In vivo doses of butadiene epoxides as estimated from in vitro enzyme kinetics by using cob(I)alamin and measured hemoglobin adducts: An inter-species extrapolation approach
“…In such case an inter-species comparison of the doses (AUC) of the carcinogenic metabolites in humans might be obtained from in vivo doses in exposed animals and metabolism studies through a parallelogram approach (cf. Motwani and Törnqvist, 201434). The derived in vivo doses based on the albumin adducts can then further be applied in different procedures to aid in quantitative cancer risk estimation of PAHs.…”
Carcinogenicity of benzo[a]pyrene {B[a]P, a polycyclic aromatic hydrocarbon (PAH)} involves DNA-modification by B[a]P diol epoxide (BPDE) metabolites. Adducts to serum albumin (SA) are not repaired, unlike DNA adducts, and therefore considered advantageous in assessment of in vivo dose of BPDEs. In the present work, kinetic experiments were performed in relation to the dose (i.e. concentration over time) of different BPDE isomers, where human SA (hSA) was incubated with respective BPDEs under physiological conditions. A liquid chromatography (LC) tandem mass spectrometry methodology was employed for characterising respective BPDE-adducts at histidine and lysine. This strategy allowed to structurally distinguish between the adducts from racemic anti- and syn-BPDE and between (+)- and (−)-anti-BPDE, which has not been attained earlier. The adduct levels quantified by LC-UV and the estimated rate of disappearance of BPDEs in presence of hSA gave an insight into the reactivity of the diol epoxides towards the N-sites on SA. The structure specific method and dosimetry described in this work could be used for accurate estimation of in vivo dose of the BPDEs following exposure to B[a]P, primarily in dose response studies of genotoxicity, e.g. in mice, to aid in quantitative risk assessment of PAHs.
“…In such case an inter-species comparison of the doses (AUC) of the carcinogenic metabolites in humans might be obtained from in vivo doses in exposed animals and metabolism studies through a parallelogram approach (cf. Motwani and Törnqvist, 201434). The derived in vivo doses based on the albumin adducts can then further be applied in different procedures to aid in quantitative cancer risk estimation of PAHs.…”
Carcinogenicity of benzo[a]pyrene {B[a]P, a polycyclic aromatic hydrocarbon (PAH)} involves DNA-modification by B[a]P diol epoxide (BPDE) metabolites. Adducts to serum albumin (SA) are not repaired, unlike DNA adducts, and therefore considered advantageous in assessment of in vivo dose of BPDEs. In the present work, kinetic experiments were performed in relation to the dose (i.e. concentration over time) of different BPDE isomers, where human SA (hSA) was incubated with respective BPDEs under physiological conditions. A liquid chromatography (LC) tandem mass spectrometry methodology was employed for characterising respective BPDE-adducts at histidine and lysine. This strategy allowed to structurally distinguish between the adducts from racemic anti- and syn-BPDE and between (+)- and (−)-anti-BPDE, which has not been attained earlier. The adduct levels quantified by LC-UV and the estimated rate of disappearance of BPDEs in presence of hSA gave an insight into the reactivity of the diol epoxides towards the N-sites on SA. The structure specific method and dosimetry described in this work could be used for accurate estimation of in vivo dose of the BPDEs following exposure to B[a]P, primarily in dose response studies of genotoxicity, e.g. in mice, to aid in quantitative risk assessment of PAHs.
