Identification of the Human P‐450 Enzymes Responsible for the Sulfoxidation and Thiono‐Oxidation of Diethyldithiocarbamate Methyl Ester: Role of P‐450 Enzymes in Disulfiram Bioactivation
Identifieur interne : 000E77 ( Main/Corpus ); précédent : 000E76; suivant : 000E78Identification of the Human P‐450 Enzymes Responsible for the Sulfoxidation and Thiono‐Oxidation of Diethyldithiocarbamate Methyl Ester: Role of P‐450 Enzymes in Disulfiram Bioactivation
Auteurs : Ajay Madan ; Andrew Parkinson ; Morris D. FaimanSource :
- Alcoholism: Clinical and Experimental Research [ 0145-6008 ] ; 1998-09.
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- KwdEn :
Abstract
Diethyldithiocarbamate methyl ester (DDTC‐Me) is a precursor to the formation of S‐methyl‐N,N‐diethyliolcarbamate sulfoxide, the active metabolite proposed to be responsible for the alcohol deterrent effects of disulfiram. The present study investigated the role of human cytochrome P‐450 (CYP) enzymes in sulfoxidation and thiono‐oxidation of DDTC‐Me, intermediary steps in the activation of disulfiram. Several approaches were used in an attempt to delineate the particular P‐450 enzyme(s) involved in the sulfoxidation and thiono‐oxidation of DDTC‐Me. These approaches included the use of cDNA‐expressed human P‐450 enzymes, correlation analysis with sample‐to‐sample variation in human P‐450 enzymes in a bank of human liver microsomes, and chemical and antibody inhibition studies. Multiple human P‐450 enzymes (CYP3A4, CYPlA2, CYP2A6, and CYP2D6) catalyzed the sulfoxidation of DDTC‐Me, as determined with cDNA‐expressed enzymes. Several lines of evidence suggest that the sulfoxidation of DDTC‐Me by human liver microsomes is primarily catalyzed by CYP3A4/5, including (1) a high correlation between DDTC‐Me sulfoxidation and testosterone 6β‐hydroxylation; (2) increased DDTC‐Me sulfoxidation in the presence of α‐naphthoflavone, an activator of CYP3A enzymes; (3) inhibition of this reaction by inhibitors of CYP3A4/5 enzymes, such as troleandomycin and ketoconazole; and (4) inhibition of DDTC‐Mesulfoxidation by antibodies against CYP3A enzymes. On the other hand, several lines of evidence suggested that the thiono‐oxidation of DDTC‐Me by human liver microsomes is catalyzed in part by CYPlA2, CYP266, CYPPEl, and CYP3A4/5, including (1) these human P450 enzymes among others have the capacity to catalyze this reaction, as determined with cDNA‐expressed enzymes; (2) a high correlation between DDTC‐Me thiono‐oxidation and testosterone 6β‐hydroxylation, weak inhibition by ketoconazole, troleandomycin, and anti‐CYP3A antibodies suggested a minor role for CYP3A4; (3) a high correlation with immunoreactive CYP2B6 suggested involvement of this enzyme; (4) weak inhibition of DDTC‐Me thiono‐oxidation by furafylline and anti‐CYPlA antibody suggested involvement of CYPlA2, and (5) inhibition of DDTC‐Me thiono‐oxidation by DDTC and anti‐CYP2E antibodies suggested a role for CYP2E1. Collectively, these data suggested CYP3A4/5 enzymes are the major contributors to the sulfoxidation of DDTC‐Me by human liver microsomes, and CYPlA2, CYP2B6, CYP2E1, and CYP3A4/5 contribute toward DDTC‐Me thiono‐oxidation by human liver microsomes. This study, in conjunction with others (Madan et al., Drug Metab. Dispos. 23:1153–1162, 1995), may help explain the variability in disulfiram's effectiveness as an alcohol deterrent.
