Cyanamide-mediated Inhibition of N-acetyltransferase 1.
Identifieur interne : 000475 ( PubMed/Checkpoint ); précédent : 000474; suivant : 000476Cyanamide-mediated Inhibition of N-acetyltransferase 1.
Auteurs : Dorothea Dierolf [Allemagne] ; Simone Scheitza ; Jutta Bonifas ; Brunhilde BlömekeSource :
- Toxicology [ 1879-3185 ] ; 2012.
English descriptors
- KwdEn :
- 4-Aminobenzoic Acid (metabolism), Acetylation, Arylamine N-Acetyltransferase (antagonists & inhibitors), Arylamine N-Acetyltransferase (drug effects), Arylamine N-Acetyltransferase (metabolism), Cell Line, Tumor, Coenzyme A (metabolism), Cyanamide (administration & dosage), Cyanamide (metabolism), Cyanamide (pharmacology), Cytosol (metabolism), Dithiothreitol (pharmacology), Dose-Response Relationship, Drug, Humans, Isoenzymes (antagonists & inhibitors), Liver (metabolism), Monocytes (drug effects), Monocytes (metabolism), Time Factors.
- MESH :
- chemical , administration & dosage : Cyanamide.
- chemical , antagonists & inhibitors : Arylamine N-Acetyltransferase, Isoenzymes.
- chemical , drug effects : Arylamine N-Acetyltransferase.
- chemical , metabolism : 4-Aminobenzoic Acid, Arylamine N-Acetyltransferase, Coenzyme A, Cyanamide.
- chemical , pharmacology : Cyanamide, Dithiothreitol.
- drug effects : Monocytes.
- metabolism : Cytosol, Liver, Monocytes.
- Acetylation, Cell Line, Tumor, Dose-Response Relationship, Drug, Humans, Time Factors.
Abstract
Cyanamide has been used for decades for medical intentions in the treatment of alcoholism and for agricultural purposes as a plant growth regulator and bud-breaking agent. Its therapeutic effect is mediated by reversible inhibition of aldehyde dehydrogenase and it was reported to be metabolized in vivo mainly via coenzyme A dependent N-acetylation by N-acetyltransferases. Although described to be a substrate for N-acetyltransferases (NATs), cyanamide has a different molecular structure to arylamines and hydrazines, the preferred substrates for N-acetyltransferases. Therefore, a more detailed investigation of its interrelations with N-acetyltransferases was performed. We analyzed the impact of cyanamide on NAT1 activities of human monocytes (monocytic THP-1 cells) using the classical substrate p-aminobenzoic acid. We found that a 24h treatment with physiologically relevant concentrations of cyanamide decreased the NAT1 activity significantly. Based on this observation we performed additional experiments using recombinant human NAT1 and NAT2 to achieve further insights. In detail a significant dose- and time-dependent inhibition of NAT1 activity was observed for 100 and 1000μM cyanamide using recombinant human NAT1*4. However, cyanamide did not inhibit recombinant NAT2*4. Experiments testing cyanamide as substrate did not provide evidence that cyanamide is metabolized via coenzyme A dependent N-acetylation in vitro by human NAT1 or NAT2, THP-1 or human liver cytosol. Therefore we can conclude that the observed enzyme inhibition (around 50% and 25% after treatment with 0.5 and 0.25mM CA, respectively) is not based on substrate-dependent down-regulation of NAT1. Further mechanistic and kinetic studies indicated that cyanamide reacts with the active site cysteine residue of NAT1, leading to its rapid inhibition (significant inhibition after 30min and 2h for 1000 and 100μM CA, respectively). Addition of the reduction agent dithiothreitol (DTT) did not modify the effect, indicating that oxidative processes that can be reversed by 5mM DTT are not likely involved in the inhibition. Taken together our results show that cyanamide is able to inhibit NAT1 most likely via interaction with the active site cysteine residue. Thereby cyanamide might modulate NAT1 dependent detoxification and activation of arylamines.
