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Biomedical subjects

J H Koeman

Publications and source records attributed to J H Koeman.

At least 55 records · Page 3Linked to original sources
PubMed1991

In-vitro testing and the carcinogenic potential of several nitrosated indole compounds.

4-chloro-methoxyindole is a naturally occurring compound in Vicia faba which can easily react with nitrite to form a N-nitroso compound. In this in vitro study, the potential genotoxic effects of nitrosated 4-chloro-6-methoxyindole and its structural analogue 4-chloroindole were evaluated for the first time by using both Salmonella and Chinese hamster V79 cells. Additionally, the inhibition of gap junctional intercellular communication in V79 cells by these compounds was determined; this is a validated parameter for tumor-promoting activity. Most assays were also performed with nitrosated indole-3-acetonitrile, a naturally occurring compound in brassicas. Both nitrosated chloroindoles were highly mutagenic to Salmonella typhimurium TA100 without the need of exogenous metabolic activation and were potent inducers of Sister Chromatid Exchanges. Nitrosated indole-3-acetonitrile generated the same effects, although at much higher concentrations. Equivocal results were obtained for the nitrosated chloroindoles in a forward mutation assay using the hypoxanthine guaninephosphoribosyltransferase locus. All nitrosated indole compounds significantly inhibited gap junctional intercellular communication. These results indicate that nitrosated chloroindoles and nitrosated indole-3-acetonitrile should be considered as mutagens and agents with potential tumor-promoting capacity.

Animals↗
PubMed1991

The toxicity of tetrachlorobenzyltoluenes (Ugilec 141) and polychlorobiphenyls (Aroclor 1254 and PCB-77) compared in Ah-responsive and Ah-nonresponsive mice.

The toxicity of the PCB substitute Ugilec 141, a mixture of tetrachlorobenzyltoluenes (TCBTs), is compared with the toxicity of a commercial mixture of polychlorobiphenyls (Aroclor 1254) and with the model toxic PCB-congener 3,3',4,4',-tetrachlorobiphenyl (PCB-77) as a positive control. Alterations in liver weight, hepatic cytochrome P450 content and EROD and PROD activity, plasma thyroxin and retinol level, hepatic retinoid level and liver and thyroid pathology, have been studied in Ah-responsive and Ah-nonresponsive mice. Ugilec 141 proved to induce similar toxicological changes, qualitatively and quantitatively, to Aroclor 1254. Therefore Ugilec may pose a similar environmental and health risk as PCBs. The criteria for acceptance of new substances, like Ugilec 141, on the European market are discussed.

Journal Article↗
PubMed1991

The use of pig hepatocytes to study the nature of protein-bound metabolites of furazolidone: a new analytical method for their detection.

The biotransformation of furazolidone, both in vivo and in vitro, results in the formation of so-called bound metabolites. Following the incubation of pig hepatocytes with [14C]furazolidone, a dose- and time-related increase in the formation of bound metabolites was observed. After withdrawal of the drug from the medium, levels decreased gradually to about 50% within 36 hr. Using a newly developed method, it was shown that in the case of cells and liver microsomes at least 70% of the bound residues still contained the 3-amino-2-oxazolidinone (AOZ) side chain of furazolidone. For liver samples of piglets that had been treated orally with the drug for 10 days, followed by withdrawal periods of 2 hr or 14 days, fractions of releasable AOZ were 23 and 14%, respectively, equivalent to levels of 3.8 and 0.3 micrograms furazolidone/g of tissue, respectively. The release of the AOZ side chain of furazolidone from at least part of the bound metabolites shows their drug-related nature and highlights the requirement for both adequate withdrawal periods and the need for appropriate control methods. The relative simplicity of the newly developed method may be helpful in further establishing and controlling adequate withdrawal periods.

Animals↗
PubMed1991

From comparative physiology to toxicological risk assessment.

1. Comparative physiology may help to improve the toxicologists' ability to assess and predict toxicological risks of chemicals. 2. Three main lines of approach have been distinguished, A: comparative research concerning the toxicokinetics of chemicals in different species; B: research concerning ecophysiological characteristics and C: studies aimed at the identification of biological markers that can be used to signal toxic effects in both experimental and free living populations of organisms. 3. Some remarks are made on limiting conditions to be fulfilled in order to make comparative physiology valuable from a toxicological point of view.

