Microbial Metabolism of Atovaquone and Cytotoxicity of the Produced Phase I Metabolite.
Identifieur interne : 000F18 ( Main/Exploration ); précédent : 000F17; suivant : 000F19Microbial Metabolism of Atovaquone and Cytotoxicity of the Produced Phase I Metabolite.
Auteurs : Eliane De Oliveira Silva [Brésil] ; Natália Dos Santos Gonçalves [Brésil] ; Raquel Alves Dos Santos [Brésil] ; Niege Araçari Jacometti Cardoso Furtado [Brésil]Source :
- European journal of drug metabolism and pharmacokinetics [ 2107-0180 ] ; 2016.
Descripteurs français
- KwdFr :
- Animaux (MeSH), Antipaludiques (métabolisme), Antipaludiques (pharmacologie), Atovaquone (métabolisme), Atovaquone (pharmacologie), Caenorhabditis elegans (effets des médicaments et des substances chimiques), Champignons (effets des médicaments et des substances chimiques), Concentration inhibitrice 50 (MeSH), Détoxication de phase I (physiologie), Femelle (MeSH), Fibroblastes (métabolisme), Humains (MeSH), Lignée cellulaire (MeSH), Lignée cellulaire tumorale (MeSH), Paludisme à Plasmodium falciparum (traitement médicamenteux), Proguanil (métabolisme), Proguanil (pharmacologie), Tumeurs du sein (métabolisme).
- MESH :
- effets des médicaments et des substances chimiques : Caenorhabditis elegans, Champignons.
- métabolisme : Antipaludiques, Atovaquone, Fibroblastes, Proguanil, Tumeurs du sein.
- pharmacologie : Antipaludiques, Atovaquone, Proguanil.
- physiologie : Détoxication de phase I.
- traitement médicamenteux : Paludisme à Plasmodium falciparum.
- Animaux, Concentration inhibitrice 50, Femelle, Humains, Lignée cellulaire, Lignée cellulaire tumorale.
English descriptors
- KwdEn :
- Animals (MeSH), Antimalarials (metabolism), Antimalarials (pharmacology), Atovaquone (metabolism), Atovaquone (pharmacology), Breast Neoplasms (metabolism), Caenorhabditis elegans (drug effects), Cell Line (MeSH), Cell Line, Tumor (MeSH), Female (MeSH), Fibroblasts (metabolism), Fungi (drug effects), Humans (MeSH), Inhibitory Concentration 50 (MeSH), Malaria, Falciparum (drug therapy), Metabolic Detoxication, Phase I (physiology), Proguanil (metabolism), Proguanil (pharmacology).
- MESH :
- chemical , metabolism : Antimalarials, Atovaquone, Proguanil.
- chemical , pharmacology : Antimalarials, Atovaquone, Proguanil.
- drug effects : Caenorhabditis elegans, Fungi.
- drug therapy : Malaria, Falciparum.
- metabolism : Breast Neoplasms, Fibroblasts.
- physiology : Metabolic Detoxication, Phase I.
- Animals, Cell Line, Cell Line, Tumor, Female, Humans, Inhibitory Concentration 50.
Abstract
BACKGROUND AND OBJECTIVES
Atovaquone is a hydroxynaphthoquinone with selective action in the mitochondrial respiratory chain of malaria parasite. It is employed for both the treatment and prevention of malaria, in a combination with proguanil. The aim of this study was to elucidate the in vitro metabolites from atovaquone and to evaluate their cytotoxic activities.
METHODS
The biotransformation of atovaquone was performed using Mucor rouxii NRRL 1894, Cunninghamella echinulata var. elegans ATCC 8688a and C. elegans ATCC 10028b, which have been reported as microbial models of mammalian drug metabolism. Experiments were also carried out with two probiotic strains from the human intestinal tract: Bifidobacterium sp. and Lactobacillus acidophilus. The phase I metabolite was isolated, its chemical structure was elucidated and its toxicity was evaluated using the neoplastic cell line SKBR-3 derived from human breast cancer and normal human fibroblast cell line GM07492-A. Cell cytotoxicity assays were also carried out with atovaquone.
