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At least 145 records · Page 8Linked to original sources
PubMed1993

Physico-chemical modeling of the role of free radicals in photodynamic therapy. II. Interactions of ground state sensitizers with free radicals studied by chemiluminescence spectrometry.

Chemiluminescence (CL) studies of the interaction between ground state hematoporphyrin photosensitizer (Hp) and peroxy radicals generated by the initiated oxidation of ethylbenzene at 60-80 degrees C revealed, that Hp is a singlet-singlet acceptor similarly to 9,10-diphenylanthracene. Furthermore, the fast decrease in the CL signal in the presence of Hp indicated that its consumption also took place due to chemical transformation, presumably by the attack of peroxy radicals on Hp. The rate constant of this attack has been calculated and it supports the view that such interaction can lead to an essential contribution to the bleaching processes in vivo.

Benzene Derivatives↗
PubMed1984

Base (O.-2, e-, or OH-)-induced autoxygenation of organic substrates: a model chemical system for cytochrome P-450-catalyzed monoxygenation and dehydrogenation by dioxygen.

When catalytic quantities of superoxide ion (O.-2; or of electrons from electrolysis or of OH-) are introduced into a dry acetonitrile solution that contains excess substrate (RH), ambient air (O2), 1,2-diphenylhydrazine (PhNHNHPh), and iron(II), the substrate is rapidly and efficiently monoxygenated (e.g., triphenylphosphine----triphenylphosphine oxide, benzyl alcohol----benzaldehyde, diphenylsulfoxide----diphenylsulfone) or dehydrogenated (1,4-cyclohexadiene----benzene). The model consists of (i) an O2-activation segment that produces H2O2 from an O.-2-initiated autoxidation of disubstituted hydrazine (a model for reduced flavin), (formula; see text) and (ii) a H2O2-activation segment via the iron(II)-induced formation of ferryl ion (FeO2+), Fe(II) + H2O2----FeO2 + H2O, an effective monoxygenating agent: FeO2+ + RH----Fe(II) + ROH. The combination of i and ii provides a catalytic system for the autoxidation of organic substrates with reaction cycles that are similar to those for cytochrome P-450 monoxygenases.

Cytochrome P-450 Enzyme System↗
PubMed1985

Substrate specificity of human liver cytochrome P-450 debrisoquine 4-hydroxylase probed using immunochemical inhibition and chemical modeling.

A significant population of humans (5 to 10%) are phenotypic poor metabolizers of debrisoquine. We have isolated the cytochrome P-450 isozyme from rat liver responsible for this activity and have shown that antibodies raised against the protein are able to inhibit this catalytic activity in human liver microsomes (Distlerath, L. M., and Guengerich, F. P., Proc. Natl. Acad. Sci. USA, 81: 7348-7352, 1984). These antibodies were utilized to determine which metabolic transformations are linked to debrisoquine 4-hydroxylation in human liver microsomes using techniques of immunochemical inhibition. The antibodies almost completely inhibited debrisoquine 4-hydroxylation and bufuralol 1'-hydroxylation in microsomes prepared from several different human livers. The oxidation of the pyrrolizidine alkaloids lasiocarpine and monocrotaline were inhibited by roughly one-third. The antibodies did not inhibit N,N-dimethylnitrosamine N-demethylation, oxidation of vinylidene chloride to 2,2-chloroacetaldehyde, oxidation of trichloroethylene to chloral, N-oxidation of azoprocarbazine, morphine N-demethylation, diazepam N-demethylation, oxidation of benzo(a)pyrene to alkali-soluble metabolites, oxidation of benzo(a)pyrene 7,8-dihydrodiol to products covalently bound to DNA, the N- and ring-oxidation of 1- and 2-naphthylamine and 2-aminofluorene, or the conversion of aflatoxin B1 to DNA adducts or aflatoxin Q1. Studies with space-filling models of the drugs the metabolism of which is associated with debrisoquine 4-hydroxylase in the literature indicated that all can be fitted to a general structure in which a basic nitrogen is about 5 A away from the site of carbon hydroxylation and a hydrophobic domain is near the site of hydroxylation. These results may be useful in predicting which chemicals may or may not be metabolized in an atypical manner by a segment of the human population.

