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At least 1,009 records · Page 56Linked to original sources
PubMed1989

Calphostin C (UCN-1028C), a novel microbial compound, is a highly potent and specific inhibitor of protein kinase C.

Calphostin C (UCN-1028C), a newly isolated compound from Cladosporium cladosporioides, is a potent and specific inhibitor of protein kinase C, because it was 1000 times more inhibitory to protein kinase C (IC50, 0.05 microM) than other protein kinases such as cAMP-dependent protein kinase and tyrosine-specific protein kinase (IC50, greater than 50 microM). Calphostin C did not inhibit calcium activated neutral protease (calpain)-digested protein kinase C, indicating that it interacts with the regulatory domain of protein kinase C. In addition this compound showed inhibitory effects on the binding of [3H]PDBu to protein kinase C. The potent cytotoxic activity and antitumor activity of calphostin C might be due to the inhibition of protein kinase C, and thus it may be potentially useful for the therapeutic application.

Animals↗
PubMed1992

Induction of proliferin gene expression by diverse chemical agents that promote morphological transformation in C3H/10T1/2 cultures.

Anthralin, iodoacetic acid, BHT, Tween 60 and TPA induced cytoplasmic accumulation of transcripts of the proliferin gene family at or near effective concentrations for promotion of morphological transformation of C3H/10T1/2 cells. Conversely, non-promoters (4-alpha-phorbol, formic acid and methanol) were ineffective inducers. Compounds likely to promote transformation (nickel sulphate, benzyl peroxide and t-butyl hydroperoxide) were also effective and apparently selective, proliferin inducers in C3H/10T1/2 and primary murine fibroblasts. Proliferin induction may be a useful molecular marker to predict chemically-induced promotion of morphological transformation in C3H/10T1/2 cells.

Animals↗
PubMed2006

Investigation into the role of P2X(3)/P2X(2/3) receptors in neuropathic pain following chronic constriction injury in the rat: an electrophysiological study.

1. Two P2X(3)/P2X(2/3) receptor antagonists with different potencies were profiled electrophysiologically in a rat model of nerve injury. 2. A-317491 has poor CNS penetrance (blood:brain, 1:<0.05), and was therefore administered intravenously in chronic constriction injury (CCI)- and sham-operated rats to study the involvement of P2X(3) subunit-containing receptors in the periphery in neuropathic pain. A-317491 and Compound A were administered topically to the spinal cord to investigate the central contribution. 3. There were no significant inhibitory effects of A-317491 intravenous (i.v.) seen in sham-operated animals compared to vehicle controls. In CCI-operated animals, there were significant inhibitory effects of 3 mg kg(-1) A-317491 i.v. on C fibre-evoked responses, and with 10 mg kg(-1) A-317491 i.v. on A delta and C fibre-evoked responses. No significant effects of A-317491 were observed after topical application to the spinal cord. In contrast, when Compound A was administered spinally in CCI animals, there was a decrease in A delta and C fibre-evoked responses, and wind up. 4. These changes indicate that A-317491 has a selective effect on neuronal responses in CCI animals compared to sham, demonstrating an increased involvement of P2X(3)/P2X(2/3) receptors in sensory signalling following nerve injury. In addition, the more potent antagonist Compound A was effective spinally, unmasking a potential central role of P2X(3)/P2X(2/3) receptors at this site post nerve injury. These data support a role for P2X(3)/P2X(2/3) antagonists in the modulation of neuropathic pain.

Animals↗
PubMed1979

High pressure liquid chromatographic determination of polynuclear aromatic hydrocarbons in oysters.

A high pressure liquid chromatographic (HPLC) procedure is described for determining 13 polynuclear aromatic hydrocarbon (PNA) compounds in oysters at the 2 ppb level. These compounds are extracted from shellfish with acetonitrile and partitioned into petroleum ether; the petroleum ether is removed and the residue is saponified. The aromatic compounds are isolated by passing the saponifeid residue through silica gel and further purified and fractionated by muStyragel gel permeation chromatography. The in-ividual PNAs are then quantitatively determined by using a reverse phase HPLC column coupled to fluorescence, spectrophotometric, and 254 nm absorbance detectors in series. Recoveries from spiked samples generally were greater than 80%.

