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In vitro human metabolism of permethrin isomers alone or as a mixture and the formation of the major metabolites in cryopreserved primary hepatocytes
•We estimated the Michaelis–Menten parameters of permethrin and its main metabolites.•Metabolic rates were estimated with the isomers incubated separately and in mixture.•Non-specific binding of permethrin was negligible or corrected.•The rate of formation of DCCA is higher than the one of 3-PBA.•We...
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| Published in: | Toxicology in vitro 2015-06, Vol.29 (4), p.803-812 |
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| container_title | Toxicology in vitro |
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| creator | Willemin, M.-E. Kadar, A. de Sousa, G. Leclerc, E. Rahmani, R. Brochot, C. |
| description | •We estimated the Michaelis–Menten parameters of permethrin and its main metabolites.•Metabolic rates were estimated with the isomers incubated separately and in mixture.•Non-specific binding of permethrin was negligible or corrected.•The rate of formation of DCCA is higher than the one of 3-PBA.•We observed a low inhibitory potential of cis- and trans-permethrin on each other.
In vitro metabolism of permethrin, a pyrethroid insecticide, was assessed in primary human hepatocytes. In vitro kinetic experiments were performed to estimate the Michaelis–Menten parameters and the clearances or formation rates of the permethrin isomers (cis- and trans-) and three metabolites, cis- and trans-3-(2,2 dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid (cis- and trans-DCCA) and 3-phenoxybenzoic acid (3-PBA). Non-specific binding and the activity of the enzymes involved in permethrin’s metabolism (cytochromes P450 and carboxylesterases) were quantified. Trans-permethrin was cleared more rapidly than cis-permethrin with a 2.6-factor (25.7±0.6 and 10.1±0.3μL/min/106 cells respectively). A 3-factor was observed between the formation rates of DCCA and 3-PBA obtained from trans- and cis-permethrin. For both isomers, the rate of formation of DCCA was higher than the one of 3-PBA. The metabolism of the isomers in mixture was also quantified. The co-incubation of isomers at different ratios showed the low inhibitory potential of cis- and trans-permethrin on each other. The estimates of the clearances and the formation rates in the co-incubation condition did not differ from the estimates obtained with a separate incubation. These metabolic parameters may be integrated in physiologically based pharmacokinetic (PBPK) models to predict the fate of permethrin and metabolites in the human body. |
| doi_str_mv | 10.1016/j.tiv.2015.03.003 |
| format | article |
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In vitro metabolism of permethrin, a pyrethroid insecticide, was assessed in primary human hepatocytes. In vitro kinetic experiments were performed to estimate the Michaelis–Menten parameters and the clearances or formation rates of the permethrin isomers (cis- and trans-) and three metabolites, cis- and trans-3-(2,2 dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid (cis- and trans-DCCA) and 3-phenoxybenzoic acid (3-PBA). Non-specific binding and the activity of the enzymes involved in permethrin’s metabolism (cytochromes P450 and carboxylesterases) were quantified. Trans-permethrin was cleared more rapidly than cis-permethrin with a 2.6-factor (25.7±0.6 and 10.1±0.3μL/min/106 cells respectively). A 3-factor was observed between the formation rates of DCCA and 3-PBA obtained from trans- and cis-permethrin. For both isomers, the rate of formation of DCCA was higher than the one of 3-PBA. The metabolism of the isomers in mixture was also quantified. The co-incubation of isomers at different ratios showed the low inhibitory potential of cis- and trans-permethrin on each other. The estimates of the clearances and the formation rates in the co-incubation condition did not differ from the estimates obtained with a separate incubation. These metabolic parameters may be integrated in physiologically based pharmacokinetic (PBPK) models to predict the fate of permethrin and metabolites in the human body.</description><identifier>ISSN: 0887-2333</identifier><identifier>EISSN: 1879-3177</identifier><identifier>DOI: 10.1016/j.tiv.2015.03.003</identifier><identifier>PMID: 25765475</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>3-Phenoxybenzoic acid ; Biotransformation ; cis/trans-3-(2,2 Dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid ; cis/trans-Permethrin ; Cryopreservation ; Cytochrome P-450 Enzyme System - metabolism ; Esterases - metabolism ; Female ; Hepatocytes - metabolism ; Humans ; Insecticides - chemistry ; Insecticides - metabolism ; Interaction ; Isomerism ; Life Sciences ; Male ; Michaelis–Menten parameters ; Models, Statistical ; Permethrin - chemistry ; Permethrin - metabolism ; Primary Cell Culture ; Primary human hepatocytes ; Toxicokinetics ; Toxicology</subject><ispartof>Toxicology in vitro, 2015-06, Vol.29 (4), p.803-812</ispartof><rights>2015 Elsevier Ltd</rights><rights>Copyright © 2015 Elsevier Ltd. All rights reserved.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c423t-1f6454fda85d464d61ba6608db65128e1be1f35e6272cedb3f3b152bb23dc79f3</citedby><cites>FETCH-LOGICAL-c423t-1f6454fda85d464d61ba6608db65128e1be1f35e6272cedb3f3b152bb23dc79f3</cites><orcidid>0000-0003-4166-8472</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,786,790,891,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25765475$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://ineris.hal.science/ineris-01855035$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Willemin, M.-E.</creatorcontrib><creatorcontrib>Kadar, A.</creatorcontrib><creatorcontrib>de Sousa, G.</creatorcontrib><creatorcontrib>Leclerc, E.</creatorcontrib><creatorcontrib>Rahmani, R.</creatorcontrib><creatorcontrib>Brochot, C.</creatorcontrib><title>In vitro human metabolism of permethrin isomers alone or as a mixture and the formation of the major metabolites in cryopreserved primary hepatocytes</title><title>Toxicology in vitro</title><addtitle>Toxicol In Vitro</addtitle><description>•We estimated the Michaelis–Menten parameters of permethrin and its main metabolites.•Metabolic rates were estimated with the isomers incubated separately and in mixture.•Non-specific binding of permethrin was negligible or corrected.•The rate of formation of DCCA is higher than the one of 3-PBA.•We observed a low inhibitory potential of cis- and trans-permethrin on each other.
