Assessment of in vivo and in vitro genotoxicity of glibenclamide in eukaryotic cells
Glibenclamide is an oral hypoglycemic drug commonly prescribed for the treatment of type 2 diabetes mellitus, whose anti-tumor activity has been recently described in several human cancer cells. The mutagenic potential of such an antidiabetic drug and its recombinogenic activity in eukaryotic cells...
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| description | Glibenclamide is an oral hypoglycemic drug commonly prescribed for the treatment of type 2 diabetes mellitus, whose anti-tumor activity has been recently described in several human cancer cells. The mutagenic potential of such an antidiabetic drug and its recombinogenic activity in eukaryotic cells were evaluated, the latter for the first time. The mutagenic potential of glibenclamide in therapeutically plasma (0.6 μM) and higher concentrations (10 μM, 100 μM, 240 μM and 480 μM) was assessed by the in vitro mammalian cell micronucleus test in human lymphocytes. Since the loss of heterozygosity arising from allelic recombination is an important biologically significant consequence of oxidative damage, the glibenclamide recombinogenic activity at 1 μM, 10 μM and 100 μM concentrations was evaluated by the in vivo homozygotization assay. Glibenclamide failed to alter the frequency of micronuclei between 0.6 μM and 480 μM concentrations and the cytokinesis block proliferation index between 0.6 μM and 240 μM concentrations. On the other hand, glibenclamide changed the cell-proliferation kinetics when used at 480 μM. In the homozygotization assay, the homozygotization indices for the analyzed markers were lower than 2.0 and demonstrated the lack of recombinogenic activity of glibenclamide. Data in the current study demonstrate that glibenclamide, in current experimental conditions, is devoid of significant genotoxic effects. This fact encourages further investigations on the use of this antidiabetic agent as a chemotherapeutic drug. |
| doi_str_mv | 10.1371/journal.pone.0120675 |
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The mutagenic potential of such an antidiabetic drug and its recombinogenic activity in eukaryotic cells were evaluated, the latter for the first time. The mutagenic potential of glibenclamide in therapeutically plasma (0.6 μM) and higher concentrations (10 μM, 100 μM, 240 μM and 480 μM) was assessed by the in vitro mammalian cell micronucleus test in human lymphocytes. Since the loss of heterozygosity arising from allelic recombination is an important biologically significant consequence of oxidative damage, the glibenclamide recombinogenic activity at 1 μM, 10 μM and 100 μM concentrations was evaluated by the in vivo homozygotization assay. Glibenclamide failed to alter the frequency of micronuclei between 0.6 μM and 480 μM concentrations and the cytokinesis block proliferation index between 0.6 μM and 240 μM concentrations. On the other hand, glibenclamide changed the cell-proliferation kinetics when used at 480 μM. In the homozygotization assay, the homozygotization indices for the analyzed markers were lower than 2.0 and demonstrated the lack of recombinogenic activity of glibenclamide. Data in the current study demonstrate that glibenclamide, in current experimental conditions, is devoid of significant genotoxic effects. This fact encourages further investigations on the use of this antidiabetic agent as a chemotherapeutic drug.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0120675</identifier><identifier>PMID: 25803314</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adult ; Analysis ; Angina pectoris ; Anticancer properties ; Antitumor agents ; Aspergillus nidulans ; Cancer ; Cancer therapies ; Cell Proliferation - drug effects ; Cells (Biology) ; Cells, Cultured ; Chemicals ; Chemotherapy ; Cytokinesis ; Diabetes ; Diabetes mellitus ; Diabetes mellitus (non-insulin dependent) ; Diabetes Mellitus, Type 2 - drug therapy ; Diabetes therapy ; Genotoxicity ; Glibenclamide ; Glyburide ; Glyburide - toxicity ; Heterozygosity ; Humans ; Hypoglycemic Agents - toxicity ; In vitro methods and tests ; In vivo methods and tests ; Kinetics ; Loss of heterozygosity ; Lymphocytes ; Lymphocytes - cytology ; Lymphocytes - drug effects ; Lymphocytes - metabolism ; Micronuclei ; Micronucleus Tests ; Mutagens - toxicity ; Mutation ; Potassium ; Recombination ; Rodents ; Studies ; Toxicology ; Type 2 diabetes ; Young Adult</subject><ispartof>PloS one, 2015-03, Vol.10 (3), p.e0120675</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Sant’Anna et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Sant’Anna et al 2015 Sant’Anna