Animals↗
PubMed2006

Little effect of excessive biofouling on the uptake of organic contaminants by semipermeable membrane devices.

The effects of water flow rate and antifouling agents on the extent of biofouling and on the uptake of non-polar organic contaminants by semipermeable membrane devices (SPMDs) were studied during four field experiments in the Western Wadden Sea. Biofouling densities on the sampler surface ranged from 0.3 to 16g dry weight dm(-2). Water sampling rates were estimated from the dissipation rates of performance reference compounds (PRCs). The antifouling agents Irgarol and capsaicin (33 mg per ml triolein) had no noticeable effect on the extent of fouling, and caused only a 5-10% increase in the absorbed amounts. Enhanced flow rates had only a minimal effect on the amount of biofouling, but caused the water sampling rates to increase by a factor of 1.2-2. Increases in PRC-derived sampling rates were reflected by increases in the absorbed amounts for compounds that were in the linear uptake stage of the sampling process. The results imply (1) that extreme biofouling does not always result in reduced sampling rates, (2) that extreme biofouling does not preclude the existence of flow effects on the sampling rates, and (3) that differences in uptake rates are quantitatively reflected by the dissipation rates of PRCs.

Hydrocarbons, Chlorinated↗
PubMed1989

Computer-assisted design and synthesis of novel aldose reductase inhibitors.

The design and synthesis of phenalene 26 (AY-31,358), an unsubstituted analogue of a tolrestat/ICI-105,552 computer-generated hybrid (7), are reported. Compound 7 was designed by the superimposition of the putative low-energy conformers of tolrestat (1) and ICI-105,552 (6). The more rigid aldose reductase inhibitor sorbinil (2) was used as a template to help discern a common pharmacophore in the three inhibitors. Compound 26 was synthesized as a model and was evaluated as an inhibitor of bovine lens aldose reductase. It was found to exhibit good in vitro activity as well as some in vivo activity in the nerve. It was expected that introduction of the trifluoromethyl and methoxy substituents would enhance the biological activity of model compound 26. As a result of a positive Ames test with 26, however, work has now been directed toward modifying the template in a way so as to eliminate the mutagenicity with retention of biological activity.

Aldehyde Reductase↗
PubMed1992

A model for extraction of both lipid and water soluble toxins using a procedure from Maharishi Ayurveda.

Environmental toxicity from xenobiotic compounds is a major health concern today. This paper presents a hypothetical model for the removal of toxins from the physiology employing procedures of Maharishi Ayurveda, a comprehensive system of natural medicine, which is undergoing renewal. This model combines the use of principles similar to those which are found in lipid extraction, dialysis and bulk flow. A means of testing the hypothesis is also presented.

Environmental Pollutants↗
PubMed1993

Org 33201: a new highly selective orally active aromatase inhibitor.

Org 33201 has been selected as a very potent aromatase inhibitor. The compound is an enantiomer of a SC2H5 substituted imidazoylethylphenalene. Org 33201 inhibited human aromatase activity for 50% at a concentration of 2.2 x 10(9) mol/l. More than 200-fold higher concentrations were needed for the inhibition of other cytochrome P-450 enzymes. In vivo the compound was active in rats (ED50 = 0.035 mg/kg) and dogs (1 mg/kg gave 70% inhibition) after oral administration. It can be concluded that Org 33201 is a potent and highly selective orally active aromatase inhibitor.

Administration, Oral↗
PubMed1983

Effects of toxic substances on female reproduction.

Successful reproduction requires a complex series of interdependent physiological, cellular and molecular events. In the female many of these interdependent events are vulnerable to interruption by xenobiotic compounds. The physiological steps in the female reproductive cycle are reviewed. Selected xenobiotics which interrupt this cycle are presented and their mechanisms and site of adverse effects are discussed. Finally, a more detailed discussion of chemically induced ovarian failure in the human and an experimental animal model system is presented.

Animals↗
PubMed1994

TOCOEN project.

