Physiologically based kinetic modeling of the bioactivation of myristicin

Amer J. Al-Malahmeh*, Abdelmajeed Al-Ajlouni, Sebastiaan Wesseling, Ans E.M.F. Soffers, A. Al-Subeihi, Reiko Kiwamoto, Jacques Vervoort, Ivonne M.C.M. Rietjens

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

15 Citations (Scopus)

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 (2.8–4.0)-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 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.

Original languageEnglish
Article number713
Number of pages22
JournalArchives of Toxicology
Volume91
DOIs
Publication statusPublished - 2017

Keywords

  • Alkenylbenzenes
  • Myristicin
  • Physiologically based kinetic (PBK) modeling
  • Read-across-based risk assessment
  • Safrole

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