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Drug toxicity profiling of a Saccharomyces cerevisiae deubiquitinase deletion panel shows that acetaminophen mimics tyrosine.

Identifieur interne : 000616 ( Main/Exploration ); précédent : 000615; suivant : 000617

Drug toxicity profiling of a Saccharomyces cerevisiae deubiquitinase deletion panel shows that acetaminophen mimics tyrosine.

Auteurs : Angelina Huseinovic [Pays-Bas] ; Marc Van Dijk [Pays-Bas] ; Nico P E. Vermeulen [Pays-Bas] ; Fred Van Leeuwen [Pays-Bas] ; Jan M. Kooter [Pays-Bas] ; J Chris Vos [Pays-Bas]

Source :

RBID : pubmed:29258884

Descripteurs français

English descriptors

Abstract

Post-translational protein modification by addition or removal of the small polypeptide ubiquitin is involved in a range of critical cellular processes, like proteasomal protein degradation, DNA repair, gene expression, internalization of membrane proteins, and drug sensitivity. We recently identified genes important for acetaminophen (APAP) toxicity in a comprehensive screen and our findings suggested that a small set of yeast strains carrying deletions of ubiquitin-related genes can be informative for drug toxicity profiling. In yeast, approximately 20 different deubiquitinating enzymes (DUBs) have been identified, of which only one is essential for viability. We investigated whether the toxicity profile of DUB deletion yeast strains would be informative about the toxicological mode of action of APAP. A set of DUB deletion strains was tested for sensitivity and resistance to a diverse series of compounds, including APAP, quinine, ibuprofen, rapamycin, cycloheximide, cadmium, peroxide and amino acids and a cluster analysis was performed. Most DUB deletion strains showed an altered growth pattern when exposed to these compounds by being either more sensitive or more resistant than WT. Toxicity profiling of the DUB strains revealed a remarkable overlap between the amino acid tyrosine and acetaminophen (APAP), but not its stereoisomer AMAP. Furthermore, co-exposure of cells to both APAP and tyrosine showed an enhancement of the cellular growth inhibition, suggesting that APAP and tyrosine have a similar mode of action.

DOI: 10.1016/j.tiv.2017.12.007
PubMed: 29258884


Affiliations:


