Search PubMed⌕ Search

Biomedical subjects

U Graf

Publications and source records attributed to U Graf.

At least 55 records · Page 3Linked to original sources
PubMed1989

Genotoxicity of aniline derivatives in various short-term tests.

Various substituted aniline derivatives were tested for genotoxicity in several short-term tests in order to examine the hypothesis that a substitution at both ortho positions (2,6-disubstitution) could prevent genotoxicity due to steric hindrance of an enzymatic activation to electrophilic intermediates. In the Salmonella/microsome assay, 2,6-dialkylsubstituted anilines and 2,4,6-trimethylaniline (2,4,6-TMA) were weakly mutagenic in strain TA100 when 20% S9 mix was used, although effects were small compared to those of 2,4-dimethylaniline and 2,4,5-trimethylaniline (2,4,5-TMA). In Drosophila melanogaster, however, 2,4,6-TMA and 2,4,6-trichloroaniline (TCA) were mutagenic in the wing spot test at 2-3 times lower doses than 2,4,5-TMA. In the 6-thioguanine resistance test in cultured fibroblasts, 2,4,6-TMA was again mutagenic at lower doses than 2,4,5-TMA. Two methylene-bis-aniline derivatives were also tested with the above methods: 4,4'-methylene-bis-(2-chloroaniline) (MOCA) was moderately genotoxic in all 3 test systems whereas 4,4'-methylene-bis-(2-ethyl-6-methylaniline) (MMEA) showed no genotoxicity at all. DNA binding studies in rats, however, revealed that both MOCA and MMEA produced DNA adducts in the liver at levels typically found for moderately strong genotoxic carcinogens. These results indicate that the predictive value of the in vitro test systems and particularly the Salmonella/microsome assay is inadequate to detect genotoxicity in aromatic amines. Genotoxicity seems to be a general property of aniline derivatives and does not seem to be greatly influenced by substitution at both ortho positions.

Aniline Compounds↗
PubMed1989

Thirty compounds tested in the Drosophila wing spot test.

The Drosophila wing somatic mutation and recombination test (SMART) was evaluated for its suitability in genotoxicity screening by testing 30 chemicals. Of the 2 crosses used, the mwh-flr3 cross turned out to be more convenient than the previously used mwh-flr cross. Based on the experience gained with both acute exposures and chronic exposures of different duration, we suggest that the optimal strategy in genotoxicity screening is to start with chronic exposure of 3-day-old larvae for 48 h (that is, until pupation). Only for unstable compounds and very volatile compounds and gases are acute treatments, including inhalation, recommended. In general, a qualitative evaluation of the genotoxicity of a compound in the wing assay is possible with as few as 1-2 different exposure concentrations. A more quantitative evaluation of genotoxicity, based upon dose-response data, can often be achieved with as few as 3-4 concentrations. The results reported here were obtained in 2 different laboratories, demonstrating that the wing spot test is easily transferable to other laboratories. The experience gained indicates that the assay has now been developed to an extent that a coordinated international comparative validation study is desirable.

Animals↗
PubMed1989

Genotoxicity testing of antiparasitic nitrofurans in the Drosophila wing somatic mutation and recombination test.

Nifurtimox and eight structurally related 5-nitrofuran compounds active against Trypanosoma cruzi were tested for genotoxicity in the wing somatic mutation and recombination test in Drosophila melanogaster. Nifurtimox, compound ada and compound 1B were clearly mutagenic and recombinogenic whereas the remaining six compounds were negative. In contrast to the situation in bacterial mutagenicity tests, nitroreductase activity is probably not decisive for the genotoxicity of these compounds in Drosophila. The three non-genotoxic nitrofurans with high antiparasitic activity are promising candidates for the replacement of nifurtimox. However, these compounds require further genotoxicity testing in eukaryotic assay systems for a final evaluation.

Animals↗
PubMed1986

Investigation of coffee in Drosophila genotoxicity tests.

