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

Research output: Contribution to journalArticleAcademicpeer-review

13 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

Fingerprint

Safrole
Kinetics
Metabolites
Rats
Liver
Animal Testing Alternatives
Spices
Risk Management
Risk management
Risk assessment
Toxicity
myristicin
Tumors
Animals
Chemical activation
Testing
Neoplasms

Keywords

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

Cite this

Al-Malahmeh, A. J., Al-Ajlouni, A., Wesseling, S., Soffers, A. E. M. F., Al-Subeihi, A., Kiwamoto, R., ... Rietjens, I. M. C. M. (2017). Physiologically based kinetic modeling of the bioactivation of myristicin. Archives of Toxicology, 91, [713]. https://doi.org/10.1007/s00204-016-1752-5
Al-Malahmeh, Amer J. ; Al-Ajlouni, Abdelmajeed ; Wesseling, Sebastiaan ; Soffers, Ans E.M.F. ; Al-Subeihi, A. ; Kiwamoto, Reiko ; Vervoort, Jacques ; Rietjens, Ivonne M.C.M. / Physiologically based kinetic modeling of the bioactivation of myristicin. In: Archives of Toxicology. 2017 ; Vol. 91.
@article{227999ed923b4c61806151cae016d653,
title = "Physiologically based kinetic modeling of the bioactivation of myristicin",
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.",
keywords = "Alkenylbenzenes, Myristicin, Physiologically based kinetic (PBK) modeling, Read-across-based risk assessment, Safrole",
author = "Al-Malahmeh, {Amer J.} and Abdelmajeed Al-Ajlouni and Sebastiaan Wesseling and Soffers, {Ans E.M.F.} and A. Al-Subeihi and Reiko Kiwamoto and Jacques Vervoort and Rietjens, {Ivonne M.C.M.}",
year = "2017",
doi = "10.1007/s00204-016-1752-5",
language = "English",
volume = "91",
journal = "Archives of Toxicology",
issn = "0340-5761",
publisher = "Springer Verlag",

}

Al-Malahmeh, AJ, Al-Ajlouni, A, Wesseling, S, Soffers, AEMF, Al-Subeihi, A, Kiwamoto, R, Vervoort, J & Rietjens, IMCM 2017, 'Physiologically based kinetic modeling of the bioactivation of myristicin' Archives of Toxicology, vol. 91, 713. https://doi.org/10.1007/s00204-016-1752-5

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, A.; Kiwamoto, Reiko; Vervoort, Jacques; Rietjens, Ivonne M.C.M.

In: Archives of Toxicology, Vol. 91, 713, 2017.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Physiologically based kinetic modeling of the bioactivation of myristicin

AU - Al-Malahmeh, Amer J.

AU - Al-Ajlouni, Abdelmajeed

AU - Wesseling, Sebastiaan

AU - Soffers, Ans E.M.F.

AU - Al-Subeihi, A.

AU - Kiwamoto, Reiko

AU - Vervoort, Jacques

AU - Rietjens, Ivonne M.C.M.

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Alkenylbenzenes

KW - Myristicin

KW - Physiologically based kinetic (PBK) modeling

KW - Read-across-based risk assessment

KW - Safrole

U2 - 10.1007/s00204-016-1752-5

DO - 10.1007/s00204-016-1752-5

M3 - Article

VL - 91

JO - Archives of Toxicology

JF - Archives of Toxicology

SN - 0340-5761

M1 - 713

ER -

Al-Malahmeh AJ, Al-Ajlouni A, Wesseling S, Soffers AEMF, Al-Subeihi A, Kiwamoto R et al. Physiologically based kinetic modeling of the bioactivation of myristicin. Archives of Toxicology. 2017;91. 713. https://doi.org/10.1007/s00204-016-1752-5