RESULT
Only the fungi were able to convert atovaquone to metabolite trans-3-[4'-(4″-chlorophenyl)cyclohexyl)-1,2-dioxo-dihydro-1H-indene-3-carboxylic acid. The metabolite displayed 50 % inhibitory concentration (IC50) values of 110.20 ± 2.2 and 108.80 ± 1.5 µmol/L against breast cancer cell line SKBR-3 and fibroblasts cell line GM07492-A, respectively. The IC50 values of atovaquone were 282.30 ± 1.8 and 340.50 ± 1.4 µmol/L against breast cancer and normal fibroblasts cell lines, respectively.
CONCLUSIONS
The produced metabolite was more toxic than atovaquone and was not selective to normal or cancer cell lines. The present study is the first to report the production of atovaquone metabolite.
DOI: 10.1007/s13318-015-0294-1
PubMed: 26253156
Affiliations:
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Dr. Armando Salles de Oliveira, 201, Franca, 14404-600, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Universidade de Franca, Núcleo de Pesquisas em Ciências Exatas e Tecnológicas, Av. Dr. Armando Salles de Oliveira, 201, Franca, 14404-600</wicri:regionArea><wicri:noRegion>14404-600</wicri:noRegion></affiliation></author><author><name sortKey="Alves Dos Santos, Raquel" sort="Alves Dos Santos, Raquel" uniqKey="Alves Dos Santos R" first="Raquel" last="Alves Dos Santos">Raquel Alves Dos Santos</name><affiliation wicri:level="1"><nlm:affiliation>Universidade de Franca, Núcleo de Pesquisas em Ciências Exatas e Tecnológicas, Av. Dr. Armando Salles de Oliveira, 201, Franca, 14404-600, Brazil.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Universidade de Franca, Núcleo de Pesquisas em Ciências Exatas e Tecnológicas, Av. Dr. Armando Salles de Oliveira, 201, Franca, 14404-600</wicri:regionArea><wicri:noRegion>14404-600</wicri:noRegion></affiliation></author><author><name sortKey="Jacometti Cardoso Furtado, Niege Aracari" sort="Jacometti Cardoso Furtado, Niege Aracari" uniqKey="Jacometti Cardoso Furtado N" first="Niege Araçari" last="Jacometti Cardoso Furtado">Niege Araçari Jacometti Cardoso Furtado</name><affiliation wicri:level="4"><nlm:affiliation>Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Avenida do Café, s/n, Ribeirão Preto, SP, 14040-903, Brazil. niege@fcfrp.usp.br.</nlm:affiliation><country xml:lang="fr">Brésil</country><wicri:regionArea>Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Avenida do Café, s/n, Ribeirão Preto, SP, 14040-903</wicri:regionArea><orgName type="university">Université de São Paulo</orgName><placeName><settlement type="city">São Paulo</settlement><region type="state">État de São Paulo</region></placeName></affiliation></author></analytic><series><title level="j">European journal of drug metabolism and pharmacokinetics</title><idno type="eISSN">2107-0180</idno><imprint><date when="2016" type="published">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals (MeSH)</term><term>Antimalarials (metabolism)</term><term>Antimalarials (pharmacology)</term><term>Atovaquone (metabolism)</term><term>Atovaquone (pharmacology)</term><term>Breast Neoplasms (metabolism)</term><term>Caenorhabditis elegans (drug effects)</term><term>Cell Line (MeSH)</term><term>Cell Line, Tumor (MeSH)</term><term>Female (MeSH)</term><term>Fibroblasts (metabolism)</term><term>Fungi (drug effects)</term><term>Humans (MeSH)</term><term>Inhibitory Concentration 50 (MeSH)</term><term>Malaria, Falciparum (drug therapy)</term><term>Metabolic Detoxication, Phase I (physiology)</term><term>Proguanil (metabolism)</term><term>Proguanil (pharmacology)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux (MeSH)</term><term>Antipaludiques (métabolisme)</term><term>Antipaludiques (pharmacologie)</term><term>Atovaquone (métabolisme)</term><term>Atovaquone (pharmacologie)</term><term>Caenorhabditis elegans (effets des médicaments et des substances chimiques)</term><term>Champignons (effets des médicaments et des substances chimiques)</term><term>Concentration inhibitrice 50 (MeSH)</term><term>Détoxication de phase I (physiologie)</term><term>Femelle (MeSH)</term><term>Fibroblastes (métabolisme)</term><term>Humains (MeSH)</term><term>Lignée cellulaire (MeSH)</term><term>Lignée cellulaire tumorale (MeSH)</term><term>Paludisme à Plasmodium falciparum (traitement médicamenteux)</term><term>Proguanil (métabolisme)</term><term>Proguanil (pharmacologie)</term><term>Tumeurs du sein (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Antimalarials</term><term>Atovaquone</term><term>Proguanil</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antimalarials</term><term>Atovaquone</term><term>Proguanil</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Caenorhabditis elegans</term><term>Fungi</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Malaria, Falciparum</term></keywords><keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr"><term>Caenorhabditis elegans</term><term>Champignons</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Breast Neoplasms</term><term>Fibroblasts</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Antipaludiques</term><term>Atovaquone</term><term>Fibroblastes</term><term>Proguanil</term><term>Tumeurs du sein</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antipaludiques</term><term>Atovaquone</term><term>Proguanil</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Détoxication de phase I</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Metabolic Detoxication, Phase I</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Paludisme à Plasmodium falciparum</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Cell Line</term><term>Cell Line, Tumor</term><term>Female</term><term>Humans</term><term>Inhibitory Concentration 50</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Concentration inhibitrice 50</term><term>Femelle</term><term>Humains</term><term>Lignée cellulaire</term><term>Lignée cellulaire tumorale</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p><b>BACKGROUND AND OBJECTIVES</b></p><p>Atovaquone is a hydroxynaphthoquinone with selective action in the mitochondrial respiratory chain of malaria parasite. It is employed for both the treatment and prevention of malaria, in a combination with proguanil. The aim of this study was to elucidate the in vitro metabolites from atovaquone and to evaluate their cytotoxic activities.</p></div><div type="abstract" xml:lang="en"><p><b>METHODS</b></p><p>The biotransformation of atovaquone was performed using Mucor rouxii NRRL 1894, Cunninghamella echinulata var. elegans ATCC 8688a and C. elegans ATCC 10028b, which have been reported as microbial models of mammalian drug metabolism. Experiments were also carried out with two probiotic strains from the human intestinal tract: Bifidobacterium sp. and Lactobacillus acidophilus. The phase I metabolite was isolated, its chemical structure was elucidated and its toxicity was evaluated using the neoplastic cell line SKBR-3 derived from human breast cancer and normal human fibroblast cell line GM07492-A. Cell cytotoxicity assays were also carried out with atovaquone.</p></div><div type="abstract" xml:lang="en"><p><b>RESULT</b></p><p>Only the fungi were able to convert atovaquone to metabolite trans-3-[4'-(4″-chlorophenyl)cyclohexyl)-1,2-dioxo-dihydro-1H-indene-3-carboxylic acid. The metabolite displayed 50 % inhibitory concentration (IC50) values of 110.20 ± 2.2 and 108.80 ± 1.5 µmol/L against breast cancer cell line SKBR-3 and fibroblasts cell line GM07492-A, respectively. The IC50 values of atovaquone were 282.30 ± 1.8 and 340.50 ± 1.4 µmol/L against breast cancer and normal fibroblasts cell lines, respectively.</p></div><div type="abstract" xml:lang="en"><p><b>CONCLUSIONS</b></p><p>The produced metabolite was more toxic than atovaquone and was not selective to normal or cancer cell lines. The present study is the first to report the production of atovaquone metabolite.</p></div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">26253156</PMID><DateCompleted><Year>2017</Year><Month>03</Month><Day>28</Day></DateCompleted><DateRevised><Year>2018</Year><Month>11</Month><Day>13</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">2107-0180</ISSN><JournalIssue CitedMedium="Internet"><Volume>41</Volume><Issue>5</Issue><PubDate><Year>2016</Year><Month>Oct</Month></PubDate></JournalIssue><Title>European journal of drug metabolism and pharmacokinetics</Title><ISOAbbreviation>Eur J Drug Metab Pharmacokinet</ISOAbbreviation></Journal><ArticleTitle>Microbial Metabolism of Atovaquone and Cytotoxicity of the Produced Phase I Metabolite.</ArticleTitle><Pagination><MedlinePgn>645-50</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1007/s13318-015-0294-1</ELocationID><Abstract><AbstractText Label="BACKGROUND AND OBJECTIVES" NlmCategory="OBJECTIVE">Atovaquone is a hydroxynaphthoquinone with selective action in the mitochondrial respiratory chain of malaria parasite. It is employed for both the treatment and prevention of malaria, in a combination with proguanil. The aim of this study was to elucidate the in vitro metabolites from atovaquone and to evaluate their cytotoxic activities.