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DOI: 10.1111/j.1530-0277.1998.tb03901.x
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<record><TEI wicri:istexFullTextTei="biblStruct"><teiHeader><fileDesc><titleStmt><title xml:lang="en">Identification of the Human P‐450 Enzymes Responsible for the Sulfoxidation and Thiono‐Oxidation of Diethyldithiocarbamate Methyl Ester: Role of P‐450 Enzymes in Disulfiram Bioactivation</title><author><name sortKey="Madan, Ajay" sort="Madan, Ajay" uniqKey="Madan A" first="Ajay" last="Madan">Ajay Madan</name><affiliation><mods:affiliation>Department of Pharmacology and Toxicology (A.M., M.D.F.), University of Kansas, Lawrence, Kansas; and the Department of Pharmacology, Toxicology and Therapeutics (A.P.), Center for Environmental and Occupational Health, University of Kansas Medical Center, Kansas City, Kansas.</mods:affiliation></affiliation></author><author><name sortKey="Parkinson, Andrew" sort="Parkinson, Andrew" uniqKey="Parkinson A" first="Andrew" last="Parkinson">Andrew Parkinson</name><affiliation><mods:affiliation>Department of Pharmacology and Toxicology (A.M., M.D.F.), University of Kansas, Lawrence, Kansas; and the Department of Pharmacology, Toxicology and Therapeutics (A.P.), Center for Environmental and Occupational Health, University of Kansas Medical Center, Kansas City, Kansas.</mods:affiliation></affiliation></author><author><name sortKey="Faiman, Morris D" sort="Faiman, Morris D" uniqKey="Faiman M" first="Morris D." last="Faiman">Morris D. Faiman</name><affiliation><mods:affiliation>Department of Pharmacology and Toxicology (A.M., M.D.F.), University of Kansas, Lawrence, Kansas; and the Department of Pharmacology, Toxicology and Therapeutics (A.P.), Center for Environmental and Occupational Health, University of Kansas Medical Center, Kansas City, Kansas.</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:AFB99194112CC8BA254EEC9E9DDAF16F4001E2E4</idno><date when="1998" year="1998">1998</date><idno type="doi">10.1111/j.1530-0277.1998.tb03901.x</idno><idno type="url">https://api.istex.fr/document/AFB99194112CC8BA254EEC9E9DDAF16F4001E2E4/fulltext/pdf</idno><idno type="wicri:Area/Main/Corpus">000E77</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Identification of the Human P‐450 Enzymes Responsible for the Sulfoxidation and Thiono‐Oxidation of Diethyldithiocarbamate Methyl Ester: Role of P‐450 Enzymes in Disulfiram Bioactivation</title><author><name sortKey="Madan, Ajay" sort="Madan, Ajay" uniqKey="Madan A" first="Ajay" last="Madan">Ajay Madan</name><affiliation><mods:affiliation>Department of Pharmacology and Toxicology (A.M., M.D.F.), University of Kansas, Lawrence, Kansas; and the Department of Pharmacology, Toxicology and Therapeutics (A.P.), Center for Environmental and Occupational Health, University of Kansas Medical Center, Kansas City, Kansas.</mods:affiliation></affiliation></author><author><name sortKey="Parkinson, Andrew" sort="Parkinson, Andrew" uniqKey="Parkinson A" first="Andrew" last="Parkinson">Andrew Parkinson</name><affiliation><mods:affiliation>Department of Pharmacology and Toxicology (A.M., M.D.F.), University of Kansas, Lawrence, Kansas; and the Department of Pharmacology, Toxicology and Therapeutics (A.P.), Center for Environmental and Occupational Health, University of Kansas Medical Center, Kansas City, Kansas.</mods:affiliation></affiliation></author><author><name sortKey="Faiman, Morris D" sort="Faiman, Morris D" uniqKey="Faiman M" first="Morris D." last="Faiman">Morris D. Faiman</name><affiliation><mods:affiliation>Department of Pharmacology and Toxicology (A.M., M.D.F.), University of Kansas, Lawrence, Kansas; and the Department of Pharmacology, Toxicology and Therapeutics (A.P.), Center for Environmental and Occupational Health, University of Kansas Medical Center, Kansas City, Kansas.</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Alcoholism: Clinical and Experimental Research</title><idno type="ISSN">0145-6008</idno><idno type="eISSN">1530-0277</idno><imprint><publisher>Blackwell Publishing Ltd</publisher><pubPlace>Oxford, UK</pubPlace><date type="published" when="1998-09">1998-09</date><biblScope unit="volume">22</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="1212">1212</biblScope><biblScope unit="page" to="1219">1219</biblScope></imprint><idno type="ISSN">0145-6008</idno></series><idno type="istex">AFB99194112CC8BA254EEC9E9DDAF16F4001E2E4</idno><idno type="DOI">10.1111/j.1530-0277.1998.tb03901.x</idno><idno type="ArticleID">ACER1212</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0145-6008</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Aldehyde Dehydrogenase</term><term>Cytochrome P‐450</term><term>Disulfiram</term><term>Dlethyldithiocarbamate