The basic goals of the TOCOEN project (Toxic Organic COmpounds in the ENvironment) are to detect and understand the fate of selected organic pollutants (PAHs, PCBs and PCDDs/Fs mainly) in the environment. The TOCOEN project was established in 1988 as a free association of Czech and Slovak environmental chemists, ecototoxicologists and other environmentalists.

Air Pollutants↗
PubMedDate not supplied

Purity of recycled fibre-based materials.

In order to study the purity of recycled fibre-based materials, products containing recycled fibre as well as recycled pulp were examined with regard to their chemical impurities, toxicity and microbiological quality. The study was carried out to clarify both qualitatively and quantitatively the variations in microbiological quality. The levels of several classes of chemical substances were analysed and semi-volatile and volatile substances identified. The toxicity and mutagenicity of virgin fibre and recycled fibre materials were screened using the Photobacter toxicity test and the Ames Salmonella mutagenicity test. Preliminary chemical characterization of the mutagens was carried out. Identification of the compounds found in the mutagenic fractions was performed by gas chromatography/mass spectrometry (GC/MS). The concentration of various substances analysed was found to be low, although the variety of substances present appeared to be very broad. Preliminary chemical characterization revealed that some samples contained compounds known to have mutagenic or other toxic activity. Also, the recycled fibre pulps contained large amounts of various microbes, the microbial load consisting mainly of aerobic spore-forming bacteria. The paper-making process was found to clearly have reduced the total microbial counts.

Benzofurans↗
PubMed2002

Development and validation of a new bitumen fume generation system which generates polycyclic aromatic hydrocarbon concentrations proportional to fume concentrations.

Bitumen fumes emitted during road paving and roofing contain polycyclic aromatic compounds (PACs) of potential health concern. Little information is available for an experimental device devoted to inhalation experiments with animals exposed to bitumen fumes, and in all studies the systems were never validated for a range of fume concentrations, which prohibited their use for toxicological concentration-effect studies. Therefore, the purpose of this study was to validate a new experimental device able to generate bitumen fumes at different total particulate matter (TPM) concentrations with a linear correlation between TPM and the concentrations of different PACs, thus allowing toxicological dose-response studies with fumes representative of those in the field. Atmosphere samples collected from an animal exposure chamber allowed the determination of TPM, toluene soluble matter, polycyclic aromatic hydrocarbons (PAHs) and semi-volatiles. The particulate size distributions were determined in order to assess the deposition pattern in the respiratory tract. The temperature of 170 degrees C was chosen by analogy with the upper range of the temperature used during paving operations. The temperature of the air passing over the fume emission area was regulated to 20 degrees C and stirring of the heated bitumen was restricted to 90 r.p.m. The data show that the objective of developing a static fume generation system that reproducibly produces fumes in the inhalation chamber for specified target concentrations (TPM) were successful. The within-day variation coefficients for TPM were between 2.5 and 6.1%. The day-to-day variations for TPM concentration were between 4.1 and 5.8%. The concentrations of the 4-5 ring PAHs and the polycyclic aromatic sulphur heterocycles were proportional to the TPM concentration. The 2 and 3 ring PAH concentrations showed a deviation from proportionality with the TPM, probably due to their re-evaporation during sampling. The mass median aerodynamic diameter of airborne particles varied from 1.4 micro m at a fume concentration of 5 mg/m(3) to 3.2 micro m at 100 mg/m(3). In conclusion, this equipment was suitable for nose-only inhalation studies in the 5-100 mg/m(3) range of TPM. Bitumen fumes were generated with a good reproducibility under well-controlled conditions. Finally, the PAH profiles from atmospheric samples were in good agreement with those measured during road paving.

Hydrocarbons↗
PubMed1989

Role of the aromatic group in the inhibition of phencyclidine binding and dopamine uptake by PCP analogs.

