A Computational Inter-Species Study on Safrole Phase I Metabolism-Dependent Bioactivation: A Mechanistic Insight into the Study of Possible Differences among Species
Safrole, a 162.2 Da natural compound belonging to the alkenylbenzenes class, is classified as a possible carcinogen to humans by IARC (group IIB) and has proven to be genotoxic and carcinogenic to rodents. Despite its use as a food or feed additive, it is forbidden in many countries due to its docum...
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| Format: | Article |
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MDPI AG
2023-01-01
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| Series: | Toxins |
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| Online Access: | https://www.mdpi.com/2072-6651/15/2/94 |
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| author | Lorenzo Pedroni Jochem Louisse Ans Punt Jean Lou C. M. Dorne Chiara Dall’Asta Luca Dellafiora |
| author_facet | Lorenzo Pedroni Jochem Louisse Ans Punt Jean Lou C. M. Dorne Chiara Dall’Asta Luca Dellafiora |
| author_sort | Lorenzo Pedroni |
| collection | DOAJ |
| description | Safrole, a 162.2 Da natural compound belonging to the alkenylbenzenes class, is classified as a possible carcinogen to humans by IARC (group IIB) and has proven to be genotoxic and carcinogenic to rodents. Despite its use as a food or feed additive, it is forbidden in many countries due to its documented toxicity; yet, it is still broadly present within food and feed and is particularly abundant in spices, herbs and essential oils. Specifically, safrole may exert its toxicity upon bioactivation to its proximate carcinogen 1′-hydroxy-safrole via specific members of the cytochrome P450 protein family with a certain inter/intra-species variability. To investigate this variability, an in-silico workflow based on molecular modelling, docking and molecular dynamics has been successfully applied. This work highlighted the mechanistic basis underpinning differences among humans, cats, chickens, goats, sheep, dogs, mice, pigs, rats and rabbits. The chosen metric to estimate the likeliness of formation of 1′-hydroxy-safrole by the species-specific cytochrome P450 under investigation allowed for the provision of a knowledge-based ground to rationally design and prioritise further experiments and deepen the current understanding of alkenylbenzenes bioactivation and CYPs mechanics. Both are crucial for a more informed framework of analysis for safrole toxicity. |
| first_indexed | 2024-03-11T08:04:24Z |
| format | Article |
| id | doaj.art-ebf0a3bb97974406a935bad225008780 |
| institution | Directory Open Access Journal |
| issn | 2072-6651 |
| language | English |
| last_indexed | 2024-03-11T08:04:24Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Toxins |
| spelling | doaj.art-ebf0a3bb97974406a935bad2250087802023-11-16T23:38:29ZengMDPI AGToxins2072-66512023-01-011529410.3390/toxins15020094A Computational Inter-Species Study on Safrole Phase I Metabolism-Dependent Bioactivation: A Mechanistic Insight into the Study of Possible Differences among SpeciesLorenzo Pedroni0Jochem Louisse1Ans Punt2Jean Lou C. M. Dorne3Chiara Dall’Asta4Luca Dellafiora5Department of Food and Drug, University of Parma, 43124 Parma, ItalyWageningen Food Safety Research, P.O. Box 230, 6700 AE Wageningen, The NetherlandsWageningen Food Safety Research, P.O. Box 230, 6700 AE Wageningen, The NetherlandsMethodology and Scientific Support Unit (MESE), European Food Safety Authority, 43126 Parma, ItalyDepartment of Food and Drug, University of Parma, 43124 Parma, ItalyDepartment of Food and Drug, University of Parma, 43124 Parma, ItalySafrole, a 162.2 Da natural compound belonging to the alkenylbenzenes class, is classified as a possible carcinogen to humans by IARC (group IIB) and has proven to be genotoxic and carcinogenic to rodents. Despite its use as a food or feed additive, it is forbidden in many countries due to its documented toxicity; yet, it is still broadly present within food and feed and is particularly abundant in spices, herbs and essential oils. Specifically, safrole may exert its toxicity upon bioactivation to its proximate carcinogen 1′-hydroxy-safrole via specific members of the cytochrome P450 protein family with a certain inter/intra-species variability. To investigate this variability, an in-silico workflow based on molecular modelling, docking and molecular dynamics has been successfully applied. This work highlighted the mechanistic basis underpinning differences among humans, cats, chickens, goats, sheep, dogs, mice, pigs, rats and rabbits. The chosen metric to estimate the likeliness of formation of 1′-hydroxy-safrole by the species-specific cytochrome P450 under investigation allowed for the provision of a knowledge-based ground to rationally design and prioritise further experiments and deepen the current understanding of alkenylbenzenes bioactivation and CYPs mechanics. Both are crucial for a more informed framework of analysis for safrole toxicity.https://www.mdpi.com/2072-6651/15/2/94alkenylbenzenescytochrome P450safroleestragoleCYP1A2CYP2A6 |
| spellingShingle | Lorenzo Pedroni Jochem Louisse Ans Punt Jean Lou C. M. Dorne Chiara Dall’Asta Luca Dellafiora A Computational Inter-Species Study on Safrole Phase I Metabolism-Dependent Bioactivation: A Mechanistic Insight into the Study of Possible Differences among Species Toxins alkenylbenzenes cytochrome P450 safrole estragole CYP1A2 CYP2A6 |
| title | A Computational Inter-Species Study on Safrole Phase I Metabolism-Dependent Bioactivation: A Mechanistic Insight into the Study of Possible Differences among Species |
| title_full | A Computational Inter-Species Study on Safrole Phase I Metabolism-Dependent Bioactivation: A Mechanistic Insight into the Study of Possible Differences among Species |
| title_fullStr | A Computational Inter-Species Study on Safrole Phase I Metabolism-Dependent Bioactivation: A Mechanistic Insight into the Study of Possible Differences among Species |
| title_full_unstemmed | A Computational Inter-Species Study on Safrole Phase I Metabolism-Dependent Bioactivation: A Mechanistic Insight into the Study of Possible Differences among Species |
| title_short | A Computational Inter-Species Study on Safrole Phase I Metabolism-Dependent Bioactivation: A Mechanistic Insight into the Study of Possible Differences among Species |
| title_sort | computational inter species study on safrole phase i metabolism dependent bioactivation a mechanistic insight into the study of possible differences among species |
| topic | alkenylbenzenes cytochrome P450 safrole estragole CYP1A2 CYP2A6 |
| url | https://www.mdpi.com/2072-6651/15/2/94 |
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