Methyl Ester</term><term>S‐methyl‐N,N‐diethyiolcarbamate Sulfoxide</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Diethyldithiocarbamate methyl ester (DDTC‐Me) is a precursor to the formation of S‐methyl‐N,N‐diethyliolcarbamate sulfoxide, the active metabolite proposed to be responsible for the alcohol deterrent effects of disulfiram. The present study investigated the role of human cytochrome P‐450 (CYP) enzymes in sulfoxidation and thiono‐oxidation of DDTC‐Me, intermediary steps in the activation of disulfiram. Several approaches were used in an attempt to delineate the particular P‐450 enzyme(s) involved in the sulfoxidation and thiono‐oxidation of DDTC‐Me. These approaches included the use of cDNA‐expressed human P‐450 enzymes, correlation analysis with sample‐to‐sample variation in human P‐450 enzymes in a bank of human liver microsomes, and chemical and antibody inhibition studies. Multiple human P‐450 enzymes (CYP3A4, CYPlA2, CYP2A6, and CYP2D6) catalyzed the sulfoxidation of DDTC‐Me, as determined with cDNA‐expressed enzymes. Several lines of evidence suggest that the sulfoxidation of DDTC‐Me by human liver microsomes is primarily catalyzed by CYP3A4/5, including (1) a high correlation between DDTC‐Me sulfoxidation and testosterone 6β‐hydroxylation; (2) increased DDTC‐Me sulfoxidation in the presence of α‐naphthoflavone, an activator of CYP3A enzymes; (3) inhibition of this reaction by inhibitors of CYP3A4/5 enzymes, such as troleandomycin and ketoconazole; and (4) inhibition of DDTC‐Mesulfoxidation by antibodies against CYP3A enzymes. On the other hand, several lines of evidence suggested that the thiono‐oxidation of DDTC‐Me by human liver microsomes is catalyzed in part by CYPlA2, CYP266, CYPPEl, and CYP3A4/5, including (1) these human P450 enzymes among others have the capacity to catalyze this reaction, as determined with cDNA‐expressed enzymes; (2) a high correlation between DDTC‐Me thiono‐oxidation and testosterone 6β‐hydroxylation, weak inhibition by ketoconazole, troleandomycin, and anti‐CYP3A antibodies suggested a minor role for CYP3A4; (3) a high correlation with immunoreactive CYP2B6 suggested involvement of this enzyme; (4) weak inhibition of DDTC‐Me thiono‐oxidation by furafylline and anti‐CYPlA antibody suggested involvement of CYPlA2, and (5) inhibition of DDTC‐Me thiono‐oxidation by DDTC and anti‐CYP2E antibodies suggested a role for CYP2E1. Collectively, these data suggested CYP3A4/5 enzymes are the major contributors to the sulfoxidation of DDTC‐Me by human liver microsomes, and CYPlA2, CYP2B6, CYP2E1, and CYP3A4/5 contribute toward DDTC‐Me thiono‐oxidation by human liver microsomes. This study, in conjunction with others (Madan et al., Drug Metab. Dispos. 23:1153–1162, 1995), may help explain the variability in disulfiram's effectiveness as an alcohol deterrent.</div></front></TEI><istex><corpusName>wiley</corpusName><author><json:item><name>Ajay Madan</name><affiliations><json:string>Department of Pharmacology and Toxicology (A.M., M.D.F.), University of Kansas, Lawrence, Kansas; and the Department of Pharmacology, Toxicology and Therapeutics (A.P.), Center for Environmental and Occupational Health, University of Kansas Medical Center, Kansas City, Kansas.</json:string></affiliations></json:item><json:item><name>Andrew Parkinson</name><affiliations><json:string>Department of Pharmacology and Toxicology (A.M., M.D.F.), University of Kansas, Lawrence, Kansas; and the Department of Pharmacology, Toxicology and Therapeutics (A.P.), Center for Environmental and Occupational Health, University of Kansas Medical Center, Kansas City, Kansas.</json:string></affiliations></json:item><json:item><name>Morris D. Faiman</name><affiliations><json:string>Department of Pharmacology and Toxicology (A.M., M.D.F.), University of Kansas, Lawrence, Kansas; and the Department of Pharmacology, Toxicology and Therapeutics (A.P.), Center for Environmental and Occupational Health, University of Kansas Medical Center, Kansas City, Kansas.</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Disulfiram</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>S‐methyl‐N,N‐diethyiolcarbamate Sulfoxide</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Cytochrome P‐450</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Dlethyldithiocarbamate Methyl Ester</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Aldehyde Dehydrogenase</value></json:item></subject><articleId><json:string>ACER1212</json:string></articleId><language><json:string>eng</json:string></language><abstract>Diethyldithiocarbamate methyl ester (DDTC‐Me) is a precursor to the formation of S‐methyl‐N,N‐diethyliolcarbamate sulfoxide, the active metabolite proposed to be responsible for the