et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-1dc6bb067ed72fb6939e3b8621586dd3a8800bd58e63d46bc74c580b1415748f3</citedby><cites>FETCH-LOGICAL-c692t-1dc6bb067ed72fb6939e3b8621586dd3a8800bd58e63d46bc74c580b1415748f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4372363/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4372363/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79569,79570</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25803314$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>de Sant'Anna, Juliane Rocha</creatorcontrib><creatorcontrib>Franco, Claudinéia Conationi da Silva</creatorcontrib><creatorcontrib>Mathias, Paulo Cezar de Freitas</creatorcontrib><creatorcontrib>de Castro-Prado, Marialba Avezum Alves</creatorcontrib><title>Assessment of in vivo and in vitro genotoxicity of glibenclamide in eukaryotic cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Glibenclamide is an oral hypoglycemic drug commonly prescribed for the treatment of type 2 diabetes mellitus, whose anti-tumor activity has been recently described in several human cancer cells. The mutagenic potential of such an antidiabetic drug and its recombinogenic activity in eukaryotic cells were evaluated, the latter for the first time. The mutagenic potential of glibenclamide in therapeutically plasma (0.6 μM) and higher concentrations (10 μM, 100 μM, 240 μM and 480 μM) was assessed by the in vitro mammalian cell micronucleus test in human lymphocytes. Since the loss of heterozygosity arising from allelic recombination is an important biologically significant consequence of oxidative damage, the glibenclamide recombinogenic activity at 1 μM, 10 μM and 100 μM concentrations was evaluated by the in vivo homozygotization assay. Glibenclamide failed to alter the frequency of micronuclei between 0.6 μM and 480 μM concentrations and the cytokinesis block proliferation index between 0.6 μM and 240 μM concentrations. On the other hand, glibenclamide changed the cell-proliferation kinetics when used at 480 μM. In the homozygotization assay, the homozygotization indices for the analyzed markers were lower than 2.0 and demonstrated the lack of recombinogenic activity of glibenclamide. Data in the current study demonstrate that glibenclamide, in current experimental conditions, is devoid of significant genotoxic effects. This fact encourages further investigations on the use of this antidiabetic agent as a chemotherapeutic drug.</description><subject>Adult</subject><subject>Analysis</subject><subject>Angina pectoris</subject><subject>Anticancer properties</subject><subject>Antitumor agents</subject><subject>Aspergillus nidulans</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>Cell Proliferation - drug effects</subject><subject>Cells (Biology)</subject><subject>Cells, Cultured</subject><subject>Chemicals</subject><subject>Chemotherapy</subject><subject>Cytokinesis</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes mellitus (non-insulin dependent)</subject><subject>Diabetes Mellitus, Type 2 - drug therapy</subject><subject>Diabetes therapy</subject><subject>Genotoxicity</subject><subject>Glibenclamide</subject><subject>Glyburide</subject><subject>Glyburide - toxicity</subject><subject>Heterozygosity</subject><subject>Humans</subject><subject>Hypoglycemic Agents - toxicity</subject><subject>In vitro methods and tests</subject><subject>In vivo methods and tests</subject><subject>Kinetics</subject><subject>Loss of heterozygosity</subject><subject>Lymphocytes</subject><subject>Lymphocytes - cytology</subject><subject>Lymphocytes - drug effects</subject><subject>Lymphocytes - metabolism</subject><subject>Micronuclei</subject><subject>Micronucleus Tests</subject><subject>Mutagens - toxicity</subject><subject>Mutation</subject><subject>Potassium</subject><subject>Recombination</subject><subject>Rodents</subject><subject>Studies</subject><subject>Toxicology</subject><subject>Type 2 diabetes</subject><subject>Young Adult</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl-L1DAUxYso7rr6DUQLguDDjEnT3rQvwrD4Z2BhQVdfQ5rcdjKmzdikw-63N-N0lykoSB8akt8993A4SfKSkiVlnL7funHopV3uXI9LQjMCvHiUnNOKZQvICHt8cj5Lnnm_JaRgJcDT5CwrSsIYzc-Tm5X36H2HfUhdk5o-3Zu9S2Wvj-cwuLTF3gV3a5QJdweotabGXlnZGY0HDMefcrhzwahUobX-efKkkdbji-l_kXz_9PHm8svi6vrz-nJ1tVBQZWFBtYK6jr5R86ypoWIVsrqEjBYlaM1kWRJS66JEYDqHWvFcReM1zWnB87JhF8nro-7OOi-mQLygAMBIxQsaifWR0E5uxW4wXTQqnDTiz4UbWiGH6NuiKIAB6ooiSIjLiCSM5CVFRjXjwA_bPkzbxrpDrWJkg7Qz0flLbzaidXuRM54xYFHgzSQwuF8j-vAPyxPVyujK9I2LYqozXolVnmWME4A8Usu_UPHT2BkVK9GYeD8beDcbiEzA29DK0Xux_vb1_9nrH3P27Qm7QWnDxjs7BuN6PwfzI6gG5_2AzUNylIhDo-_TEIdGi6nRcezVaeoPQ_cVZr8B2Ivv3g</recordid><startdate>20150324</startdate><enddate>20150324</enddate><creator>de Sant'Anna, Juliane Rocha</creator><creator>Franco, Claudinéia Conationi da Silva</creator><creator>Mathias, Paulo Cezar de Freitas</creator><creator>de Castro-Prado, Marialba Avezum