Thirty-seven arylcyclohexylamines including phencyclidine (PCP) and derivatives, N[1-(2-thienyl)cyclohexyl]piperidine (TCP) and derivatives and N-[1-(2-benzo(b)thiophenyl)cyclohexyl]piperidine (BTCP) were assessed for their ability to inhibit [3H]PCP binding and [3H]dopamine ([3H]DA) synaptosomal uptake. Their pharmacological property (ataxia) was measured by means of the rotarod test. A very good correlation was observed between the inhibition of [3H]PCP binding and the [3H]DA uptake only for arylcyclohexylamines bearing an unmodified phenyl group. Conversely the comparison between the inhibition of [3H]PCP binding and the activity in the rotarod test shows a good correlation with arylcyclohexylamines having any aromatic group (phenyl, substituted phenyl and thienyl rings). This study outlined a new compound (BTCP) without ataxic effect, which is one of the more potent inhibitors of the [3H]DA uptake (IC50 = 8 nM) and which seems very specific since it has a low affinity for [3H]PCP receptors (IC50 = 6 microM). These data show that the aromatic group of the compounds leads to molecules that bind differently to the PCP receptor and to the DA uptake complex. They also suggest that the behavioral properties of arylcyclohexylamines revealed by the rotarod test occur essentially as a result of an interaction with the sites labeled with [3H]PCP and that TCP is more selective than PCP itself in this recognition.

Animals↗
PubMed2000

Pressurised liquid extraction of ketones of polycyclic aromatic hydrocarbons from soil.

Pressurised liquid extraction (PLE) was used in the extraction of three ketones of polycyclic aromatic hydrocarbons from the sample of a soil highly contaminated with polycyclic polyaromatic compounds. The choice of solvent was the only factor that considerably influenced the extraction efficiency of PLE under the conditions recommended in Method 3545A promulgated by the United States Environmental Protection Agency. The dichloromethane-ethanol solvent mixture was found to be the most efficient solvent. PLE using this mixture provided better recoveries of all analysed ketones relative to Soxhlet extraction.

Gas Chromatography-Mass Spectrometry↗
PubMed2002

Substituted pentacyclic carbazolones as novel muscarinic allosteric agents: synthesis and structure-affinity and cooperativity relationships.

Two series of pentacyclic carbazolones, 22 and 23, have been synthesized utilizing a facile intramolecular Dielsminus signAlder reaction and are allosteric modulators at muscarinic acetylcholine receptors. Their affinities and cooperativities with acetylcholine and the antagonist N-methylscopolamine (NMS) at M(1)minus signM(4) receptors have been analyzed and compared. All of the synthesized compounds are negatively cooperative with acetylcholine. In contrast, the majority of the compounds exhibit positive cooperativity with NMS, particularly at M(2) and M(4) receptors. The subtype selectivity, in terms of affinity, was in general M(2) > M(1) > M(4) > M(3). The largest increases in affinity produced by a single substitution of the core structure were given by the 1-OMe (22b) and 1-Cl (22d) derivatives. The position of the N in the ring did not appear to be important for binding affinity or cooperativity. Two compounds 22y and 23i, both trisubstituted analogues, were the most potent compounds synthesized, with dissociation constants of 30minus sign100 nM for the M(2) NMS-liganded and unliganded receptor, respectively. The results indicate that the allosteric site, like the primary binding site, is capable of high-affinity interactions with molecules of relatively low molecular weight.

Acetylcholine↗
PubMed1981

Metabolism of chemical carcinogens by cultured human and rat bladder epithelial cells.

The metabolism of benzo[a]pyrene, aflatoxin B1, N-nitrosodimethylamine, N-nitrosoethylmethylamine, and N-nitrosopyrrolidine has been studied in cultures of normal human and rat urinary bladder epithelial cells. The cultures were incubated with radioactively labeled carcinogens for 24 h, and the metabolism was assayed by binding of reactive metabolites to DNa and by the release of metabolites into the medium. Only slight variation in binding level of benzo[a]pyrene to DNa among the three human bladder cell lines was seen, the level of binding being higher than to rat DNA. The major benzo[a]pyrene-DNA adduct (80%) in human bladder cells eluted prior to the adducts formed by reaction of 7,8-dihydroxy-9,10-epoxy - 7,8,9,10-tetrahydrobenz[a]pyrene with guanine by high pressure liquid chromatography, but has yet to be identified. The benzo[a]pyrene-DNA adducts were quickly removed and only about 10% of the radioactivity remained associated with human bladder DNA 72 h post-treatment with benzo[a]pyrene. The 7,8- and 9,10-diols of benzo[a]pyrene were the major organo-soluble metabolites formed by both rat and human bladder cells. The primary benzo[a]pyrene metabolites were conjugated to a minor extent only. The highest level of modification of DNA was seen in the case of N-nitrosodimethylamine. N-Nitrosopyrrolidine was oxidized in both the alpha-and beta-position by all three cell lines, the oxidation at the alpha-position being predominant. No binding to DNA was detectable with N-nitrosoethylmethylamine, although this compound was metabolized as measured by the formation of CO2 and aldehydes. These results add the urinary bladder to the list of human organs which have been shown to metabolize chemical carcinogens into electropositive metabolites. However, qualitative differences exist between the data from bladder cells and those from other human organs.

