In vitro-in vivo correlation of the chiral pesticide prothioconazole after interaction with human CYP450 enzymes
Autor(a) principal: | |
---|---|
Data de Publicação: | 2022 |
Outros Autores: | , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1016/j.fct.2022.112947 http://hdl.handle.net/11449/231639 |
Resumo: | Growing human demand for food has culminated in increased use of pesticides worldwide. Prothioconazole (PTC), a profungicide, is bioactivated by metabolic PTC oxidation to prothioconazole-desthio (D-PTC). Here, the in vitro phase I metabolism of PTC to D-PTC in human liver microsomes and human CYP450 forms was studied. The kinetic parameters for the formation of (+)-D-PTC (KM = 1.2 μmol L−1, VMAX = 1.7 pmol min−1 mg−1), (−)-D-PTC (KM = 7 μmol L−1, VMAX = 5.1 pmol min−1 mg−1), and both D-PTC enantiomers (KM = 9 μmol L−1, VMAX = 7 pmol min−1 mg−1) from rac-PTC indicated an enantioselective behavior. Formation of the enantiomer (+)-D-PTC was twice more extensive than the formation of the enantiomer (−)-D-PTC. Furthermore, CLH prediction revealed the same enantioselective behavior. The phenotyping study indicated that CYP2C19 was the sole CYP450 form accounting for the metabolism of PTC. The estimated apparent distribution volume of PTC was predicted as 2 L kg−1. This study showed that D-PTC may be formed in the human organism due to hepatic metabolism of PTC, mediated by CYP2C19 and that the enantiomer (+)-D-PTC is preferentially formed. However, it was not extensively formed (~1%). Considering a risk assessment point of view, this study provided positive evidence of PTC safety. |
id |
UNSP_cd232c9083b8db57c44b79b33b8157a5 |
---|---|
oai_identifier_str |
oai:repositorio.unesp.br:11449/231639 |
network_acronym_str |
UNSP |
network_name_str |
Repositório Institucional da UNESP |
repository_id_str |
2946 |
spelling |
In vitro-in vivo correlation of the chiral pesticide prothioconazole after interaction with human CYP450 enzymesChiral pesticideEnantioselectiveHuman liver microsomesIn vitro-in vivoMetabolismProthioconazoleGrowing human demand for food has culminated in increased use of pesticides worldwide. Prothioconazole (PTC), a profungicide, is bioactivated by metabolic PTC oxidation to prothioconazole-desthio (D-PTC). Here, the in vitro phase I metabolism of PTC to D-PTC in human liver microsomes and human CYP450 forms was studied. The kinetic parameters for the formation of (+)-D-PTC (KM = 1.2 μmol L−1, VMAX = 1.7 pmol min−1 mg−1), (−)-D-PTC (KM = 7 μmol L−1, VMAX = 5.1 pmol min−1 mg−1), and both D-PTC enantiomers (KM = 9 μmol L−1, VMAX = 7 pmol min−1 mg−1) from rac-PTC indicated an enantioselective behavior. Formation of the enantiomer (+)-D-PTC was twice more extensive than the formation of the enantiomer (−)-D-PTC. Furthermore, CLH prediction revealed the same enantioselective behavior. The phenotyping study indicated that CYP2C19 was the sole CYP450 form accounting for the metabolism of PTC. The estimated apparent distribution volume of PTC was predicted as 2 L kg−1. This study showed that D-PTC may be formed in the human organism due to hepatic metabolism of PTC, mediated by CYP2C19 and that the enantiomer (+)-D-PTC is preferentially formed. However, it was not extensively formed (~1%). Considering a risk assessment point of view, this study provided positive evidence of PTC safety.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Departamento de Química Faculdade de Filosofia Ciências e Letras de Ribeirão Preto Universidade de São Paulo, SPNúcleo de Pesquisas de Produtos Naturais e Sintéticos Departamento de Ciências Biomoleculares Faculdade de Ciências Farmacêuticas de Ribeirão Preto Universidade de São Paulo, SPNational Institute for Alternative Technologies of Detection Toxicological Evaluation and Removal of Micropollutants and Radioactives (INCT–DATREM) Unesp Institute of Chemistry, P.O. Box 355, SPNational Institute for Alternative Technologies of Detection Toxicological Evaluation and Removal of Micropollutants and Radioactives (INCT–DATREM) Unesp Institute of Chemistry, P.O. Box 355, SPFAPESP: 2014/50945-4FAPESP: 2016/14668-7FAPESP: 2018/07534-4FAPESP: 2020/02139-0FAPESP: 2021/10098-4CNPq: 465571/2014-0Universidade de São Paulo (USP)Universidade Estadual Paulista (UNESP)Perovani, Icaro SalgadoSantos Barbetta, Maike FelipeMoreira da Silva, RodrigoLopes, Norberto PeporineMoraes de Oliveira, Anderson Rodrigo [UNESP]2022-04-29T08:46:42Z2022-04-29T08:46:42Z2022-05-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1016/j.fct.2022.112947Food and Chemical Toxicology, v. 163.1873-63510278-6915http://hdl.handle.net/11449/23163910.1016/j.fct.2022.1129472-s2.0-85126881672Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengFood and Chemical Toxicologyinfo:eu-repo/semantics/openAccess2024-06-24T14:52:02Zoai:repositorio.unesp.br:11449/231639Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T21:53:34.220820Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