alcohol deterrent effects of disulfiram. The present study investigated the role of human cytochrome P‐450 (CYP) enzymes in sulfoxidation and thiono‐oxidation of DDTC‐Me, intermediary steps in the activation of disulfiram. Several approaches were used in an attempt to delineate the particular P‐450 enzyme(s) involved in the sulfoxidation and thiono‐oxidation of DDTC‐Me. These approaches included the use of cDNA‐expressed human P‐450 enzymes, correlation analysis with sample‐to‐sample variation in human P‐450 enzymes in a bank of human liver microsomes, and chemical and antibody inhibition studies. Multiple human P‐450 enzymes (CYP3A4, CYPlA2, CYP2A6, and CYP2D6) catalyzed the sulfoxidation of DDTC‐Me, as determined with cDNA‐expressed enzymes. Several lines of evidence suggest that the sulfoxidation of DDTC‐Me by human liver microsomes is primarily catalyzed by CYP3A4/5, including (1) a high correlation between DDTC‐Me sulfoxidation and testosterone 6β‐hydroxylation; (2) increased DDTC‐Me sulfoxidation in the presence of α‐naphthoflavone, an activator of CYP3A enzymes; (3) inhibition of this reaction by inhibitors of CYP3A4/5 enzymes, such as troleandomycin and ketoconazole; and (4) inhibition of DDTC‐Mesulfoxidation by antibodies against CYP3A enzymes. On the other hand, several lines of evidence suggested that the thiono‐oxidation of DDTC‐Me by human liver microsomes is catalyzed in part by CYPlA2, CYP266, CYPPEl, and CYP3A4/5, including (1) these human P450 enzymes among others have the capacity to catalyze this reaction, as determined with cDNA‐expressed enzymes; (2) a high correlation between DDTC‐Me thiono‐oxidation and testosterone 6β‐hydroxylation, weak inhibition by ketoconazole, troleandomycin, and anti‐CYP3A antibodies suggested a minor role for CYP3A4; (3) a high correlation with immunoreactive CYP2B6 suggested involvement of this enzyme; (4) weak inhibition of DDTC‐Me thiono‐oxidation by furafylline and anti‐CYPlA antibody suggested involvement of CYPlA2, and (5) inhibition of DDTC‐Me thiono‐oxidation by DDTC and anti‐CYP2E antibodies suggested a role for CYP2E1. Collectively, these data suggested CYP3A4/5 enzymes are the major contributors to the sulfoxidation of DDTC‐Me by human liver microsomes, and CYPlA2, CYP2B6, CYP2E1, and CYP3A4/5 contribute toward DDTC‐Me thiono‐oxidation by human liver microsomes. This study, in conjunction with others (Madan et al., Drug Metab. Dispos. 23:1153–1162, 1995), may help explain the variability in disulfiram's effectiveness as an alcohol deterrent.</abstract><qualityIndicators><score>8.414</score><pdfVersion>1.4</pdfVersion><pdfPageSize>594 x 792 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>5</keywordCount><abstractCharCount>2726</abstractCharCount><pdfWordCount>4914</pdfWordCount><pdfCharCount>34176</pdfCharCount><pdfPageCount>8</pdfPageCount><abstractWordCount>367</abstractWordCount></qualityIndicators><title>Identification of the Human P‐450 Enzymes Responsible for the Sulfoxidation and Thiono‐Oxidation of Diethyldithiocarbamate Methyl Ester: Role of P‐450 Enzymes in Disulfiram Bioactivation</title><genre><json:string>article</json:string></genre><host><volume>22</volume><publisherId><json:string>ACER</json:string></publisherId><pages><total>8</total><last>1219</last><first>1212</first></pages><issn><json:string>0145-6008</json:string></issn><issue>6</issue><genre><json:string>Journal</json:string></genre><language><json:string>unknown</json:string></language><eissn><json:string>1530-0277</json:string></eissn><title>Alcoholism: Clinical and Experimental Research</title><doi><json:string>10.1111/(ISSN)1530-0277</json:string></doi></host><publicationDate>1998</publicationDate><copyrightDate>1998</copyrightDate><doi><json:string>10.1111/j.1530-0277.1998.tb03901.x</json:string></doi><id>AFB99194112CC8BA254EEC9E9DDAF16F4001E2E4</id><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/AFB99194112CC8BA254EEC9E9DDAF16F4001E2E4/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/AFB99194112CC8BA254EEC9E9DDAF16F4001E2E4/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/AFB99194112CC8BA254EEC9E9DDAF16F4001E2E4/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a" type="main" xml:lang="en">Identification of the Human P‐450 Enzymes Responsible for the Sulfoxidation and Thiono‐Oxidation of Diethyldithiocarbamate Methyl Ester: Role of P‐450 Enzymes in Disulfiram Bioactivation</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Blackwell Publishing Ltd</publisher><pubPlace>Oxford, UK</pubPlace><availability><p>WILEY</p></availability><date>1998</date></publicationStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Identification of the Human P‐450 Enzymes Responsible for the Sulfoxidation and Thiono‐Oxidation of Diethyldithiocarbamate Methyl Ester: Role of P‐450 Enzymes in Disulfiram Bioactivation</title><author><persName><forename type="first">Ajay</forename><surname>Madan</surname></persName><affiliation>Department of Pharmacology and Toxicology (A.M., M.D.F.), University of Kansas, Lawrence, Kansas; and the Department of Pharmacology, Toxicology and Therapeutics (A.P.), Center for Environmental and Occupational Health, University of Kansas Medical Center, Kansas City, Kansas.