An in vitromodel to quantify interspecies differences in kinetics for intestinal microbial bioactivation and detoxification of zearalenone

Mendez-Catala, Diana M.; Spenkelink, A.; Rietjens, Ivonne M.C.M.; Beekmann, Karsten

doi:10.1016/j.toxrep.2020.07.010

Cited by 17 publications

(30 citation statements)

References 64 publications

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“…The importance of taking differences kinetics into account when defining relative potencies of PAs was previously shown to also hold for the PAs themselves for which substantial differences in clearance may exist (Lester et al 2019). Successful incorporation of intestinal microbiota in PBK models has been demonstrated so far in only a few other studies (Mendez-Catala et al 2020;Wang et al 2020) and the current study provides another proof-of-principle for this approach.…”

Section: Discussionmentioning

confidence: 53%

Physiologically based kinetic modelling predicts the in vivo relative potency of riddelliine N-oxide compared to riddelliine in rat to be dose dependent

2021

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Pyrrolizidine alkaloids (PAs) are toxic plant constituents occurring often in their N-oxide form. This raises the question on the relative potency (REP) values of PA-N-oxides compared to the corresponding parent PAs. The present study aims to quantify the in vivo REP value of riddelliine N-oxide compared to riddelliine using physiologically based kinetic (PBK) modelling, taking into account that the toxicity of riddelliine N-oxide depends on its conversion to riddelliine by intestinal microbiota and in the liver. The models predicted a lower Cmax and higher Tmax for the blood concentration of riddelliine upon oral administration of riddelliine N-oxide compared to the Cmax and Tmax predicted for an equimolar oral dose of riddelliine. Comparison of the area under the riddelliine concentration–time curve (AUCRID) obtained upon dosing either the N-oxide or riddelliine itself revealed a ratio of 0.67, which reflects the in vivo REP for riddelliine N-oxide compared to riddelliine, and appeared to closely match the REP value derived from available in vivo data. The models also predicted that the REP value will decrease with increasing dose level, because of saturation of riddelliine N-oxide reduction by the intestinal microbiota and of riddelliine clearance by the liver. It is concluded that PBK modeling provides a way to define in vivo REP values of PA-N-oxides as compared to their parent PAs, without a need for animal experiments.

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Section: Discussionmentioning

confidence: 53%

Physiologically based kinetic modelling predicts the in vivo relative potency of riddelliine N-oxide compared to riddelliine in rat to be dose dependent

2021

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“…Species Metabolite Calculated from [(V max , in vitro) × (mg S9 protein/g liver) × (g liver) × (60 min h −1 )]/(10 6 μmol pmol −1 )/kg bw. For rat and human the mg S9 protein/g liver were 143 and 120.7, respectively; b) Malekinejad et al [35] ; c) Mendez-Catala et al [10] Table 4. In vitro and scaled in vivo kinetic parameter for the conversion of ZEN to 𝛼-ZEL and 𝛽-ZEL by the intestinal microbiota as derived from anaerobic in vitro incubations of ZEN with rat and human fecal slurries.…”

Section: Pbk Model Evaluationmentioning

confidence: 96%

“…In vitro and scaled in vivo kinetic parameter for the conversion of ZEN to 𝛼-ZEL and 𝛽-ZEL by the intestinal microbiota as derived from anaerobic in vitro incubations of ZEN with rat and human fecal slurries. [10] Species Metabolite…”

Section: Pbk Model Evaluationmentioning

confidence: 99%

PBK Model‐Based Prediction of Intestinal Microbial and Host Metabolism of Zearalenone and Consequences for its Estrogenicity

