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 <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 BMDL10derived 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.
authors.affiliation: Division of Toxicology, Wageningen University, Building 124, Stippeneng 4, 6708 WE, Wageningen, The Netherlands. amer.almalahmeh@wur.nl.|Aqaba International Laboratories/BENHAYYAN, ASEZA, Aqaba, 77110, Jordan. amer.almalahmeh@wur.nl.
authors.forename: Amer J
authors.initials: AJ
authors.lastname: Al-Malahmeh
authors.affiliation: Division of Toxicology, Wageningen University, Building 124, Stippeneng 4, 6708 WE, Wageningen, The Netherlands.|Aqaba International Laboratories/BENHAYYAN, ASEZA, Aqaba, 77110, Jordan.
authors.forename: Abdelmajeed
authors.initials: A
authors.lastname: Al-Ajlouni
authors.affiliation: Division of Toxicology, Wageningen University, Building 124, Stippeneng 4, 6708 WE, Wageningen, The Netherlands.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Wesseling
authors.affiliation: Division of Toxicology, Wageningen University, Building 124, Stippeneng 4, 6708 WE, Wageningen, The Netherlands.
authors.forename: Ans E M F
authors.initials: AE
authors.lastname: Soffers
authors.affiliation: Faculty of Pharmacy, Philadelphia University, P.O. Box 1, Amman, 19392, Jordan.
authors.forename: Ala'
authors.initials: A
authors.lastname: Al-Subeihi
authors.affiliation: Division of Toxicology, Wageningen University, Building 124, Stippeneng 4, 6708 WE, Wageningen, The Netherlands.
authors.forename: Reiko
authors.initials: R
authors.lastname: Kiwamoto
authors.affiliation: Department of Biochemistry, Wageningen University, Building 124, Stippeneng 4, 6708 WE, Wageningen, The Netherlands.
authors.forename: Jacques
authors.initials: J
authors.lastname: Vervoort
authors.affiliation: Division of Toxicology, Wageningen University, Building 124, Stippeneng 4, 6708 WE, Wageningen, The Netherlands.
authors.forename: Ivonne M C M
authors.initials: IM
authors.lastname: Rietjens
mesh_terms: D065767:Activation, Metabolic; D000081248:Allylbenzene Derivatives; D000818:Animals; D001593:Benzyl Compounds / Q000493:pharmacokinetics*; D002273:Carcinogens / Q000493:pharmacokinetics; D004148:Dioxolanes / Q000493:pharmacokinetics*; D006801:Humans; D008658:Inactivation, Metabolic; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D008962:Models, Theoretical; D010084:Oxidation-Reduction; D011748:Pyrogallol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment / Q000379:methods; D012451:Safrole / Q000493:pharmacokinetics
chemical_list: C000614632:1'-sulfoxymyristicin; D000081248:Allylbenzene Derivatives; D001593:Benzyl Compounds; D002273:Carcinogens; D004148:Dioxolanes; D011748:Pyrogallol; C005246:myristicin; D012451:Safrole
keywords: Alkenylbenzenes; Myristicin; Physiologically based kinetic (PBK) modeling; Read-across-based risk assessment; Safrole