</affiliation></author><author><persName><forename type="first">Andrew</forename><surname>Parkinson</surname></persName><affiliation>Department of Pharmacology and Toxicology (A.M., M.D.F.), University of Kansas, Lawrence, Kansas; and the Department of Pharmacology, Toxicology and Therapeutics (A.P.), Center for Environmental and Occupational Health, University of Kansas Medical Center, Kansas City, Kansas.</affiliation></author><author><persName><forename type="first">Morris D.</forename><surname>Faiman</surname></persName><note type="correspondence"><p>Correspondence: Reprint requests: Morris D. Faiman, Ph.D., Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS‐66045.</p></note><affiliation>Department of Pharmacology and Toxicology (A.M., M.D.F.), University of Kansas, Lawrence, Kansas; and the Department of Pharmacology, Toxicology and Therapeutics (A.P.), Center for Environmental and Occupational Health, University of Kansas Medical Center, Kansas City, Kansas.</affiliation></author></analytic><monogr><title level="j">Alcoholism: Clinical and Experimental Research</title><idno type="pISSN">0145-6008</idno><idno type="eISSN">1530-0277</idno><idno type="DOI">10.1111/(ISSN)1530-0277</idno><imprint><publisher>Blackwell Publishing Ltd</publisher><pubPlace>Oxford, UK</pubPlace><date type="published" when="1998-09"></date><biblScope unit="volume">22</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="1212">1212</biblScope><biblScope unit="page" to="1219">1219</biblScope></imprint></monogr><idno type="istex">AFB99194112CC8BA254EEC9E9DDAF16F4001E2E4</idno><idno type="DOI">10.1111/j.1530-0277.1998.tb03901.x</idno><idno type="ArticleID">ACER1212</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>1998</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Diethyldithiocarbamate methyl ester (DDTC‐Me) is a precursor to the formation of S‐methyl‐N,N‐diethyliolcarbamate sulfoxide, the active metabolite proposed to be responsible for the alcohol deterrent effects of disulfiram. The present study investigated the role of human cytochrome P‐450 (CYP) enzymes in sulfoxidation and thiono‐oxidation of DDTC‐Me, intermediary steps in the activation of disulfiram. Several approaches were used in an attempt to delineate the particular P‐450 enzyme(s) involved in the sulfoxidation and thiono‐oxidation of DDTC‐Me. These approaches included the use of cDNA‐expressed human P‐450 enzymes, correlation analysis with sample‐to‐sample variation in human P‐450 enzymes in a bank of human liver microsomes, and chemical and antibody inhibition studies. Multiple human P‐450 enzymes (CYP3A4, CYPlA2, CYP2A6, and CYP2D6) catalyzed the sulfoxidation of DDTC‐Me, as determined with cDNA‐expressed enzymes. Several lines of evidence suggest that the sulfoxidation of DDTC‐Me by human liver microsomes is primarily catalyzed by CYP3A4/5, including (1) a high correlation between DDTC‐Me sulfoxidation and testosterone 6β‐hydroxylation; (2) increased DDTC‐Me sulfoxidation in the presence of α‐naphthoflavone, an activator of CYP3A enzymes; (3) inhibition of this reaction by inhibitors of CYP3A4/5 enzymes, such as troleandomycin and ketoconazole; and (4) inhibition of DDTC‐Mesulfoxidation by antibodies against CYP3A enzymes. On the other hand, several lines of evidence suggested that the thiono‐oxidation of DDTC‐Me by human liver microsomes is catalyzed in part by CYPlA2, CYP266, CYPPEl, and CYP3A4/5, including (1) these human P450 enzymes among others have the capacity to catalyze this reaction, as determined with cDNA‐expressed enzymes; (2) a high correlation between DDTC‐Me thiono‐oxidation and testosterone 6β‐hydroxylation, weak inhibition by ketoconazole, troleandomycin, and anti‐CYP3A antibodies suggested a minor role for CYP3A4; (3) a high correlation with immunoreactive CYP2B6 suggested involvement of this enzyme; (4) weak inhibition of DDTC‐Me thiono‐oxidation by furafylline and anti‐CYPlA antibody suggested involvement of CYPlA2, and (5) inhibition of DDTC‐Me thiono‐oxidation by DDTC and anti‐CYP2E antibodies suggested a role for CYP2E1. Collectively, these data suggested CYP3A4/5 enzymes are the major contributors to the sulfoxidation of DDTC‐Me by human liver microsomes, and CYPlA2, CYP2B6, CYP2E1, and CYP3A4/5 contribute toward DDTC‐Me thiono‐oxidation by human liver microsomes. This study, in conjunction with others (Madan et al., Drug Metab. Dispos. 