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In silico methods for metabolomic and toxicity prediction of zearalenone, α-zearalenone and β-zearalenone

Zearalenone (ZEA), α-zearalenol (α-ZEL) and β-zearalenol (β-ZEL) (ZEA's metabolites) are co/present in cereals, fruits or their products. All three with other compounds, constitute a cocktail-mixture that consumers (and also animals) are exposed and never entirely evaluated, nor in vitro nor in...

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Autores principales: Agahi, Fojan, Juan, Cristina, Font, Guillermina, Juan-García, Ana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Ltd. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576377/
https://www.ncbi.nlm.nih.gov/pubmed/33098936
http://dx.doi.org/10.1016/j.fct.2020.111818
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author Agahi, Fojan
Juan, Cristina
Font, Guillermina
Juan-García, Ana
author_facet Agahi, Fojan
Juan, Cristina
Font, Guillermina
Juan-García, Ana
author_sort Agahi, Fojan
collection PubMed
description Zearalenone (ZEA), α-zearalenol (α-ZEL) and β-zearalenol (β-ZEL) (ZEA's metabolites) are co/present in cereals, fruits or their products. All three with other compounds, constitute a cocktail-mixture that consumers (and also animals) are exposed and never entirely evaluated, nor in vitro nor in vivo. Effect of ZEA has been correlated to endocrine disruptor alterations as well as its metabolites (α-ZEL and β-ZEL); however, toxic effects associated to metabolites generated once ingested are unknown and difficult to study. The present study defines the metabolomics profile of all three mycotoxins (ZEA, α-ZEL and β-ZEL) and explores the prediction of their toxic effects proposing an in silico workflow by using three programs of predictions: MetaTox, SwissADME and PASS online. Metabolomic profile was also defined and toxic effect evaluated for all metabolite products from Phase I and II reaction (a total of 15 compounds). Results revealed that products describing metabolomics profile were: from O-glucuronidation (1z and 2z for ZEA and 1 ab, 2 ab and 3 ab for ZEA's metabolites), S-sulfation (3z and 4z for ZEA and 4 ab, 5 ab and 6 ab for ZEA's metabolites) and hydrolysis (5z and 7 ab for ZEA's metabolites, respectively). Lipinsky's rule-of-five was followed by all compounds except those coming from O-glucuronidation (HBA>10). Metabolite products had better properties to reach blood brain barrier than initial mycotoxins. According to Pa values (probability of activation) order of toxic effects studied was carcinogenicity > nephrotoxic > hepatotoxic > endocrine disruptor > mutagenic (AMES TEST) > genotoxic. Prediction of inhibition, induction and substrate function on different isoforms of Cytochrome P450 (CYP1A1, CYP1A2, CYP2C9 and CYP3A4) varied for each compounds analyzed; similarly, for activation of caspases 3 and 8. Relying to our findings, the metabolomics profile of ZEA, α-ZEL and β-ZEL analyzed by in silico programs predicts alteration of systems/pathways/mechanisms that ends up causing several toxic effects, giving an excellent sight and direct studies before starting in vitro or in vivo assays contributing to 3Rs principle; however, confirmation can be only demonstrated by performing those assays.
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spelling pubmed-75763772020-10-21 In silico methods for metabolomic and toxicity prediction of zearalenone, α-zearalenone and β-zearalenone Agahi, Fojan Juan, Cristina Font, Guillermina Juan-García, Ana Food Chem Toxicol Article Zearalenone (ZEA), α-zearalenol (α-ZEL) and β-zearalenol (β-ZEL) (ZEA's metabolites) are co/present in cereals, fruits or their products. All three with other compounds, constitute a cocktail-mixture that consumers (and also animals) are exposed and never entirely evaluated, nor in vitro nor in vivo. Effect of ZEA has been correlated to endocrine disruptor alterations as well as its metabolites (α-ZEL and β-ZEL); however, toxic effects associated to metabolites generated once ingested are unknown and difficult to study. The present study defines the metabolomics profile of all three mycotoxins (ZEA, α-ZEL and β-ZEL) and explores the prediction of their toxic effects proposing an in silico workflow by using three programs of predictions: MetaTox, SwissADME and PASS online. Metabolomic profile was also defined and toxic effect evaluated for all metabolite products from Phase I and II reaction (a total of 15 compounds). Results revealed that products describing metabolomics profile were: from O-glucuronidation (1z and 2z for ZEA and 1 ab, 2 ab and 3 ab for ZEA's metabolites), S-sulfation (3z and 4z for ZEA and 4 ab, 5 ab and 6 ab for ZEA's metabolites) and hydrolysis (5z and 7 ab for ZEA's metabolites, respectively). Lipinsky's rule-of-five was followed by all compounds except those coming from O-glucuronidation (HBA>10). Metabolite products had better properties to reach blood brain barrier than initial mycotoxins. According to Pa values (probability of activation) order of toxic effects studied was carcinogenicity > nephrotoxic > hepatotoxic > endocrine disruptor > mutagenic (AMES TEST) > genotoxic. Prediction of inhibition, induction and substrate function on different isoforms of Cytochrome P450 (CYP1A1, CYP1A2, CYP2C9 and CYP3A4) varied for each compounds analyzed; similarly, for activation of caspases 3 and 8. Relying to our findings, the metabolomics profile of ZEA, α-ZEL and β-ZEL analyzed by in silico programs predicts alteration of systems/pathways/mechanisms that ends up causing several toxic effects, giving an excellent sight and direct studies before starting in vitro or in vivo assays contributing to 3Rs principle; however, confirmation can be only demonstrated by performing those assays. Elsevier Ltd. 2020-12 2020-10-21 /pmc/articles/PMC7576377/ /pubmed/33098936 http://dx.doi.org/10.1016/j.fct.2020.111818 Text en © 2020 Elsevier Ltd. All rights reserved. Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
spellingShingle Article
Agahi, Fojan
Juan, Cristina
Font, Guillermina
Juan-García, Ana
In silico methods for metabolomic and toxicity prediction of zearalenone, α-zearalenone and β-zearalenone
title In silico methods for metabolomic and toxicity prediction of zearalenone, α-zearalenone and β-zearalenone
title_full In silico methods for metabolomic and toxicity prediction of zearalenone, α-zearalenone and β-zearalenone
title_fullStr In silico methods for metabolomic and toxicity prediction of zearalenone, α-zearalenone and β-zearalenone
title_full_unstemmed In silico methods for metabolomic and toxicity prediction of zearalenone, α-zearalenone and β-zearalenone
title_short In silico methods for metabolomic and toxicity prediction of zearalenone, α-zearalenone and β-zearalenone
title_sort in silico methods for metabolomic and toxicity prediction of zearalenone, α-zearalenone and β-zearalenone
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576377/
https://www.ncbi.nlm.nih.gov/pubmed/33098936
http://dx.doi.org/10.1016/j.fct.2020.111818
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