In vitro metabolism of permethrin, a pyrethroid insecticide, was assessed in primary human hepatocytes. In vitro kinetic experiments were performed to estimate the Michaelis–Menten parameters and the clearances or formation rates of the permethrin isomers (cis- and trans-) and three metabolites, cis- and trans-3-(2,2 dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid (cis- and trans-DCCA) and 3-phenoxybenzoic acid (3-PBA). Non-specific binding and the activity of the enzymes involved in permethrin’s metabolism (cytochromes P450 and carboxylesterases) were quantified. Trans-permethrin was cleared more rapidly than cis-permethrin with a 2.6-factor (25.7±0.6 and 10.1±0.3μL/min/106 cells respectively). A 3-factor was observed between the formation rates of DCCA and 3-PBA obtained from trans- and cis-permethrin. For both isomers, the rate of formation of DCCA was higher than the one of 3-PBA. The metabolism of the isomers in mixture was also quantified. The co-incubation of isomers at different ratios showed the low inhibitory potential of cis- and trans-permethrin on each other. The estimates of the clearances and the formation rates in the co-incubation condition did not differ from the estimates obtained with a separate incubation. These metabolic parameters may be integrated in physiologically based pharmacokinetic (PBPK) models to predict the fate of permethrin and metabolites in the human body.</description><subject>3-Phenoxybenzoic acid</subject><subject>Biotransformation</subject><subject>cis/trans-3-(2,2 Dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid</subject><subject>cis/trans-Permethrin</subject><subject>Cryopreservation</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>Esterases - metabolism</subject><subject>Female</subject><subject>Hepatocytes - metabolism</subject><subject>Humans</subject><subject>Insecticides - chemistry</subject><subject>Insecticides - metabolism</subject><subject>Interaction</subject><subject>Isomerism</subject><subject>Life Sciences</subject><subject>Male</subject><subject>Michaelis–Menten parameters</subject><subject>Models, Statistical</subject><subject>Permethrin - chemistry</subject><subject>Permethrin - metabolism</subject><subject>Primary Cell Culture</subject><subject>Primary human hepatocytes</subject><subject>Toxicokinetics</subject><subject>Toxicology</subject><issn>0887-2333</issn><issn>1879-3177</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><recordid>eNp9kc1u1DAURi0EokPhAdggL1mQ4J_YScWqqoBWGqkbWFtOfKN4FNvBdiLmQXhfPJppl13Zujrfka8_hD5SUlNC5ddDne1WM0JFTXhNCH-FdrRrbypO2_Y12pGuayvGOb9C71I6EEJEx8hbdMVEK0XTih369-DxZnMMeFqd9thB1n2YbXI4jHiBWAZTtB7bFBzEhPUcPOAQsS537OzfvEbA2hucJ8BjiE5nG_wpfRo4fSjskzVDwsU1xGNYIiSIGxi8ROt0POIJFp3DcCzQe_Rm1HOCD5fzGv3-8f3X3X21f_z5cHe7r4aG8VzRUTaiGY3uhGlkYyTttZSkM70UlHVAe6AjFyBZywYwPR95TwXre8bN0N6M_Bp9OXsnPavLO1TQVt3f7pX1EG1ShHZCEC42WvDPZ3yJ4c8KKStn0wDzrD2ENSnactYxKogsKD2jQwwpRRif9ZSoU3nqoEp56lSeIlyV8krm00W_9g7Mc-KprQJ8OwNQ_mSzEFUaLPiymo0wZGWCfUH_HwGrrYs</recordid><startdate>20150601</startdate><enddate>20150601</enddate><creator>Willemin, M.-E.</creator><creator>Kadar, A.</creator><creator>de Sousa, G.</creator><creator>Leclerc, E.</creator><creator>Rahmani, R.</creator><creator>Brochot, C.</creator><general>Elsevier Ltd</general><general>Elsevier</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>7U7</scope><scope>C1K</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0003-4166-8472</orcidid></search><sort><creationdate>20150601</creationdate><title>In vitro human metabolism of permethrin isomers alone or as a mixture and the formation of the major metabolites in cryopreserved primary hepatocytes</title><author>Willemin, M.-E. ; Kadar, A. ; de Sousa, G. ; Leclerc, E. ; Rahmani, R. ; Brochot, C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c423t-1f6454fda85d464d61ba6608db65128e1be1f35e6272cedb3f3b152bb23dc79f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>3-Phenoxybenzoic acid</topic><topic>Biotransformation</topic><topic>cis/trans-3-(2,2 Dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid</topic><topic>cis/trans-Permethrin</topic><topic>Cryopreservation</topic><topic>Cytochrome P-450 Enzyme System - metabolism</topic><topic>Esterases - metabolism</topic><topic>Female</topic><topic>Hepatocytes - metabolism</topic><topic>Humans</topic><topic>Insecticides - chemistry</topic><topic>Insecticides - metabolism</topic><topic>Interaction</topic><topic>Isomerism</topic><topic>Life Sciences</topic><topic>Male</topic><topic>Michaelis–Menten parameters</topic><topic>Models, Statistical</topic><topic>Permethrin - chemistry</topic><topic>Permethrin - metabolism</topic><topic>Primary Cell Culture</topic><topic>Primary human hepatocytes</topic><topic>Toxicokinetics</topic><topic>Toxicology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Willemin, M.