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Nitric oxide and interleukin-1β stimulate the proteasome-independent degradation of the retinoic acid hydroxylase CYP2C22 in primary rat hepatocytes
CYP2C22 was recently described as a retinoic acid-metabolizing cytochrome P450 enzyme whose transcription is induced by all-trans-retinoic acid (atRA) in hepatoma cells (Qian L, Zolfaghari R, and Ross AC (2010) J Lipid Res 51:1781-1792). We identified CYP2C22 as a putative nitric oxide (NO)-regulate...
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| Published in: | The Journal of pharmacology and experimental therapeutics 2014-01, Vol.348 (1), p.141-152 |
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| cites | cdi_FETCH-LOGICAL-c323t-6de1b742d1e545b71f7b9c3a7c46e5c172ef9a95bfdd90f9e95df993477636af3 |
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| container_title | The Journal of pharmacology and experimental therapeutics |
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| creator | Lee, Choon-myung Lee, Bang-sub Arnold, Samuel L Isoherranen, Nina Morgan, Edward T |
| description | CYP2C22 was recently described as a retinoic acid-metabolizing cytochrome P450 enzyme whose transcription is induced by all-trans-retinoic acid (atRA) in hepatoma cells (Qian L, Zolfaghari R, and Ross AC (2010) J Lipid Res 51:1781-1792). We identified CYP2C22 as a putative nitric oxide (NO)-regulated protein in a proteomic screen and raised specific polyclonal antibodies to CYP2C22 to study its protein expression. We found that CYP2C22 is a liver-specific protein that was not significantly induced by activators of the pregnane X receptor, constitutive androstane receptor, or peroxisome proliferator-activated receptor-α, but was downregulated to |
| doi_str_mv | 10.1124/jpet.113.209841 |
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We identified CYP2C22 as a putative nitric oxide (NO)-regulated protein in a proteomic screen and raised specific polyclonal antibodies to CYP2C22 to study its protein expression. We found that CYP2C22 is a liver-specific protein that was not significantly induced by activators of the pregnane X receptor, constitutive androstane receptor, or peroxisome proliferator-activated receptor-α, but was downregulated to <25% of control by the aryl hydrocarbon receptor agonist β-naphthoflavone in cultured rat hepatocytes. CYP2C22 protein and its mRNA both were induced by atRA in hepatocytes, with EC50 of 100-300 nM, whereas the maximal extent of mRNA induction was twice that of the protein. CYP2C22 protein, but not its mRNA, was rapidly downregulated in hepatocytes by interleukin-1 (IL-1) or NO-donating compounds, and the downregulation by IL-1 was blocked by inhibition of NO synthases. The NO donor (Z)-1-[N-(3-aminopropyl)-N-(3-ammoniopropyl)amino]diazen-1-ium-1,2-diolate reduced the half-life of CYP2C22 from 8.7 to 3.4 hours in the presence of cycloheximide, demonstrating that NO-dependent downregulation is due to stimulated proteolysis. No intermediate degradation products were detected. However, this degradation was insensitive to inhibitors of calpains or the canonical proteasomal or lysosomal pathways, indicating that NO-dependent degradation of CYP2C22 proceeds via a novel pathway.</description><identifier>ISSN: 0022-3565</identifier><identifier>EISSN: 1521-0103</identifier><identifier>DOI: 10.1124/jpet.113.209841</identifier><identifier>PMID: 24144795</identifier><language>eng</language><publisher>United States: The American Society for Pharmacology and Experimental Therapeutics</publisher><subject>Amino Acid Sequence ; Animals ; Cytochrome P-450 Enzyme Inhibitors ; Cytochrome P-450 Enzyme System - genetics ; Down-Regulation - physiology ; HEK293 Cells ; Hepatocytes - drug effects ; Hepatocytes - enzymology ; Humans ; Interleukin-1beta - physiology ; Male ; Metabolism, Transport, and Pharmacogenomics ; Mixed Function Oxygenases - metabolism ; Molecular Sequence Data ; Nitric Oxide - physiology ; Nitric Oxide Donors - pharmacology ; Primary Cell Culture ; Proteasome Endopeptidase Complex - physiology ; Rats ; Rats, Inbred F344 ; Rats, Sprague-Dawley ; Tretinoin - metabolism</subject><ispartof>The Journal of pharmacology and experimental therapeutics, 2014-01, Vol.348 (1), p.141-152</ispartof><rights>Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c323t-6de1b742d1e545b71f7b9c3a7c46e5c172ef9a95bfdd90f9e95df993477636af3</citedby><cites>FETCH-LOGICAL-c323t-6de1b742d1e545b71f7b9c3a7c46e5c172ef9a95bfdd90f9e95df993477636af3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,777,781,882,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24144795$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lee, Choon-myung</creatorcontrib><creatorcontrib>Lee, Bang-sub</creatorcontrib><creatorcontrib>Arnold, Samuel L</creatorcontrib><creatorcontrib>Isoherranen, Nina</creatorcontrib><creatorcontrib>Morgan, Edward T</creatorcontrib><title>Nitric oxide and interleukin-1β stimulate the proteasome-independent degradation of the retinoic acid hydroxylase CYP2C22 in primary rat hepatocytes</title><title>The Journal of pharmacology and experimental therapeutics</title><addtitle>J Pharmacol Exp Ther</addtitle><description>CYP2C22 was recently described as a retinoic acid-metabolizing cytochrome P450 enzyme whose transcription is induced by all-trans-retinoic acid (atRA) in hepatoma cells (Qian L, Zolfaghari R, and Ross AC (2010) J Lipid Res 51:1781-1792). We identified CYP2C22 as a putative nitric oxide (NO)-regulated protein in a proteomic screen and raised specific polyclonal antibodies to CYP2C22 to study its protein expression. We found that CYP2C22 is a liver-specific protein that was not significantly induced by activators of the pregnane X receptor, constitutive androstane receptor, or peroxisome proliferator-activated receptor-α, but was downregulated to <25% of control by the aryl hydrocarbon receptor agonist β-naphthoflavone in cultured rat hepatocytes. CYP2C22 protein and its mRNA both were induced by atRA in hepatocytes, with EC50 of 100-300 nM, whereas the maximal extent of mRNA induction was twice that of the protein. CYP2C22 protein, but not its mRNA, was rapidly downregulated in hepatocytes by interleukin-1 (IL-1) or NO-donating compounds, and the downregulation by IL-1 was blocked by inhibition of NO synthases. The NO donor (Z)-1-[N-(3-aminopropyl)-N-(3-ammoniopropyl)amino]diazen-1-ium-1,2-diolate reduced the half-life of CYP2C22 from 8.7 to 3.4 hours in the presence of cycloheximide, demonstrating that NO-dependent downregulation is due to stimulated proteolysis. No intermediate degradation products were detected. However, this degradation was insensitive to inhibitors of calpains or the canonical proteasomal or lysosomal pathways, indicating that NO-dependent degradation of CYP2C22 proceeds via a novel pathway.</description><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Cytochrome P-450 Enzyme Inhibitors</subject><subject>Cytochrome P-450 Enzyme System - genetics</subject><subject>Down-Regulation - physiology</subject><subject>HEK293 Cells</subject><subject>Hepatocytes - drug effects</subject><subject>Hepatocytes - enzymology</subject><subject>Humans</subject><subject>Interleukin-1beta - physiology</subject><subject>Male</subject><subject>Metabolism, Transport, and Pharmacogenomics</subject><subject>Mixed Function Oxygenases - metabolism</subject><subject>Molecular Sequence Data</subject><subject>Nitric Oxide - physiology</subject><subject>Nitric Oxide Donors - pharmacology</subject><subject>Primary Cell Culture</subject><subject>Proteasome Endopeptidase Complex - physiology</subject><subject>Rats</subject><subject>Rats, Inbred F344</subject><subject>Rats, Sprague-Dawley</subject><subject>Tretinoin - metabolism</subject><issn>0022-3565</issn><issn>1521-0103</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><recordid>eNpVkU1uFDEQhS0EIpPAmh3ykk0n_u1ub5DQiJ9IEbCABSvLbZczDt3txnajzEG4CAfhTDjMEMHG9aR6_qpKD6FnlJxTysTFzQKlKn7OiOoFfYA2VDLaEEr4Q7QhhLGGy1aeoNOcbwihQrT8MTphoqpOyQ368T6UFCyOt8EBNrPDYS6QRli_hrmhv37iXMK0jqYALjvAS4oFTI4TNGF2sEB95oIdXCfjTAlxxtH_cSYoYY4VbWxweLd3Kd7uR5MBb798ZFvG6qSKC5NJe5xMwTtYTIl2XyA_QY-8GTM8PdYz9PnN60_bd83Vh7eX21dXjeWMl6Z1QIdOMEdBCjl01HeDstx0VrQgLe0YeGWUHLxzingFSjqvFBdd1_LWeH6GXh64yzpM4Gw9JZlRH7fS0QT9f2cOO30dv2vet33fkwp4cQSk-G2FXPQUsoVxNDPENWsqWsWoorKv1ouD1aaYcwJ_P4YSfRemvguzKq4PYdYfz__d7t7_Nz3-G0UUoOA</recordid><startdate>201401</startdate><enddate>201401</enddate><creator>Lee, Choon-myung</creator><creator>Lee, Bang-sub</creator><creator>Arnold, Samuel L</creator><creator>Isoherranen, Nina</creator><creator>Morgan, Edward T</creator><general>The American Society for Pharmacology and Experimental Therapeutics</general><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>7X8</scope><scope>5PM</scope></search><sort><creationdate>201401</creationdate><title>Nitric