Evaluation of the interindividual human variation in bioactivation of methyleugenol using physiologically based kinetic modeling and Monte Carlo simulations

Al-Subeihi, Ala’ Ali Ahmad; Alhusainy, Wasma; Kiwamoto, R.; Spenkelink, Bert; Bladeren, P.J. van; Rietjens, Ivonne M.C.M.; Punt, Ans

doi:10.1016/j.taap.2014.12.009

Cited by 15 publications

(14 citation statements)

References 27 publications

(30 reference statements)

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“…The linear sensitivity analysis now performed was a simple first tier approach aiming to provide initial information about which parameters influence the predicted C max values most, while a more extended analysis of variability in the thus identified most influential parameters, for example via example Monte Carlo modeling, might provide additional insight in intraspecies differences. [ 52,53,54 ]…”

Section: Methodsmentioning

confidence: 99%

Use of Physiologically Based Kinetic Modeling to Predict Rat Gut Microbial Metabolism of the Isoflavone Daidzein to S‐Equol and Its Consequences for ERα Activation

Wang

Spenkelink

Boonpawa

et al. 2020

Molecular Nutrition Food Res

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Scope To predict gut microbial metabolism of xenobiotics and the resulting plasma concentrations of metabolites formed, an in vitro–in silico‐based testing strategy is developed using the isoflavone daidzein and its gut microbial metabolite S‐equol as model compounds. Methods and results Anaerobic rat fecal incubations are optimized and performed to derive the apparent maximum velocities (Vmax) and Michaelis–Menten constants (Km) for gut microbial conversion of daidzein to dihydrodaidzein, S‐equol, and O‐desmethylangolensin, which are input as parameters for a physiologically based kinetic (PBK) model. The inclusion of gut microbiota in the PBK model allows prediction of S‐equol concentrations and slightly reduced predicted maximal daidzein concentrations from 2.19 to 2.16 µm. The resulting predicted concentrations of daidzein and S‐equol are comparable to in vivo concentrations reported. Conclusion The optimized in vitro approach to quantify kinetics for gut microbial conversions, and the newly developed PBK model for rats that includes gut microbial metabolism, provide a unique tool to predict the in vivo consequences of daidzein microbial metabolism for systemic exposure of the host to daidzein and its metabolite S‐equol. The predictions reveal a dominant role for daidzein in ERα‐mediated estrogenicity despite the higher estrogenic potency of its microbial metabolite S‐equol.

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Section: Methodsmentioning

confidence: 99%

Use of Physiologically Based Kinetic Modeling to Predict Rat Gut Microbial Metabolism of the Isoflavone Daidzein to S‐Equol and Its Consequences for ERα Activation

Wang

Spenkelink

Boonpawa

et al. 2020

Molecular Nutrition Food Res

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“…The results obtained with the Monte Carlo simulation on the variability in the formation of 1′-sulfooxyestragole can potentially be used to derive a so-called chemical-specific adjustment factor (CSAF), which can be used to evaluate the appropriateness of the default factor of 3.16 generally assumed to reflect interindividual variation in kinetics within the human population. ,− On the basis of the guidelines of the International Program on Chemical Safety (IPCS, 2005), CSAFs can be calculated as the ratio between given percentiles (such as 90th, 95th, 97.5th, or 99th) and the median for the whole population. Using the 90th percentile to represent a sensitive individual and the 50th percentile to represent the average individual, the CSAF can be calculated to amount to 2.6 based on the results of the present study.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Interindividual Human Variation in Bioactivation and DNA Adduct Formation of Estragole in Liver Predicted by Physiologically Based Kinetic/Dynamic and Monte Carlo Modeling

Punt

Paini

Spenkelink

et al. 2016

Chem. Res. Toxicol.

