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Biomedical subjects

C A Wachtmeister

Publications and source records attributed to C A Wachtmeister.

At least 19 recordsLinked to original sources
PubMed1998

Characterization of hemoglobin adducts from a 4, 4'-methylenedianiline metabolite evidently produced by peroxidative oxidation in vivo.

4,4'-Methylenedianiline (MDA) is a widely used mutagenic and carcinogenic industrial chemical. It is also a metabolite of 4, 4'-methylenediphenyl diisocyanate (MDI), which is used in the manufacturing of polyurethane foams. Biomonitoring of MDA, like other aromatic amines, is mainly carried out by GC/MS measurement of cysteine adducts in Hb from the nitroso metabolite, released by alkaline hydrolysis. In the present study it was investigated whether the formation of Hb adducts from non-nitroso metabolites of MDA can be used for the dosimetry of MDA. The study was carried out by treatment of mice with MDA and tritiated MDA or deuterated MDA and by identification of their products of reaction with Hb, after enzymatic hydrolysis of the globin and enrichment of the adducts. The main adduct, about 50% of the total amount of MDA associated with Hb, was characterized by MS and was shown to be a reaction product of MDA and the amino group of N-terminal valine in Hb, the derived structure being 1-[(4-imino-2, 5-cyclohexadien-1-ylidene)methyl]benzene-4-azo-2-isovaleric acid. It is likely that this quinonoid MDA imine adduct to valine was formed by an attack of a metabolite formed through peroxidative oxidation of MDA, in analogy with earlier observed oxidation of some other aromatic amines, e.g., benzidine. The reactive intermediate is suggested to be [(4-imino-2, 5-cyclohexadien-1-ylidene)methyl]-4-aminobenzene. The formation of the adduct was confirmed by incubating MDA with valine methyl ester in vitro in the presence of H2O2 and lactoperoxidase. Further, the same adduct was detected in MDI-exposed and control rats, the level in the exposed animals being about 60 times higher than in the controls. This study indicates that, at least in the mouse, extrahepatic peroxidative metabolism is an important pathway for the bioactivation of MDA, possibly leading to a genotoxic reactive intermediate. This study also demonstrates the usefulness of Hb adduct analysis for the identification of reactive intermediates in vivo.

Aniline Compounds↗
PubMed1998

Mitotic disturbance by carbaryl and the metabolite 1-naphthol may involve kinase-mediated phosphorylation of 1-naphthol to the protein phosphatase inhibitor 1-naphthylphosphate.

Carbaryl causes depolymerization of spindle microtubules and apparent uncoupling of karyokinesis and cytokinesis in mitotic V79 cells. The metabolite 1-naphthol has virtually identical effects at equimolar concentrations. The closely related 2-naphthol causes similar configurations, but at a much lower frequency than 1-naphthol, showing that there are some structural requirements for these effects in mitosis. The results of the present study demonstrate that the effects of treatment are reversible; briefly (30 min) treated and thoroughly rinsed cells resume the normal appearance of cells in metaphase within 5 min, followed by anaphase approximately 15 min later. It could be demonstrated that added 1-naphthol can be converted to 1-naphthylphosphate by the cells, a recognized protein phosphatase inhibitor. With the applied method no 1-naphthylphosphate could be detected in carbaryl-treated cells, although a fraction of carbaryl was found to be converted to 1-naphthol. Carbaryl, 1-naphthol and 2-naphthol caused a decrease in protein phosphorylation of about the same magnitude. We hypothesize that 1-naphthol is a substrate for a protein kinase in mitosis and the carbaryl interferes with the same kinase. Carbaryl alone or the 1-naphthylphosphate formed may also interfere with protein phosphatase activity.

Animals↗
PubMed1994

Comparison of the potencies of (+)- and (-)-2-ethylhexanoic acid in causing peroxisome proliferation and related biological effects in mouse liver.