</AbstractText><AbstractText Label="METHODS" NlmCategory="METHODS">The biotransformation of atovaquone was performed using Mucor rouxii NRRL 1894, Cunninghamella echinulata var. elegans ATCC 8688a and C. elegans ATCC 10028b, which have been reported as microbial models of mammalian drug metabolism. Experiments were also carried out with two probiotic strains from the human intestinal tract: Bifidobacterium sp. and Lactobacillus acidophilus. The phase I metabolite was isolated, its chemical structure was elucidated and its toxicity was evaluated using the neoplastic cell line SKBR-3 derived from human breast cancer and normal human fibroblast cell line GM07492-A. Cell cytotoxicity assays were also carried out with atovaquone.</AbstractText><AbstractText Label="RESULT" NlmCategory="RESULTS">Only the fungi were able to convert atovaquone to metabolite trans-3-[4'-(4″-chlorophenyl)cyclohexyl)-1,2-dioxo-dihydro-1H-indene-3-carboxylic acid. The metabolite displayed 50 % inhibitory concentration (IC50) values of 110.20 ± 2.2 and 108.80 ± 1.5 µmol/L against breast cancer cell line SKBR-3 and fibroblasts cell line GM07492-A, respectively. The IC50 values of atovaquone were 282.30 ± 1.8 and 340.50 ± 1.4 µmol/L against breast cancer and normal fibroblasts cell lines, respectively.</AbstractText><AbstractText Label="CONCLUSIONS" NlmCategory="CONCLUSIONS">The produced metabolite was more toxic than atovaquone and was not selective to normal or cancer cell lines. The present study is the first to report the production of atovaquone metabolite.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>de Oliveira Silva</LastName><ForeName>Eliane</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Avenida do Café, s/n, Ribeirão Preto, SP, 14040-903, Brazil.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dos Santos Gonçalves</LastName><ForeName>Natália</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Universidade de Franca, Núcleo de Pesquisas em Ciências Exatas e Tecnológicas, Av. Dr. Armando Salles de Oliveira, 201, Franca, 14404-600, Brazil.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Alves Dos Santos</LastName><ForeName>Raquel</ForeName><Initials>R</Initials><AffiliationInfo><Affiliation>Universidade de Franca, Núcleo de Pesquisas em Ciências Exatas e Tecnológicas, Av. Dr. Armando Salles de Oliveira, 201, Franca, 14404-600, Brazil.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Jacometti Cardoso Furtado</LastName><ForeName>Niege Araçari</ForeName><Initials>NA</Initials><AffiliationInfo><Affiliation>Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Avenida do Café, s/n, Ribeirão Preto, SP, 14040-903, Brazil. niege@fcfrp.usp.br.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>France</Country><MedlineTA>Eur J Drug Metab Pharmacokinet</MedlineTA><NlmUniqueID>7608491</NlmUniqueID><ISSNLinking>0378-7966</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000962">Antimalarials</NameOfSubstance></Chemical><Chemical><RegistryNumber>S61K3P7B2V</RegistryNumber><NameOfSubstance UI="D002727">Proguanil</NameOfSubstance></Chemical><Chemical><RegistryNumber>Y883P1Z2LT</RegistryNumber><NameOfSubstance UI="D053626">Atovaquone</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000962" MajorTopicYN="N">Antimalarials</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D053626" MajorTopicYN="N">Atovaquone</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName><QualifierName UI="Q000494" MajorTopicYN="N">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001943" MajorTopicYN="N">Breast Neoplasms</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D017173" MajorTopicYN="N">Caenorhabditis elegans</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002460" MajorTopicYN="N">Cell Line</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D045744" MajorTopicYN="N">Cell Line, Tumor</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005260" MajorTopicYN="N">Female</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D005347" MajorTopicYN="N">Fibroblasts</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D005658" MajorTopicYN="N">Fungi</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName 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