“…This is put in perspective, for instance, by the US Environmental Protection Agency (EPA) driven guideline to reduce the need of animals for toxicity testing 4 , and the recommendation by European Food Safety Authority (EFSA) on applying 3 R principles in risk assessment approaches 5 . Within these frames we have earlier proposed a parallelogram approach for inter-species extrapolation of AUC of electrophilic genotoxic metabolites to be used in risk assessment procedures 6 . This approach is based on in vitro methods, integrated with knowledge from available in vivo data (Fig.…”
Section: Introductionmentioning
confidence: 99%
“…1 ). The basic concept is that AUC of a genotoxic metabolite in human, which is challenging to measure, can be obtained by extrapolation from measured protein adduct levels of that metabolite formed in mice/rats and through comparison with in vitro formation/elimination of the metabolite in human and the studied rodent 6 . Figure 1 Illustration of the parallelogram approach for inter-species extrapolation of AUC of a reactive metabolite in human using in vitro metabolic data.…”
Section: Introductionmentioning
confidence: 99%
“…Using the parallelogram approach, for 1,3-butadiene (BD) as the first model compound, the in vivo dose of BD’s most potent genotoxic metabolite, 1,2:3,4-diepoxbutane (DEB), was predicted in human. The inter-species extrapolation was performed using in vitro metabolic data on enzyme kinetics and published Hb adduct data 6 . This study was initiated as the AUC of DEB (AUC-DEB), in humans exposed to BD, had not been possible to measure with available methods.…”
When employing metabolism studies of genotoxic compounds/metabolites and cancer tests for risk estimation, low exposure doses in humans are roughly extrapolated from high exposure doses in animals. An improvement is to measure the in vivo dose, i.e. area under concentration-time curve (AUC), of the causative genotoxic agent. In the present work, we propose and evaluate a parallelogram based approach for estimation of the AUC of genotoxic metabolites that incorporates in vitro metabolic data and existing knowledge from published in vivo data on hemoglobin (Hb) adduct levels, using glycidamide (GA) as a case study compound that is the genotoxic metabolite of acrylamide (AA). The estimated value of AUC of GA per AUC of AA from the parallelogram approach vs. that from Hb adduct levels measured in vivo were in good agreement; 0.087 vs. 0.23 in human and 1.4 vs. 0.53 in rat, respectively. The described parallelogram approach is simple, and can be useful to provide an approximate estimation of the AUC of metabolites in humans at low exposure levels for which sensitive methods for analyzing the metabolites are not available, as well as aid in reduction of animal experiments for metabolism studies that are to be used for cancer risk assessment.
“…[40][41][42][43][44] Among several traditional methods available for their synthesis, 45-47 a number of environmentally friendlier approaches using heterogeneous catalysts have been developed. [48][49] It is in this sense that the oxides occupied a key place in the catalysis of this reaction.…”
A simple and innovative process is described for the eco-friendly preparation of ceria foams via the carboxymethylcellulose gelation by Ce 4+ cations; heat treatment of the ensuing xerogels produces ceria foams. The influence of the concentration of cerium and of the calcination temperature of the xerogels is studied. Several characterization methods have been used and the obtained results demonstrate that this technique allows the controlled growth of ceria foams. The foamy structure apparently is responsible for UV absorption and the ceria foam is basic enough to promote the epoxidation of chalcone; comparison of the catalytic activity of the ceria foam versus ceria prepared via co-precipitation method shows that the ceria foam is most active as it promotes epoxidation of electron-deficient alkenes with dilute aqueous hydrogen peroxide. spectrometer equipped with a monochromatic Al Kα X-ray source (hν = 1486.6 eV), operating at 150 W, using a multi-channel plate and delay line detector under 1.0x10-9 Torr vacuum. The survey and highresolution spectra were collected at fixed analyzer pass energies of 160 and 20 eV, respectively. The instrument work function was calibrated to give an Au4f7/2 metallic gold binding energy of 83.95 eV.The spectrometer dispersion was adjusted to give a binding energy of 932.63 eV for metallic Cu 2p3/2. Samples were mounted in a floating mode in order to avoid differential charging; charge neutralization was required for all samples. The electronic binding energy of C 1s (284.80 eV) was used as the internal standard. These data were analyzed with commercially available software, CasaXPS. The individual peaks were fitted with a Gaussian (70%)-Lorentzian (30%) (GL30) function after Shirley type background subtraction. For the UV characterization, a spectrophotometer LAMBDA 1050 UV/Vis/NIR of the company PerkinElmer was used, with a wavelength range spanning from 100 nm to 3300 nm.
SYNTHESIS OF CERIA FOAMS.The synthesis of ceria foams was accomplished using the carboxymethylcellulose (CMC) gel. 5 g of CMC were dissolved in 100 mL of deionized water (18 MΩ) at room temperature, forming a viscous solution. A separate solution was prepared by dissolving 5.5g of (NH 4 ) 2 Ce(NO 3 ) 2 in 100 mL of deionized water. Then, the CMC gel (5%: w/w) was added dropwise, at room temperature, to the cerium (IV) precursor solution via a syringe with a 0.8 mm diameter needle and constantly stirred for 1 hour. The hydrogels obtained were washed with distilled water then dried at room temperature for 24 hours or by supercritical CO 2 in order to prepare xerogels and aerogels, respectively. These beads (xerogels or aerogels) were then calcined at different temperature (350°C, 500 °C, 700 °C, 900 °C and 1100 °C).
CATALYTIC APPLICATION-EPOXIDATION OF CHALCONE WITH H 2 O 2 .Chalcone (0.581 mmol), methanol (1 mL), and catalyst (0.5 %mol) were added to a 10 mL flask. The reaction was started with the addition of aqueous hydrogen peroxide (30 wt%, 0.35 mL) at room temperature within the appropriate time under stir...
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