Male C57BL/6 mice were exposed to 1% (w/w) (+)- or (-)-2-ethylhexanoic acid or an equimolar mixture of these enantiomers in their diet for 4 or 10 days. A significant increase in liver weight and a 2- to 3-fold increase in the protein content of the mitochondrial fraction were seen in all cases. Peroxisomal palmitoyl-CoA oxidation was increased 2- to 3.5-fold after 4 days of treatment and 4- to 5-fold after 10 days, while the corresponding increases in peroxisomal lauroyl-CoA oxidase activity were 2- to 3-fold and 9- to 12-fold, respectively. Peroxisomal catalase activity was unchanged, whereas the microsomal and cytosolic activities were increased 2- to 3-fold and 6- to 16-fold, respectively. These treatments also induced microsomal omega-hydroxylation of lauric acid 7-fold and soluble epoxide hydrolase activity in the mitochondrial and cytosolic fractions, as well as microsomal epoxide hydrolase activity about 50-100%. The only significant differences observed between the effects of (+)-2-ethylhexanoic acid and its (-)-enantiomer were on peroxisomal palmitoyl-CoA oxidation and lauroyl-CoA oxidase activity after 4 days of treatment. In both these cases the (+)-enantiomer resulted in increases which were 50-75% greater than those seen with the (-)-form.

Animals↗
PubMed1983

Effects of dimethylnitrosamine on metabolism of N,N-dimethylaniline by rat liver microsomes. A comparative study of treatment in vivo, in isolated liver perfusion and in the microsomal system.

The effect of dimethylnitrosamine (DMN) on rat liver microsomal detoxication was studied, using the non-carcinogenic aromatic amine N,N-dimethylaniline (dimethylaniline) as substrate. Prior to the preparation of microsomes, the rat liver was exposed to DMN either in vivo (by i.p. injection) or in the isolated liver perfusion system (by addition to the perfusion medium). DMN treatment in vivo (20 mg/kg body wt.) caused a 40% increase in dimethylaniline N-oxygenation and a 30% decrease in dimethylaniline C-oxygenation. When DMN was added to the perfusion medium to a final concentration of 5 or 25 mM, a similar effect was observed. With the 5 mM dose, C-oxygenation was decreased by 20% with a non-significant increase in N-oxygenation. The higher dose caused a 50% increase in N-oxygenation, whereas the decrease in C-oxygenation remained at 20%. When microsomes were incubated with both DMN (5 mM) and dimethylaniline (5 mM) in the system, a small but significant decrease in both N- and C-oxygenation of dimethylaniline was observed. The effect of DMN on the amino acid incorporation into liver and plasma proteins was also studied in the liver perfusion system. The synthesis of both liver and plasma proteins was reduced by DMN.

Aniline Compounds↗
PubMed1982

Metabolism of 2,2',5,5'-tetrachlorobiphenyl: formation of mono- and bis-methyl sulphone metabolites with a selective affinity for the lung and kidney tissues in mice.

1. Distribution in mice of 2,2',5,5'-tetrachloro[14C]biphenyl has been studied by autoradiography. Radioactivity was specifically localized in the bronchial epithelium, the lung parenchyma, the kidney cortex and the adipose tissue. 2. Bis(methylsulphonyl)-2,2',5,5'-tetrachlorobiphenyl, a hitherto unknown metabolite of 2,2',5,5'-tetrachlorobiphenyl, has been identified in lung, kidney and liver of mice. 3- and 4-Methylsulphonyl-2,2'5,5'-tetrachlorobiphenyl were also present. 3. The ratio of the contents of 3- and 4-methylsulphonyl-2,2',5,5'-tetrachlorobiphenyl in the liver was 1.12 after 12 days. A lower ratio in lung and kidney indicates a high affinity of these tissues for the 4-methyl isomer.

Animals↗
PubMed1980

Cysteine and methionine-precursors of methyl sulphone metabolites of 2,4',5-trichlorobiphenyl in mice.

In order to account for the origin of the sulphur atom in methyl sulphones derived from polychlorinated biphenyls (PCB), groups of mice were treated with 2,4'-5-trichlorobiphenyl and [35S]cysteine or [35S]methionine, respectively. Control animals received the labelled amino acids only. The radioactive substances extracted from lung tissue were characterized by partition between hexane and sulphuric acid, thin-layer radiochromatography (TLRC), gas chromatography (GC) and mass fragmentography (MF). In lung extracts of both experimental groups sulphuric acid soluble metabolites were present: Their Rf-values on TLRC were identifical with that of 4-methylsulphonyl-2,4'-5-trichlorobiphenyl and their identity was confirmed by GC and GC-MF, which also indicated the presence of a minor sulphone isomer. The study shows that both cysteine and methionine could function as donors of the sulphur atom in the methyl sulphone metabolites derived from PCB.

