Predicting the Acute Liver Toxicity of Aflatoxin B1 in Rats and Humans by an In Vitro–In Silico Testing Strategy

Gilbert-Sandoval, Ixchel; Wesseling, Sebastiaan; Rietjens, Ivonne M.C.M.

doi:10.1002/mnfr.202000063

Cited by 27 publications

(14 citation statements)

References 64 publications

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“…The formulas used for the extrapolation to the whole liver hepatic clearance are shown in Equation 9 for HLM experiments and in Equation 10 for rhCYP experiments. For AFB1, an f u,B of 0.16 was reported by Gilbert-Sandoval et al, 2020 ; the f u,mic (0.9399) was estimated with Equation 3 for neutral compounds using SimCYP. The resulting CL H,B are listed in Table 5 .…”

Section: Resultsmentioning

confidence: 99%

Unravelling the pharmacokinetics of aflatoxin B1: In vitro determination of Michaelis–Menten constants, intrinsic clearance and the metabolic contribution of CYP1A2 and CYP3A4 in pooled human liver microsomes

et al. 2022

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Mycotoxins, fungal secondary metabolites, are ubiquitously present in food commodities. Acute exposure to high levels or chronic exposure to low levels has an impact on the human body. The phase I metabolism in the human liver, performed by cytochrome P450 (CYP450) enzymes, is accountable for more than 80% of the overall metabolism of exogenous and endogenous compounds. Mycotoxins are (partially) metabolized by CYP450 enzymes. In this study, in vitro research was performed on CYP450 probes and aflatoxin B1 (AFB1), a carcinogenic mycotoxin, to obtain pharmacokinetic data on AFB1, required for further experimental work. The CYP450 probes of choice were a CYP3A4 substrate, midazolam (MDZ) and a CYP1A2 substrate, phenacetin (PH) since these are the main metabolizing phase I enzymes of AFB1. Linearity experiments were performed on the three substrates indicating that linear conditions were achieved at a microsomal protein concentration and incubation time of 0.25 mg/ml and 5 min, 0.50 mg/ml and 20 min and 0.25 mg/ml and 5 min for MDZ, PH and AFB1, respectively. The Km was determined in human liver microsomes and was estimated at 2.15 μM for MDZ, 40.0 μM for PH and 40.9 μM for AFB1. The associated Vmax values were 956 pmol/(mg.min) (MDZ), 856 pmol/(mg.min) (PH) and 11,536 pmol/(mg.min) (AFB1). Recombinant CYP systems were used to determine CYP450-specific Michaelis–Menten values for AFB1, leading to a CYP3A4 Km of 49.6 μM and an intersystem extrapolation factor (ISEF) corrected Vmax of 43.6 pmol/min/pmol P450 and a CYP1A2 Km of 58.2 μM and an ISEF corrected Vmax of 283 pmol/min/pmol P450. An activity adjustment factor (AAF) was calculated to account for differences between microsome batches and was used as a correction factor in the determination of the human in vivo hepatic clearance for MDZ, PH and AFB1. The hepatic blood clearance corrected for the AAF CLH,B,MDZ,AAF, CLH,B,PH,AAF CLH,B,AFB1,AAF(CYP3A4) and CLH,B,AFB1,AAF(CYP1A2) were determined in HLM at 44.1 L/h, 21.7 L/h, 40.0 L/h and 38.5 L/h. Finally, inhibition assays in HLM showed that 45% of the AFB1 metabolism was performed by CYP3A4/3A5 enzymes and 49% by CYP1A2 enzymes.

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Section: Resultsmentioning

confidence: 99%

Unravelling the pharmacokinetics of aflatoxin B1: In vitro determination of Michaelis–Menten constants, intrinsic clearance and the metabolic contribution of CYP1A2 and CYP3A4 in pooled human liver microsomes

et al. 2022

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“…The compartment for the small intestinal lumen was divided in seven sub‐compartments enabling the description of the transition through the compartment. [ 20 , 21 , 22 , 23 ] The elimination of ZEN was modeled via its glucuronidation in intestinal and liver tissue assumed to be followed by efficient excretion.…”

Section: Methodsmentioning

confidence: 99%

“…It was assumed that the estimated Papp in vivo was the same for both rats and humans. The parameter values for the intestinal absorption rates were derived from the Papp in vivo by using the following equation [ 20 , 21 , 22 , 23 , 28 ] : Absorption rate (µmol h −1 ) = apparent permeability coefficient in vivo (Papp in vivo ; cm h −1 ) × surface area of the small intestine (cm 2 ) × luminal concentration of the compound (mM). The surface areas of the rat small and large intestine were calculated to be 94 [based on radius of 0.18 cm and small intestinal length of 83 cm [ 29 ] ] and 157 cm 2 [based on radius of 1 cm and small intestinal length of 25 cm [ 30 ] ].…”

Section: Methodsmentioning

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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“…Insects can eat wheat, and their feces can contaminate the wheat. Mycotoxin, the secondary metabolite of certain molds, is toxic to both humans and animals [4].…”

Section: Introductionmentioning

confidence: 99%

Effect of Ozone Treatment Intensity on Pasting Property, Protein Composition, and Steamed Bread Quality of Ozone-Treated Wheat Flour

Zhang

Wang

et al. 2022

Journal of Food Quality

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Wheat flours were treated with ozone gas at low- and high-intensity conditions (0.61 and 3.82 g/h) for different durations (short: 5 min; long: 30 min), and the ozone-treated flours were evaluated in quality properties, including pH, protein component, water molecular mobility of dough, pasting property, and steamed bread quality. At both conditions, ozone treatment decreased the pH of wheat flour. Long duration of high-intensity treatment aroused significant increase in insoluble polymeric protein (IPP) content of wheat flour, but other treatments did not significantly change the IPP content. Dough of ozone-treated flour had higher water molecular mobility than that of native flour. Short duration of low-intensity treatment did not significantly change most pasting viscosity parameters of wheat flour, but other treatments increased the peak viscosity, breakdown viscosity, and setback viscosity. Steamed bread of ozone-treated flour had lower specific volume and pore uniformity than that of native flour. Long duration of high-intensity treatment of flour increased the hardness and chewiness of the steamed bread product, but other treatment showed opposite effect. Among the four ozone treatments, long duration of high-intensity treatment aroused the greatest change in pH, IPP, water molecular mobility of dough, and the quality of steamed bread, while short duration of low-intensity treatment had the minimum effect. Long duration of low-intensity treatment was close to the short duration of high-intensity treatment in quality attributes of wheat flour and the total ozone yield. These results suggested that the quality of wheat flour gradually changed with the increase of total ozone yield, and overozonization would greatly deteriorate the quality of wheat flour.

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Predicting the Acute Liver Toxicity of Aflatoxin B1 in Rats and Humans by an In Vitro–In Silico Testing Strategy

Cited by 27 publications

References 64 publications

Unravelling the pharmacokinetics of aflatoxin B1: In vitro determination of Michaelis–Menten constants, intrinsic clearance and the metabolic contribution of CYP1A2 and CYP3A4 in pooled human liver microsomes

Unravelling the pharmacokinetics of aflatoxin B1: In vitro determination of Michaelis–Menten constants, intrinsic clearance and the metabolic contribution of CYP1A2 and CYP3A4 in pooled human liver microsomes

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

Effect of Ozone Treatment Intensity on Pasting Property, Protein Composition, and Steamed Bread Quality of Ozone-Treated Wheat Flour

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