In vitro-in vivo correlation of the chiral pesticide prothioconazole after interaction with human CYP450 enzymes |
title |
In vitro-in vivo correlation of the chiral pesticide prothioconazole after interaction with human CYP450 enzymes |
spellingShingle |
In vitro-in vivo correlation of the chiral pesticide prothioconazole after interaction with human CYP450 enzymes Perovani, Icaro Salgado Chiral pesticide Enantioselective Human liver microsomes In vitro-in vivo Metabolism Prothioconazole |
title_short |
In vitro-in vivo correlation of the chiral pesticide prothioconazole after interaction with human CYP450 enzymes |
title_full |
In vitro-in vivo correlation of the chiral pesticide prothioconazole after interaction with human CYP450 enzymes |
title_fullStr |
In vitro-in vivo correlation of the chiral pesticide prothioconazole after interaction with human CYP450 enzymes |
title_full_unstemmed |
In vitro-in vivo correlation of the chiral pesticide prothioconazole after interaction with human CYP450 enzymes |
title_sort |
In vitro-in vivo correlation of the chiral pesticide prothioconazole after interaction with human CYP450 enzymes |
author |
Perovani, Icaro Salgado |
author_facet |
Perovani, Icaro Salgado Santos Barbetta, Maike Felipe Moreira da Silva, Rodrigo Lopes, Norberto Peporine Moraes de Oliveira, Anderson Rodrigo [UNESP] |
author_role |
author |
author2 |
Santos Barbetta, Maike Felipe Moreira da Silva, Rodrigo Lopes, Norberto Peporine Moraes de Oliveira, Anderson Rodrigo [UNESP] |
author2_role |
author author author author |
dc.contributor.none.fl_str_mv |
Universidade de São Paulo (USP) Universidade Estadual Paulista (UNESP) |
dc.contributor.author.fl_str_mv |
Perovani, Icaro Salgado Santos Barbetta, Maike Felipe Moreira da Silva, Rodrigo Lopes, Norberto Peporine Moraes de Oliveira, Anderson Rodrigo [UNESP] |
dc.subject.por.fl_str_mv |
Chiral pesticide Enantioselective Human liver microsomes In vitro-in vivo Metabolism Prothioconazole |
topic |
Chiral pesticide Enantioselective Human liver microsomes In vitro-in vivo Metabolism Prothioconazole |
description |
Growing human demand for food has culminated in increased use of pesticides worldwide. Prothioconazole (PTC), a profungicide, is bioactivated by metabolic PTC oxidation to prothioconazole-desthio (D-PTC). Here, the in vitro phase I metabolism of PTC to D-PTC in human liver microsomes and human CYP450 forms was studied. The kinetic parameters for the formation of (+)-D-PTC (KM = 1.2 μmol L−1, VMAX = 1.7 pmol min−1 mg−1), (−)-D-PTC (KM = 7 μmol L−1, VMAX = 5.1 pmol min−1 mg−1), and both D-PTC enantiomers (KM = 9 μmol L−1, VMAX = 7 pmol min−1 mg−1) from rac-PTC indicated an enantioselective behavior. Formation of the enantiomer (+)-D-PTC was twice more extensive than the formation of the enantiomer (−)-D-PTC. Furthermore, CLH prediction revealed the same enantioselective behavior. The phenotyping study indicated that CYP2C19 was the sole CYP450 form accounting for the metabolism of PTC. The estimated apparent distribution volume of PTC was predicted as 2 L kg−1. This study showed that D-PTC may be formed in the human organism due to hepatic metabolism of PTC, mediated by CYP2C19 and that the enantiomer (+)-D-PTC is preferentially formed. However, it was not extensively formed (~1%). Considering a risk assessment point of view, this study provided positive evidence of PTC safety. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-04-29T08:46:42Z 2022-04-29T08:46:42Z 2022-05-01 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://dx.doi.org/10.1016/j.fct.2022.112947 Food and Chemical Toxicology, v. 163. 1873-6351 0278-6915 http://hdl.handle.net/11449/231639 10.1016/j.fct.2022.112947 2-s2.0-85126881672 |
url |
http://dx.doi.org/10.1016/j.fct.2022.112947 http://hdl.handle.net/11449/231639 |
identifier_str_mv |
Food and Chemical Toxicology, v. 163. 1873-6351 0278-6915 10.1016/j.fct.2022.112947 2-s2.0-85126881672 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Food and Chemical Toxicology |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.source.none.fl_str_mv |
Scopus reponame:Repositório Institucional da UNESP instname:Universidade Estadual Paulista (UNESP) instacron:UNESP |
instname_str |
Universidade Estadual Paulista (UNESP) |
instacron_str |
UNESP |
institution |
UNESP |
reponame_str |
Repositório Institucional da UNESP |
collection |
Repositório Institucional da UNESP |
repository.name.fl_str_mv |
Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP) |
repository.mail.fl_str_mv |
|
_version_ |
1808129371007877120 |