Animals↗
PubMed1990

Inhibition of intercellular communication in smooth muscle cells of humans and rats by low density lipoprotein, cigarette smoke condensate and TPA.

Inhibition by tumor promoting chemicals of intercellular communication via gap junctions may be important in carcinogenesis. In order to investigate the possible role of gap junctional intercellular communication in atherogenesis, we examined the effect of known inhibitors of intercellular communication, 12-O-tetradecanoylphorbol-13-acetate (TPA) and cigarette smoke condensate (CSC), and low density lipoproteins (LDL) and high density lipoproteins (HDL) on cellular communication in smooth muscle cells of human and rat by the microinjection-dye transfer technique. When lucifer yellow CH solution is injected into a cell, the average numbers of human and rat smooth muscle cells that become fluorescent is about 22 and 6, respectively. The tumor promoter (TPA) almost completely blocked gapjunctional communication between smooth muscle cells at 100 ng/ml after 4 h exposure. LDL and CSC were able to inhibit intercellular communication in human and rat cells in a dose-dependent manner up to 60%. LDL-pretreatment of human smooth muscle cells did not affect inhibition of intercellular communication, which suggests that this effect is mainly non-receptor mediated. HDL did not influence junctional communication. The results indicate that inhibition of intercellular communication may also contribute to the pathogenesis of atherosclerotic lesions, such as plaques.

Animals↗
PubMed1989

Side-effects of pesticides on ground-dwelling predatory arthropods in arable ecosystems.

The effects of above ground applications of pesticides in field crops on the epigeal predator fauna in the Lake Yssel polders in The Netherlands was assessed during a 20-month period by means of pitfall trapping in 17 commercially farmed fields and in one experimental field. The pesticides used during this period were the herbicides 2,4-D-amine and MCPA/MCPP and the insecticides deltamethrin, fenitrothion, and bromophos-ethyl. Deposition of the spray on the soil was determined. Bioassays were carried out in the fields in two cases. Of the taxa identified, i.e. staphylinids, carabids and spiders, the erigonid and linyphiid spiders appeared to be sensitive to the three insecticides. Long-term effects, however, could not be demonstrated. No effect was observed from the herbicide applications. Fields which were mechanically treated against weeds had a lower species diversity than chemically treated fields. Ploughing had a detrimental effect on the spiders. The effect of deltamethrin appeared to depend on weather conditions. At higher temperatures the effect was stronger than at lower temperatures, and no effects could be observed under rainy conditions. A guild of five species, i.e. Erigone atra, E. dentipalpis, Oedothorax apicatus, Meioneta rurestris and Bathyphantes gracilis, is recommended as an indicator for early detection of side-effects of insecticides on the epigeal predator fauna.

Journal Article↗
PubMed1989

A study on the carcinogenicity of human diets in rats: the influence of heating and the addition of vegetables and fruit.

The influence of dietary factors such as total composition, thermal processing, and the addition of vegetables and fruit on the tumour rate in rats was studied in a long-term experiment. Groups of 50 male and 50 female Wistar rats were fed one of the following diets: a semi-synthetic animal diet (A, control); diet A to which vegetables and fruit were added (B); an uncooked human diet (meat, bread and eggs) supplemented with semi-synthetic compounds (C); diet C with fried or baked products (D); a complete human diet consisting of heated products, vegetables and fruit prepared according to mean consumption figures in The Netherlands (E). The animal diets (A and B) contained 26.0 energy (E)% protein, 21.6 E% fat, 52.4 E% carbohydrate and 10.7% (w/w) fibre. The human diets contained 13.2 E% protein, 40.6 E% fat, 46.2 E% carbohydrate and 5% (w/w) fibre. The rats were fed ad lib. for 142 wk. In males and females fed human diets (C, D or E) hepatocellular vacuolization was observed. Male rats (but not female) fed the human diet had a significantly (P less than 0.02) higher incidence of epithelial tumours than those fed the animal diet. This increase was mainly due to tumours of the pituitary and thyroid. Frying and baking of food products (diet D) and the addition of vegetables and fruit (diet E) induced minor differences in tumour rate, but they were not statistically significant.