Aflatoxin B1↗
PubMed1995

Dioxins: model chemicals for assessing receptor-mediated toxicity.

Dioxins and related compounds are chlorinated aromatic hydrocarbons that are persistent in both environmental and biological samples. Many members of this class of compounds produce a similar spectrum of toxicity which is mediated by interaction with the Ah receptor. The toxic effects of these chemicals can best be described by their actions as growth dysregulators. Dioxins disrupt normal homeostatic processes that tightly regulate cellular growth and differentiation. Disruption in these processes produce a variety of toxicities and pathologies. The available data indicate that humans are sensitive to the toxic effects of these chemicals. Clearer definition of human responses and the body burdens associated with such effects requires more research. Comprehensive risk assessments of dioxins should include all Ah receptor ligands such as the halogenated dibenzofurans and biphenyls.

Animals↗
PubMed1981

Hydrolysis of ATP in chemical models.

Hydrolysis of ATP was found to be accelerated by the addition of hexadecyltrimethylammonium chloride (CTAC). The high acceleration was observed in the concentration below rather than above the critical micell concentration of CTAC. The catalytic effect was observed at pH's 5 and 8, while not significantly at pH 3.

Adenosine↗
PubMed2004

Response of rainbow trout transcriptome to model chemical contaminants.

We used high-density cDNA microarray in studies of responses of rainbow trout fry at sublethal ranges of beta-naphthoflavone, cadmium, carbon tetrachloride, and pyrene. The differentially expressed genes were grouped by the functional categories of Gene Ontology. Significantly different response to the studied compounds was shown by a number of classes, such as cell cycle, apoptosis, signal transduction, oxidative stress, subcellular and extracellular structures, protein biosynthesis, and modification. Cluster analysis separated responses to the contaminants at low and medium doses, whereas at high levels the adaptive reactions were masked with general unspecific response to toxicity. We found enhanced expression of many mitochondrial proteins as well as genes involved in metabolism of metal ions and protein biosynthesis. In parallel, genes related to stress and immune response, signal transduction, and nucleotide metabolism were down-regulated. We performed computer-assisted analyses of Medline abstracts retrieved for each compound, which helped us to indicate the expected and novel findings.

Animals↗
PubMed2006

Molluscan natural products as biological models: chemical ecology, histology, and laboratory culture.

The utility of some natural products from molluscs has been known for centuries. However, only recently have modern technologies and advances in the fields of chemistry, chemical ecology, anatomy, histology, and laboratory culture allowed the exploitation of new, unprecedented applications of natural products. Recent studies have dealt with (a) the role that these compounds have in the sea in protecting the animals (e.g., chemical defense), or in mediating their intraspecific communication (e.g., pheromones), (b) the geographical differences in similar or related species (and the implications of this in chemical ecology and phylogeny), and (c) the localization of these metabolites in molluscan tissues (by means of the most modern technologies), among others. The methodology for the laboratory culture of some species has also been established, thus offering new insights into this interesting field. Further applications of all these challenging studies are currently being developed.

Animals↗
PubMed2002

Modeling chemical bonding effects for protein electron crystallography: the transferable fragmental electrostatic potential (TFESP) method.

