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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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 |
format | Article |
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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.</description><identifier>ISSN: 0378-4274</identifier><identifier>EISSN: 1879-3169</identifier><identifier>DOI: 10.1016/j.toxlet.2005.08.006</identifier><identifier>PMID: 16154717</identifier><identifier>CODEN: TOLED5</identifier><language>eng</language><publisher>Shannon: Elsevier Ireland Ltd</publisher><subject>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</subject><ispartof>Toxicology letters, 2006-02, Vol.161 (1), p.61-72</ispartof><rights>2005 Elsevier Ireland Ltd</rights><rights>2006 INIST-CNRS</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c370t-5dbc4aaee788192edfa3cdd435eb70228ed6b25c5176e261fb985cdff26764d13</citedby><cites>FETCH-LOGICAL-c370t-5dbc4aaee788192edfa3cdd435eb70228ed6b25c5176e261fb985cdff26764d13</cites><orcidid>0000-0002-2646-671X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.toxlet.2005.08.006$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,315,781,785,886,3551,27929,27930,46000</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17577534$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16154717$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-00699951$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Joannard, Florence</creatorcontrib><creatorcontrib>Rissel, Mary</creatorcontrib><creatorcontrib>Gilot, David</creatorcontrib><creatorcontrib>Anderson, Alan</creatorcontrib><creatorcontrib>Orfila-Lefeuvre, Luz</creatorcontrib><creatorcontrib>Guillouzo, André</creatorcontrib><creatorcontrib>Atfi, Azzedine</creatorcontrib><creatorcontrib>Lagadic-Gossmann, Dominique</creatorcontrib><title>Role for mitogen-activated protein kinases in phenobarbital-induced expression of cytochrome P450 2B in primary cultures of rat hepatocytes</title><title>Toxicology letters</title><addtitle>Toxicol Lett</addtitle><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.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Blotting, Northern</subject><subject>Butadienes</subject><subject>Butadienes - pharmacology</subject><subject>Cells, Cultured</subject><subject>Cytochrome P-450 CYP2B1</subject><subject>Cytochrome P-450 CYP2B1 - antagonists & inhibitors</subject><subject>Cytochrome P-450 CYP2B1 - biosynthesis</subject><subject>Cytochrome P-450 CYP2B1 - genetics</subject><subject>Cytochrome P450 2B</subject><subject>Dichlororibofuranosylbenzimidazole</subject><subject>Dichlororibofuranosylbenzimidazole - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Synergism</subject><subject>Enzyme Activation</subject><subject>Enzyme Activation - drug effects</subject><subject>Enzyme Inhibitors</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Gene Expression</subject><subject>Gene Expression - drug effects</subject><subject>Hepatocytes</subject><subject>Hepatocytes - cytology</subject><subject>Hepatocytes - drug effects</subject><subject>Hepatocytes - metabolism</subject><subject>Imidazoles</subject><subject>Imidazoles - pharmacology</subject><subject>Life Sciences</subject><subject>Liver</subject><subject>Luciferases, Firefly</subject><subject>Luciferases, Firefly - genetics</subject><subject>Luciferases, Firefly - metabolism</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mitogen-activated protein kinase</subject><subject>Mitogen-Activated Protein Kinase 3</subject><subject>Mitogen-Activated Protein Kinase 3 - genetics</subject><subject>Mitogen-Activated Protein Kinase 3 - metabolism</subject><subject>Mitogen-Activated Protein Kinases</subject><subject>Mitogen-Activated Protein Kinases - genetics</subject><subject>Mitogen-Activated Protein Kinases - metabolism</subject><subject>Mutation</subject><subject>Nitriles</subject><subject>Nitriles - pharmacology</subject><subject>p38</subject><subject>p38 Mitogen-Activated Protein Kinases</subject><subject>p38 Mitogen-Activated Protein Kinases - genetics</subject><subject>p38 Mitogen-Activated Protein Kinases - metabolism</subject><subject>Phenobarbital</subject><subject>Phenobarbital - pharmacology</subject><subject>Phosphorylation</subject><subject>Phosphorylation - drug effects</subject><subject>Pyridines</subject><subject>Pyridines - pharmacology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA, Messenger</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>SB-203580</subject><subject>Toxicology</subject><subject>Transfection</subject><issn>0378-4274</issn><issn>1879-3169</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp90UGL1DAUB_Agiju7-g1EclHw0JqkSdNehHVxXWFAET2HNHl1MnaaMUmHnc_glza1xb15Sgi_9_J4f4ReUFJSQuu3-zL5-wFSyQgRJWlKQupHaEMb2RYVrdvHaEMq2RScSX6BLmPckyx4LZ6iC1pTwSWVG_T7qx8A9z7gg0v-B4yFNsmddAKLj8EncCP-6UYdIeJ8Pe5g9J0OnUt6KNxoJ5Mh3B8DxOj8iH2PzTl5swv-APgLFwSz938rgzvocMZmGtKU9SyDTngHR539OUF8hp70eojwfD2v0PfbD99u7ort54-fbq63hakkSYWwneFaA8imoS0D2-vKWMsrAZ0kjDVg644JI6isgdW079pGGNv3rJY1t7S6Qm-Wvjs9qHUu5bVTd9dbNb_lPbVtK-hptq8Xm5fxa4KY1MFFA8OgR_BTVFQyRrgkGfIFmuBjDND_60yJmgNTe7UEpubAFGnmb3LZy7X_1B3APhStCWXwagU6Gj30QY_GxQcnhZSi4tm9WxzkzZ0cBBWNgzHH4wKYpKx3_5_kDzVHuGs</recordid><startdate>20060208</startdate><enddate>20060208</enddate><creator>Joannard, Florence</creator><creator>Rissel, Mary</creator><creator>Gilot, David</creator><creator>Anderson, Alan</creator><creator>Orfila-Lefeuvre, Luz</creator><creator>Guillouzo, André</creator><creator>Atfi, Azzedine</creator><creator>Lagadic-Gossmann, Dominique</creator><general>Elsevier