23:1153–1162, 1995), may help explain the variability in disulfiram's effectiveness as an alcohol deterrent.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>Disulfiram</term></item><item><term>S‐methyl‐N,N‐diethyiolcarbamate Sulfoxide</term></item><item><term>Cytochrome P‐450</term></item><item><term>Dlethyldithiocarbamate Methyl Ester</term></item><item><term>Aldehyde Dehydrogenase</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="1998-09">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/AFB99194112CC8BA254EEC9E9DDAF16F4001E2E4/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Wiley, elements deleted: body"><istex:xmlDeclaration>version="1.0" encoding="UTF-8" standalone="yes"</istex:xmlDeclaration><istex:document><component version="2.0" type="serialArticle" xml:lang="en"><header><publicationMeta level="product"><publisherInfo><publisherName>Blackwell Publishing Ltd</publisherName><publisherLoc>Oxford, UK</publisherLoc></publisherInfo><doi origin="wiley" registered="yes">10.1111/(ISSN)1530-0277</doi><issn type="print">0145-6008</issn><issn type="electronic">1530-0277</issn><idGroup><id type="product" value="ACER"></id><id type="publisherDivision" value="ST"></id></idGroup><titleGroup><title type="main" sort="ALCOHOLISM CLINICAL EXPERIMENTAL RESEARCH">Alcoholism: Clinical and Experimental Research</title></titleGroup></publicationMeta><publicationMeta level="part" position="09006"><doi origin="wiley">10.1111/acer.1998.22.issue-6</doi><numberingGroup><numbering type="journalVolume" number="22">22</numbering><numbering type="journalIssue" number="6">6</numbering></numberingGroup><coverDate startDate="1998-09">September 1998</coverDate></publicationMeta><publicationMeta level="unit" type="article" position="0121200" status="forIssue"><doi origin="wiley">10.1111/j.1530-0277.1998.tb03901.x</doi><idGroup><id type="unit" value="ACER1212"></id></idGroup><countGroup><count type="pageTotal" number="8"></count></countGroup><titleGroup><title type="tocHeading1">PRECLINICAL</title></titleGroup><eventGroup><event type="firstOnline" date="2006-05-30"></event><event type="publishedOnlineFinalForm" date="2006-05-30"></event><event type="xmlConverted" agent="Converter:BPG_TO_WML3G version:2.3.5 mode:FullText source:HeaderRef result:HeaderRef" date="2010-04-07"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:3.8.8" date="2013-12-31"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-10-14"></event></eventGroup><numberingGroup><numbering type="pageFirst" number="1212">1212</numbering><numbering type="pageLast" number="1219">1219</numbering></numberingGroup><correspondenceTo>Reprint requests: Morris D. Faiman, Ph.D., Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS‐66045.</correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:ACER.ACER1212.pdf"></link></linkGroup></publicationMeta><contentMeta><unparsedEditorialHistory>Received for publication October 30, 1997; accepted March 31, 1998</unparsedEditorialHistory><countGroup><count type="referenceTotal" number="34"></count><count type="linksCrossRef" number="4"></count></countGroup><titleGroup><title type="main">Identification of the Human P‐450 Enzymes Responsible for the Sulfoxidation and Thiono‐Oxidation of Diethyldithiocarbamate Methyl Ester: Role of P‐450 Enzymes in Disulfiram Bioactivation</title></titleGroup><creators><creator creatorRole="author" xml:id="cr1" affiliationRef="#a1"><personName><givenNames>Ajay</givenNames><familyName>Madan</familyName></personName></creator><creator creatorRole="author" xml:id="cr2" affiliationRef="#a1"><personName><givenNames>Andrew</givenNames><familyName>Parkinson</familyName></personName></creator><creator creatorRole="author" xml:id="cr3" affiliationRef="#a1" corresponding="yes"><personName><givenNames>Morris D.</givenNames><familyName>Faiman</familyName></personName></creator></creators><affiliationGroup><affiliation xml:id="a1" countryCode="US"><unparsedAffiliation>Department of Pharmacology and Toxicology (A.M., M.D.F.), University of Kansas, Lawrence, Kansas; and the Department of Pharmacology, Toxicology and Therapeutics (A.P.), Center for Environmental and Occupational Health, University of Kansas Medical Center, Kansas City, Kansas.