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Estragole is a known hepatocarcinogen in rodents at high doses following metabolic conversion to the DNA-reactive metabolite 1'-sulfooxyestragole. The aim of the present study was to model possible levels of DNA adduct formation in (individual) humans upon exposure to estragole. This was done by extending a previously defined PBK model for estragole in humans to include (i) new data on interindividual variation in the kinetics for the major PBK model parameters influencing the formation of 1'-sulfooxyestragole, (ii) an equation describing the relationship between 1'-sulfooxyestragole and DNA adduct formation, (iii) Monte Carlo modeling to simulate interindividual human variation in DNA adduct formation in the population, and (iv) a comparison of the predictions made to human data on DNA adduct formation for the related alkenylbenzene methyleugenol. Adequate model predictions could be made, with the predicted DNA adduct levels at the estimated daily intake of estragole of 0.01 mg/kg bw ranging between 1.6 and 8.8 adducts in 10(8) nucleotides (nts) (50th and 99th percentiles, respectively). This is somewhat lower than values reported in the literature for the related alkenylbenzene methyleugenol in surgical human liver samples. The predicted levels seem to be below DNA adduct levels that are linked with tumor formation by alkenylbenzenes in rodents, which were estimated to amount to 188-500 adducts per 10(8) nts at the BMD10 values of estragole and methyleugenol. Although this does not seem to point to a significant health concern for human dietary exposure, drawing firm conclusions may have to await further validation of the model's predictions.

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“…Likewise, the occurrence of N-acetyl-S-[3 -(4-methoxyphenyl)allyl]-L-cysteine-the mercapturic acid formed from 1 -sulfoxy estragole-in the urine of human volunteers after drinking fennel tea [52], as well as the detection of DNA adducts of 1 -sulfoxymethyleugenol in human liver samples [84,85], underlines the formation of reactive cations in humans. Of note, interindividual human variations, such as polymorphisms and lifestyle factors influencing the activity of certain enzymes involved in the metabolism of allylalkoxybenzenes, may also influence the level of bioactivation of these compounds [85][86][87][88]. To illustrate this, Tremmel et al have shown that the number of methyleugenol-derived DNA adducts in human liver samples is associated with the SULT1A1 copy number polymorphism [85].…”

Section: Toxicity Of Alkenylbenzenes 221 Toxicokinetic Impact On Toxic Properties Of Alkenylbenzenesmentioning

confidence: 99%

Alkenylbenzenes in Foods: Aspects Impeding the Evaluation of Adverse Health Effects

Eisenreich

Götz

Sachse

et al. 2021

Foods

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Alkenylbenzenes are naturally occurring secondary plant metabolites, primarily present in different herbs and spices, such as basil or fennel seeds. Thus, alkenylbenzenes, such as safrole, methyleugenol, and estragole, can be found in different foods, whenever these herbs and spices (or extracts thereof) are used for food production. In particular, essential oils or other food products derived from the aforementioned herbs and spices, such as basil-containing pesto or plant food supplements, are often characterized by a high content of alkenylbenzenes. While safrole or methyleugenol are known to be genotoxic and carcinogenic, the toxicological relevance of other alkenylbenzenes (e.g., apiol) regarding human health remains widely unclear. In this review, we will briefly summarize and discuss the current knowledge and the uncertainties impeding a conclusive evaluation of adverse effects to human health possibly resulting from consumption of foods containing alkenylbenzenes, especially focusing on the genotoxic compounds, safrole, methyleugenol, and estragole.

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Evaluation of the interindividual human variation in bioactivation of methyleugenol using physiologically based kinetic modeling and Monte Carlo simulations

Cited by 15 publications

References 27 publications

Use of Physiologically Based Kinetic Modeling to Predict Rat Gut Microbial Metabolism of the Isoflavone Daidzein to S‐Equol and Its Consequences for ERα Activation

Use of Physiologically Based Kinetic Modeling to Predict Rat Gut Microbial Metabolism of the Isoflavone Daidzein to S‐Equol and Its Consequences for ERα Activation

Evaluation of Interindividual Human Variation in Bioactivation and DNA Adduct Formation of Estragole in Liver Predicted by Physiologically Based Kinetic/Dynamic and Monte Carlo Modeling

Alkenylbenzenes in Foods: Aspects Impeding the Evaluation of Adverse Health Effects

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