Animals↗
PubMed1989

Monoclonal antibodies against rat glutathione S-transferase isoenzymes 2-2 and 3-3.

Monoclonal antibodies were prepared against rat glutathione S-transferase isoenzymes 2-2 and 3-3. Three clones were capable of specifically differentiating their respective antigens from other rat isoenzymes as well as human isoenzymes, in ELISA and on Western blot. One clone produced antibodies specific for isoenzyme 2-2, and 2 hybridomas were specific for isoenzyme 3-3. Balb/c mice did not respond to immunization with glutathione S-transferase isoenzymes 1-1 and 4-4. However, an immune response was obtained in some other strains of mice, with differential H-2 haplotypes, notably CBA/BrARij mice and CBA/CaHRij-T6 mice for isoenzyme 1-1 and CBA/BrARij mice for isoenzyme 4-4, which offers perspectives for obtaining additional specific monoclonal antibodies against these glutathione S-transferases.

Animals↗
PubMed1988

Organ specific metabolic activation of five extracts of indoor and outdoor particulate matter.

In this study liver and lung homogenates of untreated and Aroclor 1254-pretreated rats (Wistar) and mice (Swiss) were compared for their P-450 content and their capacity to activate extracts of airborne particulate matter, sampled indoors and outdoors. Results show that in addition to liver, lung homogenates of rat (Wistar) and mouse (Swiss) are also able to activate extracts of airborne particulate matter in a comparative way. Uninduced liver and lung homogenates showed only minor differences in activation capacity in the metabolism of airborne particles. In contrast to liver homogenates, Aroclor 1254 pretreatment of test animals did not give strong induction of metabolic activation capacity of lung homogenates. P-450 content was observed in all liver and lung homogenates of mouse and rat and in human lung homogenates. The results obtained in this study suggest that the respiratory tract may be an important site for in vivo bioactivation of respirable particles.

Air Pollutants↗
PubMed1988

Reversible interaction of a reactive intermediate derived from furazolidone with glutathione and protein.

Swine liver microsomes convert the nitrofuran furazolidone into N-(4-cyano-2-oxo-3-butenylidene)-3-amino-2-oxazolidone, a reactive open-chain acrylonitrile derivative. This derivative may be trapped with such thiol-group-containing agents as glutathione and mercaptoethanol. However, this reaction is reversible; e.g., adding an excess of mercaptoethanol to an aqueous solution (pH 7.4) of the glutathione conjugate results in conversion of 43% of this compound into the mercaptoethanol conjugate. In addition, when microsomal protein is added to the glutathione conjugate or the mercaptoethanol conjugate, 36 and 44%, respectively, become covalently bound to the protein. The amount of this covalently bound radioactivity decreases again on prolonged incubation at 37 degrees C (42% disappearance within 24 hr), suggesting that the acrylonitrile derivative also reacts reversibly with thiol groups of microsomal protein. Indeed an excess of mercaptoethanol could remove covalently bound radioactivity from microsomal protein resulting in the formation of the mercaptoethanol conjugate. The reversibility of the reaction is dependent on pH, as is demonstrated for the mercaptoethanol conjugate. Below pH 2 this conjugate is stable; optimal exchange to microsomal protein is found between pH 7 and 10. At very high pH (greater than 11) no binding to protein is found, although the conjugate disappears rapidly. The mercaptoethanol conjugate exhibits mutagenic activity in the Salmonella/microsome test indicating that the acrylonitrile derivative of furazolidone also interacts with DNA.

Animals↗
PubMed1988

Effect of retinol and cigarette-smoke condensate on dye-coupled intercellular communication between hamster tracheal epithelial cells.