Mendez-Catala

Wang

Rietjens

2021

Molecular Nutrition Food Res

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The aim of the present study is to develop physiologically-based kinetic (PBK) models for rat and human that include intestinal microbial and hepatic metabolism of zearalenone (ZEN) in order to predict systemic concentrations of ZEN and to obtain insight in the contribution of metabolism by the intestinal microbiota to the overall metabolism of ZEN. Methods and Results: In vitro derived kinetic parameters, apparent maximum velocities (V max ) and Michaelis-Menten constants (K m ) for liver and intestinal microbial metabolism of ZEN are included in the PBK models. The models include a sub-model for the metabolite, 𝜶-zearalenol (𝜶-ZEL), a metabolite known to be 60-times more potent as an estrogen than ZEN. Integrating intestinal microbial ZEN metabolism into the PBK models revealed that hepatic metabolism drives the formation of 𝜶-ZEL. Furthermore, the models predicted that at the tolerable daily intake (TDI) of 0.25 µg kg −1 bw the internal concentration of ZEN and 𝜶-ZEL are three-orders of magnitude below concentrations reported to induce estrogenicity in vitro. Conclusion: It is concluded that combining kinetic data on liver and intestinal microbial metabolism in a PBK model facilitates a holistic view on the role of the intestinal microbiota in the overall metabolism of the foodborne xenobiotic ZEN and its bioactivation to 𝜶-ZEL.

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“…Based on toxicokinetic information, the bioavailability of ZEN in pigs is as high as 80% to 85%, while it is less than 10% in poultry and mice ( Mendez-Catala et al., 2020 ; Yang et al., 2017 ). The hydroxylation of ZEN is considered a detoxification process.…”

Section: Possible Mechanisms Of Low Reproductive Toxicity Of Zearalenone In Poultrymentioning

confidence: 99%

“…Studies have used an in vitro model system to evaluate the contribution of intestinal microbial metabolism to the activation and detoxification of ZEN. It was found that the activity of intestinal microbes was equivalent to 36% of liver activity, and this may also be one of the important factors in the sensitivity of different animals to ZEN ( Mendez-Catala et al., 2020 ). However, this system has only been established in mammals.…”

Section: Possible Mechanisms Of Low Reproductive Toxicity Of Zearalenone In Poultrymentioning

confidence: 99%

The insensitive mechanism of poultry to zearalenone: A review

Ren

Gong

et al. 2021

Animal Nutrition

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Zearalenone (ZEN) is one of the most common contaminating mycotoxins and is mainly produced by Fusarium graminearum . ZEN and its metabolites can interfere with estrogen function and affect animals' reproductive ability. Pigs are most susceptible to ZEN, and ZEN is less harmful to poultry than to pigs. The exact mechanism for the difference in susceptibility remains unclear. In this review, we summarized some possible reasons for the relative insensitivity of poultry to ZEN, such as the lower total amount of α-zearalenol (α-ZOL) and the α-ZOL-to-β-ZOL ratio which reduce the toxicity of ZEN to poultry. The faster hepatic and enteric circulation, and excretion capacity in poultry can excrete more ZEN and its metabolites. There are other possible factors such as the transformation of intestinal microorganisms, differences in hydroxysteroid dehydrogenases' activity, high estrogen levels, and low estrogen receptors affinity which can also cause poultry to be relatively insensitive to ZEN. In this review, we summarized the hazards, pollution status, metabolic pathways, and some measures to mitigate ZEN's harmfulness. Specifically, we discussed the possible mechanisms of low reproductive toxicity by ZEN in poultry.

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An in vitromodel to quantify interspecies differences in kinetics for intestinal microbial bioactivation and detoxification of zearalenone

Abstract: Graphical abstract

Cited by 17 publications

References 64 publications

Physiologically based kinetic modelling predicts the in vivo relative potency of riddelliine N-oxide compared to riddelliine in rat to be dose dependent

Physiologically based kinetic modelling predicts the in vivo relative potency of riddelliine N-oxide compared to riddelliine in rat to be dose dependent

PBK Model‐Based Prediction of Intestinal Microbial and Host Metabolism of Zearalenone and Consequences for its Estrogenicity

The insensitive mechanism of poultry to zearalenone: A review

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