Ireland Ltd</general><general>Elsevier Science</general><general>Elsevier</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7U7</scope><scope>C1K</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0002-2646-671X</orcidid></search><sort><creationdate>20060208</creationdate><title>Role for mitogen-activated protein kinases in phenobarbital-induced expression of cytochrome P450 2B in primary cultures of rat hepatocytes</title><author>Joannard, Florence ; Rissel, Mary ; Gilot, David ; Anderson, Alan ; Orfila-Lefeuvre, Luz ; Guillouzo, André ; Atfi, Azzedine ; Lagadic-Gossmann, Dominique</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c370t-5dbc4aaee788192edfa3cdd435eb70228ed6b25c5176e261fb985cdff26764d13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Blotting, Northern</topic><topic>Butadienes</topic><topic>Butadienes - pharmacology</topic><topic>Cells, Cultured</topic><topic>Cytochrome P-450 CYP2B1</topic><topic>Cytochrome P-450 CYP2B1 - antagonists & inhibitors</topic><topic>Cytochrome P-450 CYP2B1 - biosynthesis</topic><topic>Cytochrome P-450 CYP2B1 - genetics</topic><topic>Cytochrome P450 2B</topic><topic>Dichlororibofuranosylbenzimidazole</topic><topic>Dichlororibofuranosylbenzimidazole - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Synergism</topic><topic>Enzyme Activation</topic><topic>Enzyme Activation - drug effects</topic><topic>Enzyme Inhibitors</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Gene Expression</topic><topic>Gene Expression - drug effects</topic><topic>Hepatocytes</topic><topic>Hepatocytes - cytology</topic><topic>Hepatocytes - drug effects</topic><topic>Hepatocytes - metabolism</topic><topic>Imidazoles</topic><topic>Imidazoles - pharmacology</topic><topic>Life Sciences</topic><topic>Liver</topic><topic>Luciferases, Firefly</topic><topic>Luciferases, Firefly - genetics</topic><topic>Luciferases, Firefly - metabolism</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mitogen-activated protein kinase</topic><topic>Mitogen-Activated Protein Kinase 3</topic><topic>Mitogen-Activated Protein Kinase 3 - genetics</topic><topic>Mitogen-Activated Protein Kinase 3 - metabolism</topic><topic>Mitogen-Activated Protein Kinases</topic><topic>Mitogen-Activated Protein Kinases - genetics</topic><topic>Mitogen-Activated Protein Kinases - metabolism</topic><topic>Mutation</topic><topic>Nitriles</topic><topic>Nitriles - pharmacology</topic><topic>p38</topic><topic>p38 Mitogen-Activated Protein Kinases</topic><topic>p38 Mitogen-Activated Protein Kinases - genetics</topic><topic>p38 Mitogen-Activated Protein Kinases - metabolism</topic><topic>Phenobarbital</topic><topic>Phenobarbital - pharmacology</topic><topic>Phosphorylation</topic><topic>Phosphorylation - drug effects</topic><topic>Pyridines</topic><topic>Pyridines - pharmacology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA, Messenger</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Messenger - metabolism</topic><topic>SB-203580</topic><topic>Toxicology</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Joannard, Florence</creatorcontrib><creatorcontrib>Rissel, Mary</creatorcontrib><creatorcontrib>Gilot, David</creatorcontrib><creatorcontrib>Anderson, Alan</creatorcontrib><creatorcontrib>Orfila-Lefeuvre, Luz</creatorcontrib><creatorcontrib>Guillouzo, André</creatorcontrib><creatorcontrib>Atfi, Azzedine</creatorcontrib><creatorcontrib>Lagadic-Gossmann, Dominique</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>Toxicology letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Joannard, Florence</au><au>Rissel, Mary</au><au>Gilot, David</au><au>Anderson, Alan</au><au>Orfila-Lefeuvre, Luz</au><au>Guillouzo, André</au><au>Atfi, Azzedine</au><au>Lagadic-Gossmann, Dominique</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Role for mitogen-activated protein kinases in phenobarbital-induced expression of cytochrome P450 2B in primary cultures of rat hepatocytes</atitle><jtitle>Toxicology letters</jtitle><addtitle>Toxicol Lett</addtitle><date>2006-02-08</date><risdate>2006</risdate><volume>161</volume><issue>1</issue><spage>61</spage><epage>72</epage><pages>61-72</pages><issn>0378-4274</issn><eissn>1879-3169</eissn><coden>TOLED5</coden><abstract>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.</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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