The dye-coupled intercellular communication across gap junctions in primary hamster tracheal epithelial cells has been studied in serum-free, hormone-supplemented medium. In the absence of vitamin A, non-cytotoxic concentrations of cigarette-smoke condensate (CSC) inhibited intercellular communication between tracheal epithelial cells in a concentration-dependent way. All-trans retinol and retinoic acid showed biphasic effects on intercellular communication depending on their concentration. Physiological concentrations of retinol and retinoic acid increased the dye-coupled transfer of Lucifer Yellow CH via gap junctions compared with the dimethylsulfoxide-treated tracheal epithelial cells. At pharmacological concentrations retinol slightly increased the intercellular communication in the first 2 h of the exposure period, whereas upon longer treatment times with retinol and retinoic acid, gap-junction-mediated intercellular communication was inhibited almost completely. When retinol was given to tracheal epithelial cells before exposure to CSC or simultaneously with CSC-exposure, retinol counteracted the inhibitory potential of CSC on intercellular communication. The results of the present study clearly indicate that both CSC and all-trans retinol influence the intercellular communication between primary hamster tracheal epithelial cells in serum-free, hormone-supplemented culture medium.

Animals↗
PubMed1985

A carcinogenicity study with mutagenic organic concentrates of drinking-water in the Netherlands.

The carcinogenicity in male and female Wistar SSP TOX rats of organic drinking-water concentrates that are positive in the Ames test was studied at three doses. The organic mutagenic concentrates were prepared weekly from drinking-water from one location in The Netherlands by adsorption onto XAD-4/8 resins and elution with dimethylsulphoxide. The organic concentrates in dimethylsulphoxide were mixed with non-mutagenic drinking-water before exposure of the rats. Dose levels were based on multiples of expected human exposure levels. For the calculation the average human daily intake of drinking-water was taken as 2 litres for a body weight of 70 kg. There was no significant increase in tumour induction when male Wistar SSP TOX rats were exposed for 106 wk to 4.5, 14 or 40 times the expected human exposure level and females to 7,22 or 68 times the human level. The development and types of tumours were similar in the treated and control groups. The numbers of animals with tumours and of animals that died as a result of tumours in the exposed groups did not differ significantly from those in the control groups. These results suggest that these organic mutagenic drinking-water concentrates did not contain very potent carcinogens in effective concentrations.

Animals↗
PubMed1983

Mutagenicity testing of two tropical plant materials with pesticidal potential in Salmonella typhimurium: Phytolacca dodecandra berries and oil from seeds of Azadirachta indica.

In this study the mutagenic potential of two tropical plant materials was investigated in Salmonella typhimurium strains TA98 and TA100. The oil extract from seeds of Azadirachta indica showed no mutagenic activity in either strain with or without addition of metabolizing systems. When extracts of Phytolacca dodecandra berries were tested, only the butanol extract caused direct mutagenicity in TA98. After addition of rat liver homogenate, again only the butanol extract was positive in TA98. Addition of gut flora extract as metabolizing system generated positive effects in both the methanol extract and the butanol extract. The water extract showed only a slight positive effect, which can most probably be ascribed to the presence of histidine in the sample.

Animals↗
PubMed1982

The effect of glutathione conjugation and microsomal oxidation on the mutagenicity of dichloromethane in S. typhimurium.

The effect of mammalian metabolizing enzymes on the mutagenicity of dichloromethane was investigated in S. typhimurium strain TA100. The compound was directly mutagenic towards this strain, but the mutagenic activity was enhanced upon addition of either rat-liver microsomes or the cytosol fraction. Further experiments showed that both the cytochrome P450 oxygenases and the glutathione-S-transferases are involved in the bioactivation of dichloromethane.

Animals↗
PubMed1982

The killifish Nothobranchius rachowi, a new animal in genetic toxicology.

Nothobranchius rachowi, a tropical fish that belongs to the family of the Cyprinodontidae, is introduced as a new animal for genetic toxicological studies. The karyotype of N. rachowi consists of 16 large chromosomes. This species can be used for studies on chromosomal aberrations as well as for observations on sister-chromatid exchanges (SCEs). Exposure to 120 mg ethyl methanesulphonate per litre water induced 0.66 SCEs per chromosome, whereas the spontaneous frequency amounted to 0.10 SCEs per chromosome. A comparative study with Umbra pygmaea indicated that the sensitivity for this kind of mutagen is the same in both species. After exposure of N. rachowi to 50 mg cyclophosphamide per litre of water, 0.35 SCEs per chromosome were induced, showing that promutagens could be detected. It is postulated that N. rachowi can be used for screening both pure compounds and surface water for genotoxic potential. An advantage of N. rachowi over Umbra spp. is that the former species is more likely to breed under laboratory conditions.

Animals↗