Alves</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PHGZM</scope><scope>PHGZT</scope><scope>PIMPY</scope><scope>PJZUB</scope><scope>PKEHL</scope><scope>PPXIY</scope><scope>PQEST</scope><scope>PQGLB</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150324</creationdate><title>Assessment of in vivo and in vitro genotoxicity of glibenclamide in eukaryotic cells</title><author>de Sant'Anna, Juliane Rocha ; Franco, Claudinéia Conationi da Silva ; Mathias, Paulo Cezar de Freitas ; de Castro-Prado, Marialba Avezum Alves</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-1dc6bb067ed72fb6939e3b8621586dd3a8800bd58e63d46bc74c580b1415748f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adult</topic><topic>Analysis</topic><topic>Angina pectoris</topic><topic>Anticancer properties</topic><topic>Antitumor agents</topic><topic>Aspergillus nidulans</topic><topic>Cancer</topic><topic>Cancer therapies</topic><topic>Cell Proliferation - drug effects</topic><topic>Cells (Biology)</topic><topic>Cells, Cultured</topic><topic>Chemicals</topic><topic>Chemotherapy</topic><topic>Cytokinesis</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes mellitus (non-insulin dependent)</topic><topic>Diabetes Mellitus, Type 2 - drug therapy</topic><topic>Diabetes therapy</topic><topic>Genotoxicity</topic><topic>Glibenclamide</topic><topic>Glyburide</topic><topic>Glyburide - toxicity</topic><topic>Heterozygosity</topic><topic>Humans</topic><topic>Hypoglycemic Agents - toxicity</topic><topic>In vitro methods and tests</topic><topic>In vivo methods and tests</topic><topic>Kinetics</topic><topic>Loss of heterozygosity</topic><topic>Lymphocytes</topic><topic>Lymphocytes - cytology</topic><topic>Lymphocytes - drug effects</topic><topic>Lymphocytes - metabolism</topic><topic>Micronuclei</topic><topic>Micronucleus Tests</topic><topic>Mutagens - toxicity</topic><topic>Mutation</topic><topic>Potassium</topic><topic>Recombination</topic><topic>Rodents</topic><topic>Studies</topic><topic>Toxicology</topic><topic>Type 2 diabetes</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>de Sant'Anna, Juliane Rocha</creatorcontrib><creatorcontrib>Franco, Claudinéia Conationi da Silva</creatorcontrib><creatorcontrib>Mathias, Paulo Cezar de Freitas</creatorcontrib><creatorcontrib>de Castro-Prado, Marialba Avezum Alves</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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The mutagenic potential of such an antidiabetic drug and its recombinogenic activity in eukaryotic cells were evaluated, the latter for the first time. The mutagenic potential of glibenclamide in therapeutically plasma (0.6 μM) and higher concentrations (10 μM, 100 μM, 240 μM and 480 μM) was assessed by the in vitro mammalian cell micronucleus test in human lymphocytes. Since the loss of heterozygosity arising from allelic recombination is an important biologically significant consequence of oxidative damage, the glibenclamide recombinogenic activity at 1 μM, 10 μM and 100 μM concentrations was evaluated by the in vivo homozygotization assay. Glibenclamide failed to alter the frequency of micronuclei between 0.6 μM and 480 μM concentrations and the cytokinesis block proliferation index between 0.6 μM and 240 μM concentrations. On the other hand, glibenclamide changed the cell-proliferation kinetics when used at 480 μM. In the homozygotization assay, the homozygotization indices for the analyzed markers were lower than 2.0 and demonstrated the lack of recombinogenic activity of glibenclamide. Data in the current study demonstrate that glibenclamide, in current experimental conditions, is devoid of significant genotoxic effects. This fact encourages further investigations on the use of this antidiabetic agent as a chemotherapeutic drug.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25803314</pmid><doi>10.1371/journal.pone.0120675</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Adult Analysis Angina pectoris Anticancer properties Antitumor agents Aspergillus nidulans Cancer Cancer therapies Cell Proliferation - drug effects Cells (Biology) Cells, Cultured Chemicals Chemotherapy Cytokinesis Diabetes Diabetes mellitus Diabetes mellitus (non-insulin dependent) Diabetes Mellitus, Type 2 - drug therapy Diabetes therapy Genotoxicity Glibenclamide Glyburide Glyburide - toxicity Heterozygosity Humans Hypoglycemic Agents - toxicity In vitro methods and tests In vivo methods and tests Kinetics Loss of heterozygosity Lymphocytes Lymphocytes - cytology Lymphocytes - drug effects Lymphocytes - metabolism Micronuclei Micronucleus Tests Mutagens - toxicity Mutation Potassium Recombination Rodents Studies Toxicology Type 2 diabetes Young Adult |
| title | Assessment of in vivo and in vitro genotoxicity of glibenclamide in eukaryotic cells |
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