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At least 127 records · Page 7Linked to original sources
PubMed1997

Parallel dermal subcompartments for modeling chemical absorption.

Understanding the absorption of chemicals through the skin is of importance to many fields of study. Biologically-based models can be used to simulate the absorption process and predict the rate of absorption and the amount of the chemical in various parts of the body and skin. When these models consist of physiological and biochemical parameters that can be measured, they can be extremely useful. When a model is appropriately validated, the results can be extrapolated across species to predict the effect of human exposure. In this paper we develop two new physiologically-based pharmacokinetic (PBPK) models which predict the concentration of Dibromomethane in the blood of rats after dermal vapor exposure. These two new models expand a previously developed homogeneous skin model by adding parallel skin subcompartments to represent skin appendages and layered subcompartments to represent the distinct layers of the skin. The predictions of these new models match the experimental data better than the original homogeneous model, as well as being more physiologically descriptive. Sensitivity analysis showed us which parameters were the most sensitive to change and thus revealing the parameters we should be most concerned with measuring. After being properly validated, these models could be a great improvement over previous models in the ability to extrapolate results for different species, doses, and durations.

Animals↗
PubMedDate not supplied

[Kinetic mechano-chemical model of a muscle with a six-stage cross-bridge cycle].

A kinetic scheme of the mechano-chemical cycle of the cross-bridges and a mathematical model based on this scheme are proposed. The main assumptions accepted in the scheme are: the step of the inorganic phosphate release precedes the force-generating step of a cross-bridge; the rate-limiting step of the ATP hydrolysis is isomerization of the actomyosin-ADP complex. It is shown that the model well describes the mechanical and biochemical transients initiated by the temperature jump and flash photolysis of the caged compounds in skinned muscle fibres.

Actomyosin↗
PubMedDate not supplied

Ring-testing and field-validation of a terrestrial model ecosystem (TME)--an instrument for testing potentially harmful substances: fate of the model chemical carbendazim.

The fate of the fungicide carbendazim (applied in the formulation Derosal) in soil was determined in Terrestrial Model Ecosystem (TME) tests and corresponding field-validation studies, which were performed in four different countries (United Kingdom, Germany, Portugal, and The Netherlands). The tests used different soil types, and lasted for 16 weeks. On three of the four sites, grassland soils were used while the fourth site had an arable soil. TMEs consisted of intact soil columns (diameter 17.5 cm; length 40 cm) and were taken from the site where the field study was performed. In the first series of TME tests, carbendazim was applied at four dosages ranging between 0.36 and 77.8 kg a.i./ha, while in the second series of TME tests and the field-validation studies six dosages between 0.36 and 87.5 kg a.i./ha were applied. DT50 values for the dissipation of carbendazim in the TME and field tests were in most cases not significantly affected by the dosage used and ranged between 3.1 and 13.9 weeks in the top 15 cm soil layers. Corresponding DT90 values ranged between 10.1 and 46.1 weeks. DT50 and DT90 values tended to be higher in the more acidic soils of Amsterdam and Flörsheim (pH-KCl 4.8-5.1 and 5.3-5.9, respectively) than in the less acidic soils of Bangor and Coimbra (pH-KCl 5.8-6.6 and 6.4-7.1, respectively). Fate of carbendazim in soil showed similar patterns in the two TME tests and the corresponding field-validation study performed at each site. The only exception was Flörsheim, where the compound was significantly more persistent in the field probably due to different climatic conditions. Carbendazim was not recovered from leachates produced in the TME tests, nor was the compound detected in soil layers deeper than 15 cm. This demonstrates that no significant leaching occurred. This study demonstrates the the TME tests were quite successful in predicting the fate of carbendazim under field conditions.

Benzimidazoles↗
PubMed2001

Quantum chemical modeling of Co--C bond activation in B(12)-dependent enzymes.

Recent progress in computational modeling of the catalytic activation of cobalt-carbon bond cleavage shows that quantum chemical calculations could be an important part of coenzyme B(12) research. Particular emphasis has been placed on density functional theory, which is now emerging as a powerful tool to elucidate the electronic structure and spectroscopic properties of the active sites of metalloenzymes.

Cobalt↗
PubMed1976

The effects of N-hexyl-O-glucosyl sphingosine on normal cultured human fibroblasts: a chemical model for Gaucher's disease.