-E.</creatorcontrib><creatorcontrib>Kadar, A.</creatorcontrib><creatorcontrib>de Sousa, G.</creatorcontrib><creatorcontrib>Leclerc, E.</creatorcontrib><creatorcontrib>Rahmani, R.</creatorcontrib><creatorcontrib>Brochot, C.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>Toxicology in vitro</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Willemin, M.-E.</au><au>Kadar, A.</au><au>de Sousa, G.</au><au>Leclerc, E.</au><au>Rahmani, R.</au><au>Brochot, C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>In vitro human metabolism of permethrin isomers alone or as a mixture and the formation of the major metabolites in cryopreserved primary hepatocytes</atitle><jtitle>Toxicology in vitro</jtitle><addtitle>Toxicol In Vitro</addtitle><date>2015-06-01</date><risdate>2015</risdate><volume>29</volume><issue>4</issue><spage>803</spage><epage>812</epage><pages>803-812</pages><issn>0887-2333</issn><eissn>1879-3177</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>•We estimated the Michaelis–Menten parameters of permethrin and its main metabolites.•Metabolic rates were estimated with the isomers incubated separately and in mixture.•Non-specific binding of permethrin was negligible or corrected.•The rate of formation of DCCA is higher than the one of 3-PBA.•We observed a low inhibitory potential of cis- and trans-permethrin on each other.
In vitro metabolism of permethrin, a pyrethroid insecticide, was assessed in primary human hepatocytes. In vitro kinetic experiments were performed to estimate the Michaelis–Menten parameters and the clearances or formation rates of the permethrin isomers (cis- and trans-) and three metabolites, cis- and trans-3-(2,2 dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid (cis- and trans-DCCA) and 3-phenoxybenzoic acid (3-PBA). Non-specific binding and the activity of the enzymes involved in permethrin’s metabolism (cytochromes P450 and carboxylesterases) were quantified. Trans-permethrin was cleared more rapidly than cis-permethrin with a 2.6-factor (25.7±0.6 and 10.1±0.3μL/min/106 cells respectively). A 3-factor was observed between the formation rates of DCCA and 3-PBA obtained from trans- and cis-permethrin. For both isomers, the rate of formation of DCCA was higher than the one of 3-PBA. The metabolism of the isomers in mixture was also quantified. The co-incubation of isomers at different ratios showed the low inhibitory potential of cis- and trans-permethrin on each other. The estimates of the clearances and the formation rates in the co-incubation condition did not differ from the estimates obtained with a separate incubation. These metabolic parameters may be integrated in physiologically based pharmacokinetic (PBPK) models to predict the fate of permethrin and metabolites in the human body.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>25765475</pmid><doi>10.1016/j.tiv.2015.03.003</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0003-4166-8472</orcidid></addata></record> |
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| subjects | 3-Phenoxybenzoic acid Biotransformation cis/trans-3-(2,2 Dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid cis/trans-Permethrin Cryopreservation Cytochrome P-450 Enzyme System - metabolism Esterases - metabolism Female Hepatocytes - metabolism Humans Insecticides - chemistry Insecticides - metabolism Interaction Isomerism Life Sciences Male Michaelis–Menten parameters Models, Statistical Permethrin - chemistry Permethrin - metabolism Primary Cell Culture Primary human hepatocytes Toxicokinetics Toxicology |
| title | In vitro human metabolism of permethrin isomers alone or as a mixture and the formation of the major metabolites in cryopreserved primary hepatocytes |
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