Animals↗
PubMed1979

Mutagenicity and metabolism studies on 12 thiuram and dithiocarbamate compounds used as accelerators in the Swedish rubber industry.

12 thiuram and dithiocarbamate compounds used in the rubber industry as accelerators, and to some extent as sources of sulfur, were tested, as well as carbon disulfide, a metabolite found in vivo after dithiocarbamate treatment, for mutagenicity in Salmonella typhimurium. A mutagenic effect on the base-substitution-sensitive strains TA1535 and TA100 was found for 7 compounds. The most potent directly acting mutagens were: tetramethylthiuram disulfide (TMTD), zinc dimethyldithiocarbamate (ziram), cadmium diethyldithiocarbamate and zinc diethyldithiocarbamate. Tetraethylthiuram disulfide (TETD), also known as Antabus, and carbon disulfide were non-mutagenic. The relatively low direct mutagenic effect of tetramethylthiuram monosulfide (TMTM) was enhanced in the presence of a metabolizing system (S9 mix). A hypothesis is given regarding the activation process of the monosulfide TMTM.

Animals↗
PubMed1976

On the reaction kinetics in water of 1,3-propane sultone and 1,4-butane sultone: a comparison of reaction rates and mutagenic activities of some alkylating agents.

To determine correlations between the biological action pattern and chemical reactivity of alkylating agents, the rate constants for reactions of 1,3-propane sultone and 1,4-butane sultone with a series of nucleophiles at 37 degrees C have been determined. Previously published data on the mutagenicity of the two sultones and of some alkyl methanesulfonates and dialkyl sulfates towards Schizosaccharomyces pombe have been used in the evaluation of the dependence of mutagenic effectiveness on chemical reactivity. It is of interest to note that the mutagenic effectiveness of the two sultones, if expressed per alkylating event at a certain low nucleophilicity is the same as that of e.g. methyl methanesulfonate and ethyl methanesulfonate.

Alkanesulfonates↗
PubMed1976

The mutagenicity of chloroethylene oxide, chloroacetaldehyde, 2-chloroethanol and chloroacetic acid, conceivable metabolites of vinyl chloride.

Previous investigations have shown that the carcinogen vinyl chloride causes base-pair substitution in the bacterium Salmonella typhimurium. The ability of four conceivable metabolites-chloroethylene oxide, chloroacetaldehyde, 2-chloroethanol and chloroacetic acid-to cause base-pair substitution directly in Salmonella typhimurium TA1535 has been compared. The main comparison was performed at initial concentrations from 0.1 to 1.5 mM. In this region, however, a mutagenic effect was observed only with chloroethylene oxide and chloroacetaldehyde, the former being approximately 20 times more effective than the aldehyde when compared on a molar basis.2-Chloroethanol and chloroacetic acid were studied also at higher concentration (1 mM-1 M), and a weak mutagenic response was found with 1 M 2-chloroethanol solution. With chloroacetic acid no enhancement of the mutation frequency could be detected. Chloroethylene oxide was found to be approximately 450 times more effective as a mutagen than chloroacetaldehyde when the comparison is based on exposure doses, defined as the time-dependent concentrations of the compounds in the treatment solutions, integrated between the times of onset and termination of treatment. Similarly, chloroethylene oxide was 10,000-15,000 times more effective as a mutagen than ethylene oxide, used as a positive control.

Acetaldehyde↗
PubMedDate not supplied

Mutagenicity of rubber vulcanization gases in Salmonella typhimurium.

Gases formed by rubber and rubber additives in the vulcanization process were collected with a laboratory-scale glass apparatus. Mutagenicity testing of the vulcanization gases by the Salmonella/microsome test was conducted with strains TA1535, TA1538, TA98, and TA100 in the absence and presence of a metabolizing system from rat liver homogenates. The mutagenicity of gases derived by heating chloroprene rubber and ethylene propylene rubber was established with both base substitution- and frameshift-sensitive strains and that of a styrene-butadiene rubber was established with the base substitution-sensitive stain TA100. Tests on pyrolysis gases from a butadiene acrylonitrile rubber revealed only toxic effects. Curing systems, additives, and filling materials from various sources were represented in the material. Gases were collected at temperature levels corresponding to both mixing and curing of these particular rubbers in the industrial operations. Attempts were made to correlate the mutagenicity of the gases to the presence of mutagenic components in the rubber mixtures.

Acrylonitrile↗