Normal human skin fibroblasts were grown in the presence of N-hexyl-O-glucosyl sphingosine (HGS), an inhibitor of aryl glucosidase and glucocerebrosidase. Tests of the cells with aryl glycosides showed that beta-glucosidase activity in the cells was drastically reduced while other enzyme activities (alpha-glucosidase, beta-galactosidase, and N-acetyl-beta-hexosaminidase) were normal or elevated. Exposure of cells to HGS for 28 days resulted in increased values for cell weight per plate, glucocerebroside concentration, and galactosyl-galactosylglucosyl ceramide concentration. The concentrations of total lipid, cholesterol, and protein were unchanged, as was the fatty acid distribution within the glycolipids. Chemically, the inhibitor-treated cells exhibited a model form of Gaucher's disease. Although many membranous cytoplasmic inclusions were induced by HGS, they were unlike the characteristic inclusions seen in individuals with the genetic disorder. Skin fibroblasts from a Gaucher patient showed no abnormalities in composition or appearance.

Cell Line↗
PubMed1977

Studies of the mechanism of the periodic acid-Schiff histochemical reaction for glycogen using infrared spectroscopy and model chemical compounds.

It has been proposed in the literature that Schiffs reagent reacts with aldehydes to form one of the following types of compounds: alkylsulfonic acids, N-sulfinic acid derivatives, or Schiff bases. Model compounds whose structures are consistent with those proposed in the literature have been synthesized and subjected to infrared analysis. Also, actual products of Schiff reagent reactions with various aldehydes have been isolated and examined using infrared spectroscopy. Comparison of the spectra of the model compounds with those of Schiff-aldehyde reaction products yielded the following conclusions: 1. The reaction of simple organic aldehydes with Schiff's reagent produces an alkylsulfonate-type reaction product. 2. The reaction of periodate-oxidized glycogen with Schiff's reagent probably involves the formation of an alklsulfonate-type compound. 3. The product of the Schiff-aldehyde reaction exists as neither an N-sulfinic acid nor a Schiff base derivative of the fuchsin molecule.

Aldehydes↗
PubMed1984

Alternative bioactivation routes for beta-hydroxynitrosamines. Biochemical and chemical model studies.

The biochemical retroaldol-like fragmentation of beta-hydroxynitrosamines has been investigated further. The extent of fragmentation of 2-hydroxy-2-methylpropyl-methylnitrosamine (HMPMN) to N-nitrosodimethylamine and acetone induced by metabolic activation increases as the NADPH level is decreased. 2-Hydroxy-2-phenylethyl-methylnitrosamine (HPhEMN) undergoes competitive oxidation to 2-oxy-2-phenylethyl-methylnitrosamine (OPhEMN) and fragmentation to benzaldehyde and N-nitroso-dimethylamine in the presence of a metabolic activation system from rat liver. The extent of the oxidation was increased by preinduction of the rats with phenobarbital, or separate addition of NADPH and NAD, but was decreased by addition of dimethyl sulfoxide. The fragmentation was observed most readily when oxidation was inhibited or was not induced by cofactors. When HPhEMN was administered to a rat intraperitoneally, benzaldehyde (fragmentation) was found in the urine with OPhEMN and the substrate, but only the last two substances were found in liver and blood. These experiments provide evidence for retroaldol-like fragmentation of beta-hydroxynitrosamines both in vitro and in vivo. In a related investigation, it was found that N-nitroso-N-4-chlorophenyl-2-aminoethanal (NCAE) is extremely reactive and induces spontaneous generation of 4-chlorobenzenediazonium ion in chloroform, as trapped by 2-naphthol. NCAE reacts with dimethylamine in chloroform, benzene or methanol to give N-nitrosodimethylamine and 4-chloroaniline, among other products. This suggests that beta-nitrosaminoaldehydes produced by the biooxidation of their corresponding alcohols could produce cell alteration through alkylation, deamination or transnitrosation.

Animals↗
PubMed2004

Synergistic interaction of endocrine-disrupting chemicals: model development using an ecdysone receptor antagonist and a hormone synthesis inhibitor.