DOI: 10.1016/j.tox.2012.06.019
PubMed: 22835378
Affiliations:
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first="Simone" last="Scheitza">Simone Scheitza</name></author><author><name sortKey="Bonifas, Jutta" sort="Bonifas, Jutta" uniqKey="Bonifas J" first="Jutta" last="Bonifas">Jutta Bonifas</name></author><author><name sortKey="Blomeke, Brunhilde" sort="Blomeke, Brunhilde" uniqKey="Blomeke B" first="Brunhilde" last="Blömeke">Brunhilde Blömeke</name></author></analytic><series><title level="j">Toxicology</title><idno type="eISSN">1879-3185</idno><imprint><date when="2012" type="published">2012</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>4-Aminobenzoic Acid (metabolism)</term><term>Acetylation</term><term>Arylamine N-Acetyltransferase (antagonists & inhibitors)</term><term>Arylamine N-Acetyltransferase (drug effects)</term><term>Arylamine N-Acetyltransferase (metabolism)</term><term>Cell Line, Tumor</term><term>Coenzyme A (metabolism)</term><term>Cyanamide (administration & dosage)</term><term>Cyanamide (metabolism)</term><term>Cyanamide (pharmacology)</term><term>Cytosol (metabolism)</term><term>Dithiothreitol (pharmacology)</term><term>Dose-Response Relationship, Drug</term><term>Humans</term><term>Isoenzymes (antagonists & inhibitors)</term><term>Liver (metabolism)</term><term>Monocytes (drug effects)</term><term>Monocytes (metabolism)</term><term>Time Factors</term></keywords><keywords scheme="MESH" type="chemical" qualifier="administration & dosage" xml:lang="en"><term>Cyanamide</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Arylamine N-Acetyltransferase</term><term>Isoenzymes</term></keywords><keywords scheme="MESH" type="chemical" qualifier="drug effects" xml:lang="en"><term>Arylamine N-Acetyltransferase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>4-Aminobenzoic Acid</term><term>Arylamine N-Acetyltransferase</term><term>Coenzyme A</term><term>Cyanamide</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Cyanamide</term><term>Dithiothreitol</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Monocytes</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Cytosol</term><term>Liver</term><term>Monocytes</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Acetylation</term><term>Cell Line, Tumor</term><term>Dose-Response Relationship, Drug</term><term>Humans</term><term>Time Factors</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Cyanamide has been used for decades for medical intentions in the treatment of alcoholism and for agricultural purposes as a plant growth regulator and bud-breaking agent. Its therapeutic effect is mediated by reversible inhibition of aldehyde dehydrogenase and it was reported to be metabolized in vivo mainly via coenzyme A dependent N-acetylation by N-acetyltransferases. Although described to be a substrate for N-acetyltransferases (NATs), cyanamide has a different molecular structure to arylamines and hydrazines, the preferred substrates for N-acetyltransferases. Therefore, a more detailed investigation of its interrelations with N-acetyltransferases was performed. We analyzed the impact of cyanamide on NAT1 activities of human monocytes (monocytic THP-1 cells) using the classical substrate p-aminobenzoic acid. We found that a 24h treatment with physiologically relevant concentrations of cyanamide decreased the NAT1 activity significantly. Based on this observation we performed additional experiments using recombinant human NAT1 and NAT2 to achieve further insights. In detail a significant dose- and time-dependent inhibition of NAT1 activity was observed for 100 and 1000μM cyanamide using recombinant human NAT1*4. However, cyanamide did not inhibit recombinant NAT2*4. Experiments testing cyanamide as substrate did not provide evidence that cyanamide is metabolized via coenzyme A dependent N-acetylation in vitro by human NAT1 or NAT2, THP-1 or human liver cytosol. Therefore we can conclude that the observed enzyme inhibition (around 50% and 25% after treatment with 0.5 and 0.25mM CA, respectively) is not based on substrate-dependent down-regulation of NAT1. Further mechanistic and kinetic studies indicated that cyanamide reacts with the active site cysteine residue of NAT1, leading to its rapid inhibition (significant inhibition after 30min and 2h for 1000 and 100μM CA, respectively). Addition of the reduction agent dithiothreitol (DTT) did not modify the effect, indicating that oxidative processes that can be reversed by 5mM DTT are not likely involved in the inhibition. Taken together our results show that cyanamide is able to inhibit NAT1 most likely via interaction with the active site cysteine residue. Thereby cyanamide might modulate NAT1 dependent detoxification and activation of arylamines.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">22835378</PMID><DateCreated><Year>2012</Year><Month>09</Month><Day>10</Day></DateCreated><DateCompleted><Year>2012</Year><Month>11</Month><Day>13</Day></DateCompleted><DateRevised><Year>2013</Year><Month>11</Month><Day>21</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1879-3185</ISSN><JournalIssue CitedMedium="Internet"><Volume>302</Volume><Issue>1</Issue><PubDate><Year>2012</Year><Month>Dec</Month><Day>08</Day></PubDate></JournalIssue><Title>Toxicology</Title><ISOAbbreviation>Toxicology</ISOAbbreviation></Journal><ArticleTitle>Cyanamide-mediated Inhibition of N-acetyltransferase 1.