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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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2016
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.
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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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