This paper addresses the problem of determining the electrostatic potential of large proteins by the superposition of potentials calculated for small fragments. The use of different atomic and molecular fragments is considered for reproducing the molecular electrostatic potential of different conformations of N-acetylalanine methylamide (NAAMA) with an acceptable degree of error as measured by conventional R factors used in crystallographic structure refinement. Three different divisions of NAAMA are tested, producing fragments that incorporate increasingly more complete descriptions of molecular bonding with diminishing accuracy in geometric fit to the parent molecule: single atoms in molecules, bonded atoms in molecules and selected functional groups, such as the backbone peptide moiety, or the alpha-carbon, beta-carbon and their associated H atoms. In the resolution range 2.5-25A, the fairly straightforward use of single atoms in molecules reduces the calculated R factors by 5-15% over a free-atom superposition. No significant further improvement was found at the lowest resolutions with a superposition of single bonds in molecules and R factors were found to degrade with larger fragments at higher resolutions because of poor geometry fits to the atoms of the parent molecule. Because the potential distribution even for single atoms depends on the environment, the best accuracy will be obtained by using a library of fragment potentials calculated for each type of atom as a function of important protein conformations.

Algorithms↗
PubMed1987

Respiratory and non-respiratory lung function indices during the development and resolution of O,S,S-trimethyl phosphorodithioate-induced lung damage in the rat. A chemical model of adult respiratory distress syndrome.

Arterial blood gases and the pulmonary uptake of putrescine and 5-hydroxytryptamine (5-HT) were studied between 6 h and 18 days after the administration to rats of an oral LD50-dose of the pneumotoxin, O,S,S-trimethyl phophorodithioate (OSSMe), a potential impurity in several organophosphorus insecticides. Aortic blood was sampled under pentobarbitone anaesthesia for measurements of arterial pH, and partial pressures of oxygen (PaO2) and carbon dioxide (PaCO2). PaO2 was significantly decreased 4 days after OSSMe administration, i.e. at the time of maximum lethality and increases in wet lung weight. This was accompanied by a significant increase in PaCO2 and acidosis. These results are compatible with an impairment of gas exchange due to diffuse lung damage. For reasons that are unclear, PaCO2 was slightly increased 2, 6 and 12 days after dosing. The uptake of putrescine (1,4-diaminobutane) and of 5-HT was measured by incubating lung slices with several concentrations of [3H]-putrescine and [14C]-5-HT, so as to estimate the apparent kinetic parameters of uptake, Vmax and Km. The Vmax for putrescine-uptake was significantly decreased 1, 2, 4, 6 and 12 days after the administration of OSSMe. The Vmax for 5-HT-uptake was significantly increased 1 day and significantly decreased 4 days after OSSMe administration. The uptake of 5-HT is an endothelial function, and the decrease in 5-HT-uptake at 4 days may reflect injury to the pulmonary vascular endothelium at this time. The uptake of putrescine probably reflects the function of the pulmonary (mainly alveolar) epithelium.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2002

Mechanistic aspects of the dehydration and dehydrohalogenation of halo-hydroxyformaldoxime conformers. A quantum chemical model study.