oxide and interleukin-1β stimulate the proteasome-independent degradation of the retinoic acid hydroxylase CYP2C22 in primary rat hepatocytes</title><author>Lee, Choon-myung ; Lee, Bang-sub ; Arnold, Samuel L ; Isoherranen, Nina ; Morgan, Edward T</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c323t-6de1b742d1e545b71f7b9c3a7c46e5c172ef9a95bfdd90f9e95df993477636af3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Cytochrome P-450 Enzyme Inhibitors</topic><topic>Cytochrome P-450 Enzyme System - genetics</topic><topic>Down-Regulation - physiology</topic><topic>HEK293 Cells</topic><topic>Hepatocytes - drug effects</topic><topic>Hepatocytes - enzymology</topic><topic>Humans</topic><topic>Interleukin-1beta - physiology</topic><topic>Male</topic><topic>Metabolism, Transport, and Pharmacogenomics</topic><topic>Mixed Function Oxygenases - metabolism</topic><topic>Molecular Sequence Data</topic><topic>Nitric Oxide - physiology</topic><topic>Nitric Oxide Donors - pharmacology</topic><topic>Primary Cell Culture</topic><topic>Proteasome Endopeptidase Complex - physiology</topic><topic>Rats</topic><topic>Rats, Inbred F344</topic><topic>Rats, Sprague-Dawley</topic><topic>Tretinoin - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lee, Choon-myung</creatorcontrib><creatorcontrib>Lee, Bang-sub</creatorcontrib><creatorcontrib>Arnold, Samuel L</creatorcontrib><creatorcontrib>Isoherranen, Nina</creatorcontrib><creatorcontrib>Morgan, Edward T</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of pharmacology and experimental therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lee, Choon-myung</au><au>Lee, Bang-sub</au><au>Arnold, Samuel L</au><au>Isoherranen, Nina</au><au>Morgan, Edward T</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nitric oxide and interleukin-1β stimulate the proteasome-independent degradation of the retinoic acid hydroxylase CYP2C22 in primary rat hepatocytes</atitle><jtitle>The Journal of pharmacology and experimental therapeutics</jtitle><addtitle>J Pharmacol Exp Ther</addtitle><date>2014-01</date><risdate>2014</risdate><volume>348</volume><issue>1</issue><spage>141</spage><epage>152</epage><pages>141-152</pages><issn>0022-3565</issn><eissn>1521-0103</eissn><abstract>CYP2C22 was recently described as a retinoic acid-metabolizing cytochrome P450 enzyme whose transcription is induced by all-trans-retinoic acid (atRA) in hepatoma cells (Qian L, Zolfaghari R, and Ross AC (2010) J Lipid Res 51:1781-1792). We identified CYP2C22 as a putative nitric oxide (NO)-regulated protein in a proteomic screen and raised specific polyclonal antibodies to CYP2C22 to study its protein expression. We found that CYP2C22 is a liver-specific protein that was not significantly induced by activators of the pregnane X receptor, constitutive androstane receptor, or peroxisome proliferator-activated receptor-α, but was downregulated to <25% of control by the aryl hydrocarbon receptor agonist β-naphthoflavone in cultured rat hepatocytes. CYP2C22 protein and its mRNA both were induced by atRA in hepatocytes, with EC50 of 100-300 nM, whereas the maximal extent of mRNA induction was twice that of the protein. CYP2C22 protein, but not its mRNA, was rapidly downregulated in hepatocytes by interleukin-1 (IL-1) or NO-donating compounds, and the downregulation by IL-1 was blocked by inhibition of NO synthases. 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| ispartof | The Journal of pharmacology and experimental therapeutics, 2014-01, Vol.348 (1), p.141-152 |
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| source | Freely Accessible Journals |
| subjects | Amino Acid Sequence Animals Cytochrome P-450 Enzyme Inhibitors Cytochrome P-450 Enzyme System - genetics Down-Regulation - physiology HEK293 Cells Hepatocytes - drug effects Hepatocytes - enzymology Humans Interleukin-1beta - physiology Male Metabolism, Transport, and Pharmacogenomics Mixed Function Oxygenases - metabolism Molecular Sequence Data Nitric Oxide - physiology Nitric Oxide Donors - pharmacology Primary Cell Culture Proteasome Endopeptidase Complex - physiology Rats Rats, Inbred F344 Rats, Sprague-Dawley Tretinoin - metabolism |
| title | Nitric oxide and interleukin-1β stimulate the proteasome-independent degradation of the retinoic acid hydroxylase CYP2C22 in primary rat hepatocytes |
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