-Activated Protein Kinases - metabolism
Phenobarbital
Phenobarbital - pharmacology
Phosphorylation
Phosphorylation - drug effects
Pyridines
Pyridines - pharmacology
Rats
Rats, Sprague-Dawley
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger
RNA, Messenger - genetics
RNA, Messenger - metabolism
SB-203580
Toxicology
Transfection
title Role for mitogen-activated protein kinases in phenobarbital-induced expression of cytochrome P450 2B in primary cultures of rat hepatocytes
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