A detailed exploration of the configurational and conformational space of chloro- and bromo-hydroxyformaldoximes, Xhfaox (X = Cl, Br) has been carried out with the aid of the B3LYP level of density functional theory, using the 6-31G(d,p) basis set. The most stable configuration in each series of the Clhfaox and Brhfaox conformers corresponds to the Z-s-cis, s-trans configuration, while the highest energy Z-(s-trans, s-cis) conformers were found at 7.0(7.6) and 6.0(6.6) kcal mol(-1), respectively, at the B3LYP(QCISD(T)) levels of theory. Saddle points were also located on the PES of the Clhfaox and Brhfaox compounds corresponding to Z-(s-cis, s-cis) conformers at 13.8(14.9) and 13.6(14.6) kcal mol(-1), respectively, at the B3LYP(QCISD(T)) levels. Upon dehydration Xhfaox could afford a number of isomeric CXNO species. The dehydration processes of Xhfaox are predicted to be endothermic, the computed heats of reactions found in the range of 20.5 to 86.2 kcal mol(-1) and 15.9 to 100.4 kcal mol(-1) at the B3LYP and QCISD(T) levels, respectively. The reaction pathways for the addition of water to halo-fulminates yielding the most stable Xhfaox conformers was predicted to be concerted with a single transition structure, but are asynchronous with activation barriers of 32.8 and 43.0 kcal mol(-1) for the chloro- and bromo-derivatives, respectively. The PES governing the isomerization reactions of the CXNO isomers have also been calculated, and possible isomerization pathways have been delineated. Upon dehydrohalogenation the Xhfaox conformers yield hydroxy-isocyanate or hydroxy-fulminate, the former being more stable by 31.8(18.8) kcal mol(-1) at the B3LYP(QCISD(T)) levels of theory. The reaction pathways for the addition of HX to hydroxy-isocyanate were predicted to be slightly exothermic, the heats of reactions being -3.2 and -5.5 kcal mol(-1), respectively, and have to surmount high activation barriers of 39.7 and 35.0 kcal mol(-1), respectively. Similarly, the addition of HX to hydroxy-fulminate was predicted to be much more exothermic, the heats of reactions being -34.7 and -37.3 kcal mol(-1), respectively, and have to surmount much lower activation barriers of only 10.5 and 7.5 kcal mol(-1) respectively, at the B3LYP level. Finally, calculated structures, relative stability, and bonding properties of all stationary points located on the PES of the systems and reactions studied are thoroughly discussed with respect to computed electronic properties.

Journal Article↗
PubMed2005

Electro-Chemical Modeling Challenges of Biological Ion Pumps.

We outline the basic operational, structural and functional features of ion motive ATPases: transmembrane proteins central to biological functions of all animal cells. As an example we discuss the modeling problems associated with the operation of the surface membrane Na(+),K(+)-ATPase and skeletal muscle sarcoplasmic reticulum Ca(2+)-ATPase and focus on the frameworks required for their solution. There are three basic problems: identification of the pathway for ion permeation, prediction of ion binding rate coefficients and affinities based on the structure of the protein, and prediction of conformational changes of protein structure and the associated movement of charges within the membrane dielectric. A solution strategy useful in approaching the first two problems and preliminary results obtained using molecular dynamics simulations are also presented.

Journal Article↗
PubMed1992

Physico-chemical modeling of the role of free radicals in photo-dynamic therapy. I. Utilization of quantum yield data of singlet oxygen formation for the study of the interaction between excited photosensitizer and stable free radicals.

The measurement of the relative quantum yield of singlet oxygen formation, a simple process without tedious sample deoxygenation, is shown to furnish data on the interaction of the excited photosensitizer with any additive (in this case stable free radicals) given to the sample. The rate constants derived from such measurements are in good agreement with direct determination of the corresponding values.

Free Radicals↗
PubMed1990

Chemical model of reaction cascades induced by activated enzymes or catalysts. Two-step cascades in visual transduction.

A dissipative system is approximated by a nonlinear rate equation: Z congruent to K1Z - K2Z3 (K2 greater than 0), in which the right side is derived from -delta G/delta Z of Taylor's series of the thermodynamic potential given by Gibbs' function G(Tc, Pc) (Z) at about the critical point C(Tc, Pc) of the control variables (parameters) T and P. The stability or instability of the system is treated by the changes in the control parameters. In the case that T not equal to P not equal to 0 in the steady state, Z = 0, and T and P pass the point C, K1 becomes negative. By this change, the G function is convex at Z = 0 and each product is created rapidly with concentration or number of the molecules Z = ([K1]/K2)1/2. This dynamic theory is applied to enzyme cascades. Based on cyclic GMP (cGMP) hypothesis in visual transduction, the cascade hydrolysis of cGMP of vertebrates is analyzed by dividing it into two-step reaction cascades: The initial process is that metarhodopsin II catalyzes the exchange of GDP for GTP by transducin (Gtd) and that GTP-Gtd complex is hydrolyzed to GDP-Gtd complex. In the following cascade cGMP is hydrolyzed with amplification of phosphodiesterase (PDE) activated by the removal of the small inhibitory subunit. The quantity of the hydrolysis of cGMP is estimated as approximately 5 x 10(4-5) molecules per photolyzed rhodopsin semiempirically, and this coincides well with experiments.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2002

Influence of mus201 and mus308 mutations of Drosophila melanogaster on the genotoxicity of model chemicals in somatic cells in vivo measured with the comet assay.