</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en"><keyword xml:id="k1">Disulfiram</keyword><keyword xml:id="k2"><i>S</i>‐methyl‐<i>N,N</i>‐diethyiolcarbamate Sulfoxide</keyword><keyword xml:id="k3">Cytochrome P‐450</keyword><keyword xml:id="k4">Dlethyldithiocarbamate Methyl Ester</keyword><keyword xml:id="k5">Aldehyde Dehydrogenase</keyword></keywordGroup><abstractGroup><abstract type="main" xml:lang="en"><p>Diethyldithiocarbamate methyl ester (DDTC‐Me) is a precursor to the formation of <i>S</i>‐methyl‐<i>N,N</i>‐diethyliolcarbamate sulfoxide, the active metabolite proposed to be responsible for the alcohol deterrent effects of disulfiram. The present study investigated the role of human cytochrome P‐450 (CYP) enzymes in sulfoxidation and thiono‐oxidation of DDTC‐Me, intermediary steps in the activation of disulfiram. Several approaches were used in an attempt to delineate the particular P‐450 enzyme(s) involved in the sulfoxidation and thiono‐oxidation of DDTC‐Me. These approaches included the use of cDNA‐expressed human P‐450 enzymes, correlation analysis with sample‐to‐sample variation in human P‐450 enzymes in a bank of human liver microsomes, and chemical and antibody inhibition studies. Multiple human P‐450 enzymes (CYP3A4, CYPlA2, CYP2A6, and CYP2D6) catalyzed the sulfoxidation of DDTC‐Me, as determined with cDNA‐expressed enzymes. Several lines of evidence suggest that the sulfoxidation of DDTC‐Me by human liver microsomes is primarily catalyzed by CYP3A4/5, including (1) a high correlation between DDTC‐Me sulfoxidation and testosterone 6β‐hydroxylation; (2) increased DDTC‐Me sulfoxidation in the presence of α‐naphthoflavone, an activator of CYP3A enzymes; (3) inhibition of this reaction by inhibitors of CYP3A4/5 enzymes, such as troleandomycin and ketoconazole; and (4) inhibition of DDTC‐Mesulfoxidation by antibodies against CYP3A enzymes. On the other hand, several lines of evidence suggested that the thiono‐oxidation of DDTC‐Me by human liver microsomes is catalyzed in part by CYPlA2, CYP266, CYPPEl, and CYP3A4/5, including (1) these human P450 enzymes among others have the capacity to catalyze this reaction, as determined with cDNA‐expressed enzymes; (2) a high correlation between DDTC‐Me thiono‐oxidation and testosterone 6β‐hydroxylation, weak inhibition by ketoconazole, troleandomycin, and anti‐CYP3A antibodies suggested a minor role for CYP3A4; (3) a high correlation with immunoreactive CYP2B6 suggested involvement of this enzyme; (4) weak inhibition of DDTC‐Me thiono‐oxidation by furafylline and anti‐CYPlA antibody suggested involvement of CYPlA2, and (5) inhibition of DDTC‐Me thiono‐oxidation by DDTC and anti‐CYP2E antibodies suggested a role for CYP2E1. Collectively, these data suggested CYP3A4/5 enzymes are the major contributors to the sulfoxidation of DDTC‐Me by human liver microsomes, and CYPlA2, CYP2B6, CYP2E1, and CYP3A4/5 contribute toward DDTC‐Me thiono‐oxidation by human liver microsomes. This study, in conjunction with others (Madan et al., <i>Drug Metab. Dispos.</i> 23:1153–1162, 1995), may help explain the variability in disulfiram's effectiveness as an alcohol deterrent.</p></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="n-fnt-1" numbered="no"><p>This work was funded in part by the National Institute of Alcohol Abuse and Alcoholism (Grant AA03577) and by the National Institute of Environmental Health and Sciences (Grant ES03765). A preliminary account of this work was presented at the 1994 annual meeting of the Society of Toxicology in Dallas, TX.</p></note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Identification of the Human P‐450 Enzymes Responsible for the Sulfoxidation and Thiono‐Oxidation of Diethyldithiocarbamate Methyl Ester: Role of P‐450 Enzymes in Disulfiram Bioactivation</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Identification of the Human P‐450 Enzymes Responsible for the Sulfoxidation and Thiono‐Oxidation of Diethyldithiocarbamate Methyl Ester: Role of P‐450 Enzymes in Disulfiram Bioactivation</title></titleInfo><name type="personal"><namePart type="given">Ajay</namePart><namePart type="family">Madan</namePart><affiliation>Department of Pharmacology and Toxicology (A.M., M.D.F.), University of Kansas, Lawrence, Kansas; and the Department of Pharmacology, Toxicology and Therapeutics (A.P.), Center for Environmental and Occupational Health, University of Kansas Medical Center, Kansas City, Kansas.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Andrew</namePart><namePart type="family">Parkinson</namePart><affiliation>Department of Pharmacology and Toxicology (A.M., M.D.F.), University of Kansas, Lawrence, Kansas; and the Department of Pharmacology, Toxicology and Therapeutics (A.P.), Center for Environmental and Occupational Health, University of Kansas Medical Center, Kansas City, Kansas.</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Morris D.</namePart><namePart type="family">Faiman</namePart><affiliation>Department of Pharmacology and Toxicology (A.M., M.D.F.), University of Kansas, Lawrence, Kansas; and the Department of Pharmacology, Toxicology and Therapeutics (A.P.), Center for Environmental and Occupational Health, University of Kansas Medical Center, Kansas City, Kansas.