Oxidative Hydrolysis of Scoparone by Cytochrome P450 CYP2C29 Reveals a Novel Metabolite
Regioselective 7-demethylation of scoparone is regularly employed as an indicator of phenobarbital-like induction of rat liver cytochrome P450 isoform CYP2B1, e.g., by the antiepileptic drug phenytoin. After induction with phenobarbital and phenytoin, a new reaction sequence catalyzed by Cyp2c29 was...
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| Veröffentlicht in: | Biochemical and biophysical research communications 2001-07, Vol.285 (1), p.32-39 |
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| creator | Meyer, Ralf Peter Hagemeyer, Christoph Eugen Knoth, Rolf Kurz, Gerhart Volk, Benedikt |
| description | Regioselective 7-demethylation of scoparone is regularly employed as an indicator of phenobarbital-like induction of rat liver cytochrome P450 isoform CYP2B1, e.g., by the antiepileptic drug phenytoin. After induction with phenobarbital and phenytoin, a new reaction sequence catalyzed by Cyp2c29 was identified in mouse liver microsomes. Cyp2c29-dependent 6-demethylation of scoparone resulted in the formation of isoscopoletin, an intermediate which is susceptible to further oxidation. This subsequent oxidation was also catalyzed by Cyp2c29 with a Km of 30,31 μM and a Vmax of 3,41 μM/min · μM P450, and resulted in the formation of the new metabolite 3-[4-methoxy-p-(3,6)-benzoquinone]-2-propenoate. This novel metabolite is the product of two consecutive oxidation reactions, proceeding over isoscopoletin to a putative lactone which is accessible to immediate hydrolysis, due to the onium character of the ring oxygen. This opening of the lactone ring corresponds to an oxidative hydrolysis. Differential oxidation of scoparone can be used as a sensitive indicator for distinguishing between different cytochrome P450 isoforms. |
| doi_str_mv | 10.1006/bbrc.2001.5111 |
| format | Article |
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After induction with phenobarbital and phenytoin, a new reaction sequence catalyzed by Cyp2c29 was identified in mouse liver microsomes. Cyp2c29-dependent 6-demethylation of scoparone resulted in the formation of isoscopoletin, an intermediate which is susceptible to further oxidation. This subsequent oxidation was also catalyzed by Cyp2c29 with a Km of 30,31 μM and a Vmax of 3,41 μM/min · μM P450, and resulted in the formation of the new metabolite 3-[4-methoxy-p-(3,6)-benzoquinone]-2-propenoate. This novel metabolite is the product of two consecutive oxidation reactions, proceeding over isoscopoletin to a putative lactone which is accessible to immediate hydrolysis, due to the onium character of the ring oxygen. This opening of the lactone ring corresponds to an oxidative hydrolysis. Differential oxidation of scoparone can be used as a sensitive indicator for distinguishing between different cytochrome P450 isoforms.</description><identifier>ISSN: 0006-291X</identifier><identifier>EISSN: 1090-2104</identifier><identifier>DOI: 10.1006/bbrc.2001.5111</identifier><identifier>PMID: 11437368</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Chromatography, High Pressure Liquid ; Coumarins - metabolism ; CYP2B1 ; Cyp2c29 ; Cytochrome P-450 Enzyme System - metabolism ; cytochrome P450 ; Cytochrome P450 Family 2 ; Electrophoresis, Polyacrylamide Gel ; Hydrolysis ; Kinetics ; liver ; Male ; Mice ; Mice, Inbred C57BL ; mouse ; Oxidation-Reduction ; oxidative hydrolysis ; Oxygenases - metabolism ; phenobarbital ; phenytoin ; Rats ; Rats, Sprague-Dawley ; scoparone</subject><ispartof>Biochemical and biophysical research communications, 2001-07, Vol.285 (1), p.32-39</ispartof><rights>2001 Academic Press</rights><rights>Copyright 2001 Academic Press.