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Arch Toxicol (2017) 91:713734 DOI 10.1007/s00204-016-1752-5
TOXICOKINETICS AND METABOLISM
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Web End = Physiologically based kinetic modeling of the bioactivation of myristicin
Amer J. AlMalahmeh1,2 Abdelmajeed AlAjlouni1,2 Sebastiaan Wesseling1 Ans E. M. F. Soffers1 Ala AlSubeihi4 Reiko Kiwamoto1 Jacques Vervoort3 Ivonne M. C. M. Rietjens1
Abstract 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 (2.84.0)-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 BMDL10 derived for safrole of 1.95.1 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
Electronic supplementary material The online version of this article (doi:http://dx.doi.org/10.1007/s00204-016-1752-5
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* Amer J. Al-Malahmeh [email protected]
1 Division of Toxicology, Wageningen University, Building 124, Stippeneng 4, 6708 WE Wageningen, The Netherlands
2 Aqaba International Laboratories/BENHAYYAN, ASEZA, Aqaba 77110, Jordan
3 Department of Biochemistry, Wageningen University, Building 124, Stippeneng 4, 6708 WE Wageningen, The Netherlands
4 Faculty of Pharmacy, Philadelphia University, P.O. Box 1, Amman 19392, Jordan
Received: 3 February 2016 / Accepted: 8 June 2016 / Published online: 22 June 2016 The Author(s) 2016. This article is published with open access at Springerlink.com
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...