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<term>Acetaminophen (analogs & derivatives)</term>
<term>Acetaminophen (chemistry)</term>
<term>Aminophenols (adverse effects)</term>
<term>Aminophenols (chemistry)</term>
<term>Analgesics, Non-Narcotic (adverse effects)</term>
<term>Analgesics, Non-Narcotic (chemistry)</term>
<term>Cluster Analysis (MeSH)</term>
<term>Deubiquitinating Enzymes (genetics)</term>
<term>Deubiquitinating Enzymes (metabolism)</term>
<term>Drug Resistance, Bacterial (MeSH)</term>
<term>Gene Deletion (MeSH)</term>
<term>Haploidy (MeSH)</term>
<term>Isoenzymes (genetics)</term>
<term>Isoenzymes (metabolism)</term>
<term>Microbial Viability (drug effects)</term>
<term>Molecular Structure (MeSH)</term>
<term>Saccharomyces cerevisiae (drug effects)</term>
<term>Saccharomyces cerevisiae (enzymology)</term>
<term>Saccharomyces cerevisiae (genetics)</term>
<term>Saccharomyces cerevisiae (growth & development)</term>
<term>Stereoisomerism (MeSH)</term>
<term>Toxicity Tests (methods)</term>
<term>Tyrosine (analogs & derivatives)</term>
<term>Tyrosine (chemistry)</term>
<term>Tyrosine (metabolism)</term>
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<term>Acétaminophène (analogues et dérivés)</term>
<term>Acétaminophène (composition chimique)</term>
<term>Acétaminophène (effets indésirables)</term>
<term>Aminophénols (composition chimique)</term>
<term>Aminophénols (effets indésirables)</term>
<term>Analgésiques non narcotiques (composition chimique)</term>
<term>Analgésiques non narcotiques (effets indésirables)</term>
<term>Analyse de regroupements (MeSH)</term>
<term>Délétion de gène (MeSH)</term>
<term>Enzymes de désubiquitinylation (génétique)</term>
<term>Enzymes de désubiquitinylation (métabolisme)</term>
<term>Haploïdie (MeSH)</term>
<term>Isoenzymes (génétique)</term>
<term>Isoenzymes (métabolisme)</term>
<term>Résistance bactérienne aux médicaments (MeSH)</term>
<term>Saccharomyces cerevisiae (croissance et développement)</term>
<term>Saccharomyces cerevisiae (effets des médicaments et des substances chimiques)</term>
<term>Saccharomyces cerevisiae (enzymologie)</term>
<term>Saccharomyces cerevisiae (génétique)</term>
<term>Structure moléculaire (MeSH)</term>
<term>Stéréoisomérie (MeSH)</term>
<term>Tests de toxicité (méthodes)</term>
<term>Tyrosine (analogues et dérivés)</term>
<term>Tyrosine (composition chimique)</term>
<term>Tyrosine (métabolisme)</term>
<term>Viabilité microbienne (effets des médicaments et des substances chimiques)</term>
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<keywords scheme="MESH" type="chemical" qualifier="adverse effects" xml:lang="en">
<term>Acetaminophen</term>
<term>Aminophenols</term>
<term>Analgesics, Non-Narcotic</term>
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<keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en">
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<term>Tyrosine</term>
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<term>Aminophenols</term>
<term>Analgesics, Non-Narcotic</term>
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<term>Isoenzymes</term>
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<term>Microbial Viability</term>
<term>Saccharomyces cerevisiae</term>
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<term>Acétaminophène</term>
<term>Aminophénols</term>
<term>Analgésiques non narcotiques</term>
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<keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr">
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<term>Haploïdie</term>
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<div type="abstract" xml:lang="en">Post-translational protein modification by addition or removal of the small polypeptide ubiquitin is involved in a range of critical cellular processes, like proteasomal protein degradation, DNA repair, gene expression, internalization of membrane proteins, and drug sensitivity. We recently identified genes important for acetaminophen (APAP) toxicity in a comprehensive screen and our findings suggested that a small set of yeast strains carrying deletions of ubiquitin-related genes can be informative for drug toxicity profiling. In yeast, approximately 20 different deubiquitinating enzymes (DUBs) have been identified, of which only one is essential for viability. We investigated whether the toxicity profile of DUB deletion yeast strains would be informative about the toxicological mode of action of APAP. A set of DUB deletion strains was tested for sensitivity and resistance to a diverse series of compounds, including APAP, quinine, ibuprofen, rapamycin, cycloheximide, cadmium, peroxide and amino acids and a cluster analysis was performed. Most DUB deletion strains showed an altered growth pattern when exposed to these compounds by being either more sensitive or more resistant than WT. Toxicity profiling of the DUB strains revealed a remarkable overlap between the amino acid tyrosine and acetaminophen (APAP), but not its stereoisomer AMAP. Furthermore, co-exposure of cells to both APAP and tyrosine showed an enhancement of the cellular growth inhibition, suggesting that APAP and tyrosine have a similar mode of action.</div>