Aged↗
PubMed1985

Toxic chemicals in marine sediment and biota from Mukilteo, Washington: relationships with hepatic neoplasms and other hepatic lesions in English sole (Parophrys vetulus).

High prevalences of idiopathic liver lesions, including 7.5% hepatic neoplasms (e.g., hepatocellular and cholangiocellular carcinomas) and 16.7% foci of cellular alteration (putative preneoplastic hepatic lesions), were found in English sole (Parophrys vetulus) from waters near Mukilteo, a small community on Puget Sound in Washington State. Sediments from the sampling sites contained particularly high concentrations of aromatic hydrocarbons. Substantially lower concentrations of these compounds were found in sediments from another Puget Sound (reference) site in which fish showed no evidence of hepatic neoplasms or foci of cellular alteration. Stomach contents from the fish at Mukilteo contained substantially higher concentrations of the chemicals than did stomach contents of fish from the relatively uncontaminated site. High concentrations of metabolites of aromatic compounds were measured in the bile of fish from Mukilteo. These findings support previously observed relationships between sediment chemicals (e.g., aromatic hydrocarbons) and high prevalences of liver lesions in English sole from Puget Sound. In addition, a dietary route of uptake by English sole of environmental chemicals, including known carcinogens, was documented.

Animals↗
PubMed1992

[Cytochrome P-450: structure, function, induction and practical significance].

The liver contains a series of microsomal hemoproteins, called cytochromes P-450 which are mixed-function oxygenases involved in the metabolic oxygenation of diverse xenobiotic chemicals (drugs, pesticides, etc.). This enzyme system converts lipophilic foreign compounds into more water soluble products, thereby facilitating their elimination from the body. In general, cytochrome P-450-catalyzed oxidation results in detoxification, however the cytochromes P-450 can also convert certain xenobiotics to more toxic or carcinogenic products. Many of the individual isoenzyme forms of cytochrome P-450 are inducible by a wide variety of chemicals. After induction the concentration of total cytochrome P-450 in liver microsomes and the activity of different cytochrome P-450 forms increase. Elevated levels of cytochrome P-450 are the result of multiple mechanisms. Increased transcription of P-450 genes is a major mechanism of cytochrome P-450 induction. Higher levels of specific mRNAs are detectable soon after treatment with either "phenobarbital-like" or polycyclic aromatic compounds. Although increased transcription plays some role in the induction of cytochromes P-450 by other inducers like pregnenolone-16 alpha-carbonitrile (PCN)/glucocorticoids and "ethanol-type" compounds, post-transcriptional events are also very important. Cytochrome P-450 induction can be achieved by message stabilization and enhanced transport of mRNA from the nucleus to the cytoplasm that also increase the specific mRNA levels at the site of protein synthesis. Elevated cytochrome P-450 levels may also result from protein stabilization. Stabilization of cytochrome P-450 protein and/or mRNA are the main processes of induction by PCN/glucocorticoids and ethanol-type inducers. Although these mechanisms exist, they do not seem to be important in the induction by "phenobarbital-like" and "3-methylcholanthrene-like" inducers. The fact that induction is produced by a large variety of xenobiotics and is mediated by multiple mechanisms suggests that cytochrome P-450 system can provide increased protection for organisms in potentially hostile chemical environment. Since cytochrome P-450 induction is a characteristic response to chemicals for various living organisms ranging from microorganisms to man, it seems to be an adaptive mechanism for organisms to increase the chance for survival.

Cytochrome P-450 Enzyme System↗