To check the possibilities of the recently developed comet assay, to be used in mechanistic studies in Drosophila melanogaster, neuroblast cells of third instar larvae are used to analyse in vivo, the effect of two repair deficient mutations: mus201, deficient on nucleotide excision repair, and mus308, deficient in a mechanism of damage bypass, on the genotoxicity of methyl methanesulphonate (MMS), ethyl methanesulphonate (EMS) and N-ethyl-N-nitrosourea (ENU). The obtained results reveal: (1) MMS-induced breaks are most probably consequence of N-alkylation damage mediated abasic (AP) site breakage; (2) MMS and at least part of the EMS induced damage leading to DNA strand breaks are efficiently repaired by the nucleotide excision repair mechanism; (3) ENU and part of EMS induced damage need a functional Mus308 protein to be processed, otherwise they can lead to DNA strand breaks. In addition, the results of this work confirm the validity of neuroblast cells to conduct the comet assay, and the usefulness of this assay in in vivo mechanistic studies related to DNA repair in D. melanogaster.

Animals↗
PubMed1998

Mutagenic interactions of model chemical mixtures.

Although current methodology for human health risk assessment assumes additive interactions among the contaminants of a complex mixture, chemical interactions may occur which produce synergistic or antagonistic effects. In this study, the mutagenic response of three f2p4l compounds, benzo(a)pyrene (B(a)P), pentachlorophenol (PCP) and 2,4,6-trinitrotoluene (TNT), were tested individually and in binary and tertiary solutions, using the Salmonella/microsome assay with each of three bacterial tester strains (TA97a, TA98, and TA100). For all strains, B(a)P was mutagenic with metabolic activation (Arochlor 1254-induced Sprague-Dawley rat liver S9 fraction), TNT was mutagenic without metabolic activation, and pentachlorophenol was inactive both with and without metabolic activation. In binary and tertiary solutions, pentachlorophenol had no effect on the mutagenicity of B(a)P or TNT, independent of metabolic activation. For strain TA97a, the mutagenicity of B(a)P with metabolic activation was slightly decreased in the presence of TNT; the mutagenicity of TNT without metabolic activation was slightly decreased in the presence of B(a)P and PCP; and the mutagenicity of the tertiary solution (496 revertants/10 ug) with metabolic activation was lower than the mutagenicity of B(a)P alone (729 revertants/10 ug). The mutagenicity of B(a)P in strain TA98 with activation was inhibited by the addition of TNT. Studies conducted using several concentrations of TNT or B(a)P indicate that the inhibition of B(a)P mutagenicity was increased as the concentration of TNT increased. Assays performed using four concentrations of S9 indicated the inhibition of B(a)P mutagenicity was relatively unaffected by the level of S9. The data suggest that an interaction in the presence of TNT limits the concentration of B(a)P that is capable of reaching or binding with bacterial DNA.

Animals↗
PubMed2000

SYMTERM--program for modelling chemical processes in non-isothermal conditions

The program SYMTERM allows to perform the numerical simulations of chemical processes which take place in the thermal analysis apparatus, considering two important factors: the exchange of heat between a sample and an environment, and the influence of heat evolved in the reaction on its kinetics. The program makes it possible to obtain kinetics profiles (DTA, TG, DTG or DSC curves) at various heating rates and permits to determine both the activation energy Eact and the reaction order of a single rate-limited step reaction with using DTA (DSC) and TG data simultaneously.

Journal Article↗