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Physiologically based kinetic modeling of the bioactivation of myristicin
The present study describes physiologically based kinetic (PBK) models for the alkenylbenzene myristicin that were developed by extension of the PBK models for the structurally related alkenylbenzene safrole in rat and human. The newly developed myristicin models revealed that the formation of the p...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5306082/ https://www.ncbi.nlm.nih.gov/pubmed/27334372 http://dx.doi.org/10.1007/s00204-016-1752-5 |
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author | Al-Malahmeh, Amer J. Al-Ajlouni, Abdelmajeed Wesseling, Sebastiaan Soffers, Ans E. M. F. Al-Subeihi, Ala’ Kiwamoto, Reiko Vervoort, Jacques Rietjens, Ivonne M. C. M. |
author_facet | Al-Malahmeh, Amer J. Al-Ajlouni, Abdelmajeed Wesseling, Sebastiaan Soffers, Ans E. M. F. Al-Subeihi, Ala’ Kiwamoto, Reiko Vervoort, Jacques Rietjens, Ivonne M. C. M. |
author_sort | Al-Malahmeh, Amer J. |
collection | PubMed |
description | The present study describes physiologically based kinetic (PBK) models for the alkenylbenzene myristicin that were developed by extension of the PBK models for the structurally related alkenylbenzene safrole in rat and human. The newly developed myristicin models revealed that the formation of the proximate carcinogenic metabolite 1′-hydroxymyristicin in liver is at most 1.8 fold higher in rat than in human and limited for the ultimate carcinogenic metabolite 1′-sulfoxymyristicin to (2.8–4.0)-fold higher in human. In addition, a comparison was made between the relative importance of bioactivation for myristicin and safrole. Model predictions indicate that for these related compounds, the formation of the 1′-sulfoxy metabolites in rat and human liver is comparable with a difference of <2.2-fold over a wide dose range. The results from this PBK analysis support that risk assessment of myristicin may be based on the BMDL(10) derived for safrole of 1.9–5.1 mg/kg bw per day. Using an estimated daily intake of myristicin of 0.0019 mg/kg bw per day resulting from the use of herbs and spices, this results in MOE values for myristicin that amount to 1000–2700, indicating a priority for risk management. The results obtained illustrate that PBK modeling provides insight into possible species differences in the metabolic activation of myristicin. Moreover, they provide an example of how PBK modeling can facilitate a read-across in risk assessment from a compound for which in vivo toxicity studies are available to a related compound for which tumor data are not reported, thus contributing to alternatives in animal testing. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00204-016-1752-5) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5306082 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-53060822017-02-24 Physiologically based kinetic modeling of the bioactivation of myristicin Al-Malahmeh, Amer J. Al-Ajlouni, Abdelmajeed Wesseling, Sebastiaan Soffers, Ans E. M. F. Al-Subeihi, Ala’ Kiwamoto, Reiko Vervoort, Jacques Rietjens, Ivonne M. C. M. Arch Toxicol Toxicokinetics and Metabolism The present study describes physiologically based kinetic (PBK) models for the alkenylbenzene myristicin that were developed by extension of the PBK models for the structurally related alkenylbenzene safrole in rat and human. The newly developed myristicin models revealed that the formation of the proximate carcinogenic metabolite 1′-hydroxymyristicin in liver is at most 1.8 fold higher in rat than in human and limited for the ultimate carcinogenic metabolite 1′-sulfoxymyristicin to (2.8–4.0)-fold higher in human. In addition, a comparison was made between the relative importance of bioactivation for myristicin and safrole. Model predictions indicate that for these related compounds, the formation of the 1′-sulfoxy metabolites in rat and human liver is comparable with a difference of <2.2-fold over a wide dose range. The results from this PBK analysis support that risk assessment of myristicin may be based on the BMDL(10) derived for safrole of 1.9–5.1 mg/kg bw per day. Using an estimated daily intake of myristicin of 0.0019 mg/kg bw per day resulting from the use of herbs and spices, this results in MOE values for myristicin that amount to 1000–2700, indicating a priority for risk management. The results obtained illustrate that PBK modeling provides insight into possible species differences in the metabolic activation of myristicin. Moreover, they provide an example of how PBK modeling can facilitate a read-across in risk assessment from a compound for which in vivo toxicity studies are available to a related compound for which tumor data are not reported, thus contributing to alternatives in animal testing. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00204-016-1752-5) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2016-06-22 2017 /pmc/articles/PMC5306082/ /pubmed/27334372 http://dx.doi.org/10.1007/s00204-016-1752-5 Text en © The Author(s) 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
spellingShingle | Toxicokinetics and Metabolism Al-Malahmeh, Amer J. Al-Ajlouni, Abdelmajeed Wesseling, Sebastiaan Soffers, Ans E. M. F. Al-Subeihi, Ala’ Kiwamoto, Reiko Vervoort, Jacques Rietjens, Ivonne M. C. M. Physiologically based kinetic modeling of the bioactivation of myristicin |
title | Physiologically based kinetic modeling of the bioactivation of myristicin |
title_full | Physiologically based kinetic modeling of the bioactivation of myristicin |
title_fullStr | Physiologically based kinetic modeling of the bioactivation of myristicin |
title_full_unstemmed | Physiologically based kinetic modeling of the bioactivation of myristicin |
title_short | Physiologically based kinetic modeling of the bioactivation of myristicin |
title_sort | physiologically based kinetic modeling of the bioactivation of myristicin |
topic | Toxicokinetics and Metabolism |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5306082/ https://www.ncbi.nlm.nih.gov/pubmed/27334372 http://dx.doi.org/10.1007/s00204-016-1752-5 |
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