Endocrine toxicants can interfere with hormone signaling through various mechanisms. Some of these mechanisms are interrelated in a manner that might result in synergistic interactions. Here we tested the hypothesis that combined exposure to chemicals that inhibit hormone synthesis and that function as hormone receptor antagonists would result in greater-than-additive toxicity. This hypothesis was tested by assessing the effects of the ecdysteroid-synthesis inhibitor fenarimol and the ecdysteroid receptor antagonist testosterone on ecdysteroid-regulated development in the crustacean Daphnia magna. Both compounds were individually characterized for effects on the development of isolated embryos. Fenarimol caused late developmental abnormalities, consistent with its effect on offspring-derived ecdysone in the maturing embryo. Testosterone interfered with both early and late development of embryos, consistent with its ability to inhibit ecdysone provided by maternal transfer (responsible for early developmental events) or de novo ecdysone synthesis (responsible for late developmental events). We predicted that, by decreasing endogenous levels of hormone, fenarimol would enhance the likelihood of testosterone binding to and inhibiting the ecdysone receptor. Indeed, fenarimol enhanced the toxicity of testosterone, while testosterone had no effect on the toxicity of fenarimol. Algorithms were developed to predict the toxicity of combinations of these two compounds based on independent joint action (IJA) alone as well as IJA with fenarimol-on-testosterone synergy (IJA+SYN). The IJA+SYN model was highly predictive of the experimentally determined combined effects of the two compounds. These results demonstrate that some endocrine toxicants can synergize, and this synergy can be accurately predicted.

Algorithms↗
PubMed1998

Chemical model studies on the monoamine oxidase-B catalyzed oxidation of 4-substituted 1-cyclopropyl-1,2,3,6-tetrahydropyridines.

Two catalytic pathways have been proposed for the flavoenzyme monoamine oxidase B (MAO-B)--one based on an initial single electron transfer (SET) step from the nitrogen lone pair and the second based on an initial alpha-carbon hydrogen atom transfer (HAT) step. The SET pathway is consistent with the mechanism based inactivation properties of various cyclopropylamines. The observation that MAO-B catalyzes the efficient oxidation of certain 1-cyclopropyl-4-substituted-1,2,3,6-tetrahydropyridines to the corresponding dihydropyridinium metabolites suggests that the catalytic pathway for these cyclic tertiary allylamines may not proceed via the putative SET generated aminyl radical cations. The present paper describes the chemical fate of a series of N-cyclopropyltetrahydropyridines examined under reaction conditions that model the SET and the HAT pathways. All of the test compounds were rapidly converted under HAT reaction conditions to their dihydropyridinium products. Although the test compounds also were oxidized rapidly under SET conditions, no evidence for dihydropyridinium product formation was observed. The products that were identified most likely were formed after cyclopropyl ring opening of the initially formed cyclopropylaminyl radical cation. The results are discussed in terms of the mechanism of MAO-B catalysis.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1984

Chemical models for toxic metabolites of bromobenzene derivatives. Relative toxicity toward isolated hepatocytes.

In the rat the hepatotoxicity of bromobenzene is greatly enhanced by the introduction of a cyano group adjacent to the bromine (i.e. o-bromobenzonitrile). Epoxide metabolites of these aryl halides are believed to be the actual toxic species, but epoxides of the latter compound also possess a second site of chemical reactivity not found in epoxides of bromobenzene, i.e. a Michael acceptor group formally related to acrylonitrile. Because these epoxides have never been isolated or synthesized for direct evaluation of their toxicity we have determined the toxicity toward isolated rat hepatocytes of a series of cyclohexene and cyclohexadiene derivatives containing epoxide and/or alpha, beta-unsaturated nitrile functional groups. Simple epoxides and unsaturated nitriles were much less toxic than bromobenzene itself, even if both groups were present in the same molecule. However, alpha, beta-unsaturated epoxides were found to be 2-3 times more toxic than bromobenzene, and at least 10 times more toxic than their saturated analogs, which is consistent with their relatively greater chemical reactivity. It is unlikely that Michael acceptor metabolites account for the increased toxicity of o-bromobenzonitrile relative to bromobenzene.

Alanine Transaminase↗
PubMed1986

Tris(picolinato)manganese(II): a chemical model for the mechanism and function of mitochondrial superoxide dismutase.

The reaction of HO2. with the allylic groups of lipids initiates their peroxidation and auto-oxidation, and probably represents the most serious biological hazard of O2.- -derived species. The presence of tris(picolinato)manganese(II) [MnII(PA)2(PAH)(H2O)], a model complex for mitochondrial superoxide dismutase, (i) efficiently catalyzes the disproportionation of O2.-, (ii) precludes the formation HO2., and thereby (iii) prevents hydrogen abstraction from allylic and thiol groups. Such protection demonstrates that a primary function of superoxide dismutase is to block the formation of HO2., which is the obligatory intermediate for the nonenzymatic proton-induced disproportionation process. This requires that the primary step for the enzyme-O2.- reaction be kinetically favored and dominant relative to the protonation reaction (HA + O2.-).

Benzene↗