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c255t-6a4de8d5e7cae3a4a3607b5a3bfc21cba7f8bf97e5d19564989b88753de461f93</citedby><cites>FETCH-LOGICAL-c255t-6a4de8d5e7cae3a4a3607b5a3bfc21cba7f8bf97e5d19564989b88753de461f93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1006/bbrc.2001.5111$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,778,782,3539,27907,27908,45978</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11437368$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Meyer, Ralf Peter</creatorcontrib><creatorcontrib>Hagemeyer, Christoph Eugen</creatorcontrib><creatorcontrib>Knoth, Rolf</creatorcontrib><creatorcontrib>Kurz, Gerhart</creatorcontrib><creatorcontrib>Volk, Benedikt</creatorcontrib><title>Oxidative Hydrolysis of Scoparone by Cytochrome P450 CYP2C29 Reveals a Novel Metabolite</title><title>Biochemical and biophysical research communications</title><addtitle>Biochem Biophys Res Commun</addtitle><description>Regioselective 7-demethylation of scoparone is regularly employed as an indicator of phenobarbital-like induction of rat liver cytochrome P450 isoform CYP2B1, e.g., by the antiepileptic drug phenytoin. After induction with phenobarbital and phenytoin, a new reaction sequence catalyzed by Cyp2c29 was identified in mouse liver microsomes. Cyp2c29-dependent 6-demethylation of scoparone resulted in the formation of isoscopoletin, an intermediate which is susceptible to further oxidation. This subsequent oxidation was also catalyzed by Cyp2c29 with a Km of 30,31 μM and a Vmax of 3,41 μM/min · μM P450, and resulted in the formation of the new metabolite 3-[4-methoxy-p-(3,6)-benzoquinone]-2-propenoate. This novel metabolite is the product of two consecutive oxidation reactions, proceeding over isoscopoletin to a putative lactone which is accessible to immediate hydrolysis, due to the onium character of the ring oxygen. This opening of the lactone ring corresponds to an oxidative hydrolysis. Differential oxidation of scoparone can be used as a sensitive indicator for distinguishing between different cytochrome P450 isoforms.</description><subject>Animals</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Coumarins - metabolism</subject><subject>CYP2B1</subject><subject>Cyp2c29</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>cytochrome P450</subject><subject>Cytochrome P450 Family 2</subject><subject>Electrophoresis, Polyacrylamide Gel</subject><subject>Hydrolysis</subject><subject>Kinetics</subject><subject>liver</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>mouse</subject><subject>Oxidation-Reduction</subject><subject>oxidative hydrolysis</subject><subject>Oxygenases - metabolism</subject><subject>phenobarbital</subject><subject>phenytoin</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>scoparone</subject><issn>0006-291X</issn><issn>1090-2104</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kDtPwzAUhS0EoqWwMiJPbCl2YifxiCKgSIVWPARMlh83wiiti51W5N-TqpWYmM5wv3Ok-yF0TsmYEpJfaR3MOCWEjjml9AANKREkSSlhh2hIeiJJBX0foJMYv3qKslwco0GfWZHl5RC9zX6cVa3bAJ50Nvimiy5iX-Nn41cq-CVg3eGqa735DH4BeM44wdXHPK1SgZ9gA6qJWOFHv4EGP0CrtG9cC6foqO4vcLbPEXq9vXmpJsl0dndfXU8Tk3LeJrliFkrLoTAKMsVUlpNCc5Xp2qTUaFXUpa5FAdxSwXMmSqHLsuCZBZbTWmQjdLnbXQX_vYbYyoWLBppGLcGvoyyIyFPGsh4c70ATfIwBarkKbqFCJymRW5Vyq1JuVcqtyr5wsV9e6wXYP3zvrgfKHQD9fxsHQUbjYGnAugCmlda7_7Z_ASHwgbs</recordid><startdate>20010706</startdate><enddate>20010706</enddate><creator>Meyer, Ralf Peter</creator><creator>Hagemeyer, Christoph Eugen</creator><creator>Knoth, Rolf</creator><creator>Kurz, Gerhart</creator><creator>Volk, Benedikt</creator><general>Elsevier Inc</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></search><sort><creationdate>20010706</creationdate><title>Oxidative Hydrolysis of Scoparone by Cytochrome P450 CYP2C29 Reveals a Novel Metabolite</title><author>Meyer, Ralf Peter ; Hagemeyer, Christoph