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<DescriptorName UI="D000627" MajorTopicYN="N">Aminophenols</DescriptorName>
<QualifierName UI="Q000009" MajorTopicYN="N">adverse effects</QualifierName>
<QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D018712" MajorTopicYN="N">Analgesics, Non-Narcotic</DescriptorName>
<QualifierName UI="Q000009" MajorTopicYN="Y">adverse effects</QualifierName>
<QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D016000" MajorTopicYN="N">Cluster Analysis</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D000072017" MajorTopicYN="N">Deubiquitinating Enzymes</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D024881" MajorTopicYN="N">Drug Resistance, Bacterial</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D017353" MajorTopicYN="N">Gene Deletion</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D006238" MajorTopicYN="N">Haploidy</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D007527" MajorTopicYN="N">Isoenzymes</DescriptorName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D050296" MajorTopicYN="N">Microbial Viability</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D015394" MajorTopicYN="N">Molecular Structure</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D012441" MajorTopicYN="N">Saccharomyces cerevisiae</DescriptorName>
<QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName>
<QualifierName UI="Q000201" MajorTopicYN="N">enzymology</QualifierName>
<QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName>
<QualifierName UI="Q000254" MajorTopicYN="N">growth & development</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D013237" MajorTopicYN="N">Stereoisomerism</DescriptorName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D018675" MajorTopicYN="N">Toxicity Tests</DescriptorName>
<QualifierName UI="Q000379" MajorTopicYN="N">methods</QualifierName>
</MeshHeading>
<MeshHeading>
<DescriptorName UI="D014443" MajorTopicYN="N">Tyrosine</DescriptorName>
<QualifierName UI="Q000031" MajorTopicYN="N">analogs & derivatives</QualifierName>
<QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName>
<QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName>
</MeshHeading>
</MeshHeadingList>
<KeywordList Owner="NOTNLM">
<Keyword MajorTopicYN="N">APAP</Keyword>
<Keyword MajorTopicYN="N">Amino acids</Keyword>
<Keyword MajorTopicYN="N">Deubiquitinase</Keyword>
<Keyword MajorTopicYN="N">Starvation</Keyword>
<Keyword MajorTopicYN="N">Toxicity</Keyword>
<Keyword MajorTopicYN="N">Tyrosine</Keyword>
<Keyword MajorTopicYN="N">Ubiquitin</Keyword>
</KeywordList>
</MedlineCitation>
<PubmedData>
<History>
<PubMedPubDate PubStatus="received">
<Year>2017</Year>
<Month>08</Month>
<Day>14</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="revised">
<Year>2017</Year>
<Month>12</Month>
<Day>05</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="accepted">
<Year>2017</Year>
<Month>12</Month>
<Day>13</Day>
</PubMedPubDate>
<PubMedPubDate PubStatus="pubmed">
<Year>2017</Year>
<Month>12</Month>
<Day>21</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="medline">
<Year>2018</Year>
<Month>9</Month>
<Day>19</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
<PubMedPubDate PubStatus="entrez">
<Year>2017</Year>
<Month>12</Month>
<Day>21</Day>
<Hour>6</Hour>
<Minute>0</Minute>
</PubMedPubDate>
</History>
<PublicationStatus>ppublish</PublicationStatus>
<ArticleIdList>
<ArticleId IdType="pubmed">29258884</ArticleId>
<ArticleId IdType="pii">S0887-2333(17)30373-9</ArticleId>
<ArticleId IdType="doi">10.1016/j.tiv.2017.12.007</ArticleId>
</ArticleIdList>
</PubmedData>
</pubmed>
<affiliations>
<list>
<country>
<li>Pays-Bas</li>
</country>
</list>
<tree>
<country name="Pays-Bas">
<noRegion>
<name sortKey="Huseinovic, Angelina" sort="Huseinovic, Angelina" uniqKey="Huseinovic A" first="Angelina" last="Huseinovic">Angelina Huseinovic</name>
</noRegion>
<name sortKey="Kooter, Jan M" sort="Kooter, Jan M" uniqKey="Kooter J" first="Jan M" last="Kooter">Jan M. Kooter</name>
<name sortKey="Van Dijk, Marc" sort="Van Dijk, Marc" uniqKey="Van Dijk M" first="Marc" last="Van Dijk">Marc Van Dijk</name>
<name sortKey="Van Leeuwen, Fred" sort="Van Leeuwen, Fred" uniqKey="Van Leeuwen F" first="Fred" last="Van Leeuwen">Fred Van Leeuwen</name>
<name sortKey="Vermeulen, Nico P E" sort="Vermeulen, Nico P E" uniqKey="Vermeulen N" first="Nico P E" last="Vermeulen">Nico P E. Vermeulen</name>
<name sortKey="Vos, J Chris" sort="Vos, J Chris" uniqKey="Vos J" first="J Chris" last="Vos">J Chris Vos</name>
</country>
</tree>
</affiliations>
</record>

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