</affiliation><description>Correspondence: Reprint requests: Morris D. Faiman, Ph.D., Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS‐66045.</description><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article"></genre><originInfo><publisher>Blackwell Publishing Ltd</publisher><place><placeTerm type="text">Oxford, UK</placeTerm></place><dateIssued encoding="w3cdtf">1998-09</dateIssued><edition>Received for publication October 30, 1997; accepted March 31, 1998</edition><copyrightDate encoding="w3cdtf">1998</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType><extent unit="references">34</extent></physicalDescription><abstract lang="en">Diethyldithiocarbamate methyl ester (DDTC‐Me) is a precursor to the formation of S‐methyl‐N,N‐diethyliolcarbamate sulfoxide, the active metabolite proposed to be responsible for the alcohol deterrent effects of disulfiram. The present study investigated the role of human cytochrome P‐450 (CYP) enzymes in sulfoxidation and thiono‐oxidation of DDTC‐Me, intermediary steps in the activation of disulfiram. Several approaches were used in an attempt to delineate the particular P‐450 enzyme(s) involved in the sulfoxidation and thiono‐oxidation of DDTC‐Me. These approaches included the use of cDNA‐expressed human P‐450 enzymes, correlation analysis with sample‐to‐sample variation in human P‐450 enzymes in a bank of human liver microsomes, and chemical and antibody inhibition studies. Multiple human P‐450 enzymes (CYP3A4, CYPlA2, CYP2A6, and CYP2D6) catalyzed the sulfoxidation of DDTC‐Me, as determined with cDNA‐expressed enzymes. Several lines of evidence suggest that the sulfoxidation of DDTC‐Me by human liver microsomes is primarily catalyzed by CYP3A4/5, including (1) a high correlation between DDTC‐Me sulfoxidation and testosterone 6β‐hydroxylation; (2) increased DDTC‐Me sulfoxidation in the presence of α‐naphthoflavone, an activator of CYP3A enzymes; (3) inhibition of this reaction by inhibitors of CYP3A4/5 enzymes, such as troleandomycin and ketoconazole; and (4) inhibition of DDTC‐Mesulfoxidation by antibodies against CYP3A enzymes. On the other hand, several lines of evidence suggested that the thiono‐oxidation of DDTC‐Me by human liver microsomes is catalyzed in part by CYPlA2, CYP266, CYPPEl, and CYP3A4/5, including (1) these human P450 enzymes among others have the capacity to catalyze this reaction, as determined with cDNA‐expressed enzymes; (2) a high correlation between DDTC‐Me thiono‐oxidation and testosterone 6β‐hydroxylation, weak inhibition by ketoconazole, troleandomycin, and anti‐CYP3A antibodies suggested a minor role for CYP3A4; (3) a high correlation with immunoreactive CYP2B6 suggested involvement of this enzyme; (4) weak inhibition of DDTC‐Me thiono‐oxidation by furafylline and anti‐CYPlA antibody suggested involvement of CYPlA2, and (5) inhibition of DDTC‐Me thiono‐oxidation by DDTC and anti‐CYP2E antibodies suggested a role for CYP2E1. Collectively, these data suggested CYP3A4/5 enzymes are the major contributors to the sulfoxidation of DDTC‐Me by human liver microsomes, and CYPlA2, CYP2B6, CYP2E1, and CYP3A4/5 contribute toward DDTC‐Me thiono‐oxidation by human liver microsomes. This study, in conjunction with others (Madan et al., Drug Metab. Dispos. 23:1153–1162, 1995), may help explain the variability in disulfiram's effectiveness as an alcohol deterrent.</abstract><subject lang="en"><genre>Keywords</genre><topic>Disulfiram</topic><topic>S‐methyl‐N,N‐diethyiolcarbamate Sulfoxide</topic><topic>Cytochrome P‐450</topic><topic>Dlethyldithiocarbamate Methyl Ester</topic><topic>Aldehyde Dehydrogenase</topic></subject><relatedItem type="host"><titleInfo><title>Alcoholism: Clinical and Experimental Research</title></titleInfo><genre type="Journal">journal</genre><identifier type="ISSN">0145-6008</identifier><identifier type="eISSN">1530-0277</identifier><identifier type="DOI">10.1111/(ISSN)1530-0277</identifier><identifier type="PublisherID">ACER</identifier><part><date>1998</date><detail type="volume"><caption>vol.</caption><number>22</number></detail><detail type="issue"><caption>no.</caption><number>6</number></detail><extent unit="pages"><start>1212</start><end>1219</end><total>8</total></extent></part></relatedItem><identifier type="istex">AFB99194112CC8BA254EEC9E9DDAF16F4001E2E4</identifier><identifier type="DOI">10.1111/j.1530-0277.1998.tb03901.x</identifier><identifier type="ArticleID">ACER1212</identifier><recordInfo><recordContentSource>WILEY</recordContentSource><recordOrigin>Blackwell Publishing Ltd</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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