Eugen ; Knoth, Rolf ; Kurz, Gerhart ; Volk, Benedikt</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c255t-6a4de8d5e7cae3a4a3607b5a3bfc21cba7f8bf97e5d19564989b88753de461f93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Animals</topic><topic>Chromatography, High Pressure Liquid</topic><topic>Coumarins - metabolism</topic><topic>CYP2B1</topic><topic>Cyp2c29</topic><topic>Cytochrome P-450 Enzyme System - metabolism</topic><topic>cytochrome P450</topic><topic>Cytochrome P450 Family 2</topic><topic>Electrophoresis, Polyacrylamide Gel</topic><topic>Hydrolysis</topic><topic>Kinetics</topic><topic>liver</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>mouse</topic><topic>Oxidation-Reduction</topic><topic>oxidative hydrolysis</topic><topic>Oxygenases - metabolism</topic><topic>phenobarbital</topic><topic>phenytoin</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>scoparone</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Meyer, Ralf Peter</creatorcontrib><creatorcontrib>Hagemeyer, Christoph Eugen</creatorcontrib><creatorcontrib>Knoth, Rolf</creatorcontrib><creatorcontrib>Kurz, Gerhart</creatorcontrib><creatorcontrib>Volk, Benedikt</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><jtitle>Biochemical and biophysical research communications</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Meyer, Ralf Peter</au><au>Hagemeyer, Christoph Eugen</au><au>Knoth, Rolf</au><au>Kurz, Gerhart</au><au>Volk, Benedikt</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Oxidative Hydrolysis of Scoparone by Cytochrome P450 CYP2C29 Reveals a Novel Metabolite</atitle><jtitle>Biochemical and biophysical research communications</jtitle><addtitle>Biochem Biophys Res Commun</addtitle><date>2001-07-06</date><risdate>2001</risdate><volume>285</volume><issue>1</issue><spage>32</spage><epage>39</epage><pages>32-39</pages><issn>0006-291X</issn><eissn>1090-2104</eissn><abstract>Regioselective 7-demethylation of scoparone is regularly employed as an indicator of phenobarbital-like induction of rat liver cytochrome P450 isoform CYP2B1, e.g., by the antiepileptic drug phenytoin. After induction with phenobarbital and phenytoin, a new reaction sequence catalyzed by Cyp2c29 was identified in mouse liver microsomes. Cyp2c29-dependent 6-demethylation of scoparone resulted in the formation of isoscopoletin, an intermediate which is susceptible to further oxidation. This subsequent oxidation was also catalyzed by Cyp2c29 with a Km of 30,31 μM and a Vmax of 3,41 μM/min · μM P450, and resulted in the formation of the new metabolite 3-[4-methoxy-p-(3,6)-benzoquinone]-2-propenoate. This novel metabolite is the product of two consecutive oxidation reactions, proceeding over isoscopoletin to a putative lactone which is accessible to immediate hydrolysis, due to the onium character of the ring oxygen. This opening of the lactone ring corresponds to an oxidative hydrolysis. Differential oxidation of scoparone can be used as a sensitive indicator for distinguishing between different cytochrome P450 isoforms.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>11437368</pmid><doi>10.1006/bbrc.2001.5111</doi><tpages>8</tpages></addata></record> |
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| subjects | Animals Chromatography, High Pressure Liquid Coumarins - metabolism CYP2B1 Cyp2c29 Cytochrome P-450 Enzyme System - metabolism cytochrome P450 Cytochrome P450 Family 2 Electrophoresis, Polyacrylamide Gel Hydrolysis Kinetics liver Male Mice Mice, Inbred C57BL mouse Oxidation-Reduction oxidative hydrolysis Oxygenases - metabolism phenobarbital phenytoin Rats Rats, Sprague-Dawley scoparone |
| title | Oxidative Hydrolysis of Scoparone by Cytochrome P450 CYP2C29 Reveals a Novel Metabolite |
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