</ArticleTitle><Pagination><MedlinePgn>1-10</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.tox.2012.06.019</ELocationID><Abstract><AbstractText>Cyanamide has been used for decades for medical intentions in the treatment of alcoholism and for agricultural purposes as a plant growth regulator and bud-breaking agent. Its therapeutic effect is mediated by reversible inhibition of aldehyde dehydrogenase and it was reported to be metabolized in vivo mainly via coenzyme A dependent N-acetylation by N-acetyltransferases. Although described to be a substrate for N-acetyltransferases (NATs), cyanamide has a different molecular structure to arylamines and hydrazines, the preferred substrates for N-acetyltransferases. Therefore, a more detailed investigation of its interrelations with N-acetyltransferases was performed. We analyzed the impact of cyanamide on NAT1 activities of human monocytes (monocytic THP-1 cells) using the classical substrate p-aminobenzoic acid. We found that a 24h treatment with physiologically relevant concentrations of cyanamide decreased the NAT1 activity significantly. Based on this observation we performed additional experiments using recombinant human NAT1 and NAT2 to achieve further insights. In detail a significant dose- and time-dependent inhibition of NAT1 activity was observed for 100 and 1000μM cyanamide using recombinant human NAT1*4. However, cyanamide did not inhibit recombinant NAT2*4. Experiments testing cyanamide as substrate did not provide evidence that cyanamide is metabolized via coenzyme A dependent N-acetylation in vitro by human NAT1 or NAT2, THP-1 or human liver cytosol. Therefore we can conclude that the observed enzyme inhibition (around 50% and 25% after treatment with 0.5 and 0.25mM CA, respectively) is not based on substrate-dependent down-regulation of NAT1. Further mechanistic and kinetic studies indicated that cyanamide reacts with the active site cysteine residue of NAT1, leading to its rapid inhibition (significant inhibition after 30min and 2h for 1000 and 100μM CA, respectively). Addition of the reduction agent dithiothreitol (DTT) did not modify the effect, indicating that oxidative processes that can be reversed by 5mM DTT are not likely involved in the inhibition. Taken together our results show that cyanamide is able to inhibit NAT1 most likely via interaction with the active site cysteine residue. Thereby cyanamide might modulate NAT1 dependent detoxification and activation of arylamines.</AbstractText><CopyrightInformation>Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Dierolf</LastName><ForeName>Dorothea</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Department of Environmental Toxicology, University of Trier, Universitätsring 15, 54296 Trier, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Scheitza</LastName><ForeName>Simone</ForeName><Initials>S</Initials></Author><Author ValidYN="Y"><LastName>Bonifas</LastName><ForeName>Jutta</ForeName><Initials>J</Initials></Author><Author ValidYN="Y"><LastName>Blömeke</LastName><ForeName>Brunhilde</ForeName><Initials>B</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2012</Year><Month>07</Month><Day>24</Day></ArticleDate></Article><MedlineJournalInfo><Country>Ireland</Country><MedlineTA>Toxicology</MedlineTA><NlmUniqueID>0361055</NlmUniqueID><ISSNLinking>0300-483X</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D007527">Isoenzymes</NameOfSubstance></Chemical><Chemical><RegistryNumber>420-04-2</RegistryNumber><NameOfSubstance UI="D003484">Cyanamide</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.3.1.5</RegistryNumber><NameOfSubstance UI="D001191">Arylamine N-Acetyltransferase</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.3.1.5</RegistryNumber><NameOfSubstance UI="C089384">N-acetyltransferase 1</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.3.1.5</RegistryNumber><NameOfSubstance UI="C478900">NAT2 protein, human</NameOfSubstance></Chemical><Chemical><RegistryNumber>SAA04E81UX</RegistryNumber><NameOfSubstance 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MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D045744" MajorTopicYN="N">Cell Line, Tumor</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D003065" MajorTopicYN="N">Coenzyme A</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D003484" MajorTopicYN="N">Cyanamide</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="N">administration & dosage</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D003600" MajorTopicYN="N">Cytosol</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004229" MajorTopicYN="N">Dithiothreitol</DescriptorName><QualifierName UI="Q000494" 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Factors</DescriptorName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2012</Year><Month>05</Month><Day>07</Day></PubMedPubDate><PubMedPubDate PubStatus="revised"><Year>2012</Year><Month>06</Month><Day>14</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2012</Year><Month>06</Month><Day>25</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2012</Year><Month>7</Month><Day>28</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2012</Year><Month>7</Month><Day>28</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2012</Year><Month>11</Month><Day>14</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">22835378</ArticleId><ArticleId IdType="pii">S0300-483X(12)00249-1</ArticleId><ArticleId 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