Two preparations of coffee (instant coffee and freeze-dried home-brew coffee) were tested in different mutagenicity assays in germ cells as well as in somatic cells of Drosophila melanogaster. The three end-points assayed in germ cells were sex-linked recessive lethals (mainly gene mutations and small chromosome aberrations), dominant lethals (cytotoxic effects as well as genotoxic effects) and sex-chromosome losses (chromosome breakage and non-disjunction). The aqueous coffee solutions were fed either to adult male flies for 3 days or to growing larvae during the whole larval development. Treated males were crossed with appropriately marked females, and the different genetic end-points were analysed in the F1 or F2 generation. The test concentrations (instant coffee 4% (w/v), home-brew coffee 3%) were acutely toxic in adult males (killing approximately 75 and 90% of the exposed flies, respectively). No increase in deaths was caused in larvae by the same concentrations. Only cytotoxic effects were observed in the test for dominant lethals. No conclusive genotoxic effects could be detected in any of the three germ cell assays. The coffee preparations were also tested for induction of mutation and mitotic recombination in somatic cells of the wing imaginal disc. Larvae trans-heterozygous for two recessive wing hair markers were fed high concentrations of the coffees for varying periods of time. Wings of surviving adult flies were analysed for mosaic spots. Twin spots exhibiting both mutant phenotypes are produced by mitotic recombination; single spots showing one or the other phenotype are the result of somatic mutation, such as gene mutation or deletion, or of mitotic recombination. Both coffees had weak effects on normal (repair-proficient) cells as well as on excision repair-defective cells in this assay. Additional experiments with pure caffeine and decaffeinated coffee show that these weak effects in somatic cells were most probably caused by the caffeine present in the two coffees.

Animals↗
PubMed1985

Aristolochic acid is mutagenic and recombinogenic in Drosophila genotoxicity tests.

Aristolochic acid (AA) has been tested for genotoxic activity in three different assays with Drosophila melanogaster (i-iii). AA induced sex-linked recessive lethals (i) and chromosome losses (ii) in male germ cells. In a newly developed fast assay with somatic cells of larvae (iii), AA induced mutant single spots as well as twin spots. The data indicate that in addition to the mutagenic activity, AA also possesses recombinogenic activity leading to somatic recombination in mitotically active cells. The experimental labor involved to detect the genotoxic activity of AA was lowest with the somatic cell assay.

Animals↗
PubMed1984

Somatic mutation and recombination test in Drosophila melanogaster.

A novel test system for the detection of mutagenic and recombinogenic activity of chemicals is described in detail. Drosophila melanogaster larvae trans-heterozygous for the mutations multiple wing hairs (mwh) and flare (flr) are exposed to the test compounds for various periods of time ranging from 96 hr to 1 hr. Induced mutations are detected as single mosaic spots on the wing blade of surviving adults that show either the multiple wing hairs or flare phenotype. Induced recombination leads to mwh and flr twin spots and also to a certain extent, to mwh single spots. Recording of the frequency and the size of the different spots allows for a quantitative determination of the mutagenic and recombinogenic effects. This and earlier studies with a small set of well-known mutagens indicate that the test detects monofunctional and polyfunctional alkylating agents (ethyl methanesulfonate, diepoxybutane, mitomycin C, Trenimon), mutagens forming large adducts (aflatoxin B1), DNA breaking agents (bleomycin), intercalating agents (5-aminoacridine, ICR-170), spindle poisons (vinblastine), and antimetabolites (methotrexate). In addition, the test detects mutagens unstable in aqueous solution (beta-propiolactone), gaseous mutagens (1,2-dibromoethane), as well as promutagens needing various pathways of metabolic activation (aflatoxin B1, diethylnitrosamine, dimethylnitrosamine, mitomycin C, and procarbazine). The rapidity and ease of performance as well as the low costs of the test necessitate a high priority for validation of this promising Drosophila short-term test.

Animals↗
PubMed1984

Mutagenic activity of the pyrrolizidine alkaloids seneciphylline and senkirkine in Drosophila and their transfer into rat milk.

Seneciphylline and senkirkine, two pyrrolizidine alkaloids that occur in animal feeds and medicinal herbs, respectively, have been tested for their ability to produce sex-linked recessive lethals in males of Drosophila melanogaster using the Basc test (3-day feeding method). Seneciphylline was found to be mutagenic at concentrations of 10(-5), 10(-4) and 10(-3)M, which produced 3.8% sex-linked recessive lethals (983 chromosomes tested). 9.0% (708) and 15.3% (327), respectively. Senkirkine (10(-5)M) produced 4.4% sex-linked recessive lethals (2541 chromosomes tested) against 0.17% (9081) in controls. Brood pattern analysis with senkirkine showed maximum sensitivity in the late spermatid stage of spermatogenesis, which agrees with evidence that pyrrolizidine alkaloids act as indirect mutagens. Flies fed with milk from lactating rats given an oral dose of 25 mg seneciphylline/kg showed 1.2% sex-linked recessive lethals (1477 chromosomes tested), against 0.3% (1533) in controls.

Animals↗
PubMed1982

Mutagenesis in spermatozoa of Drosophila melanogaster by cross-linking agents depends on the mus(1)101+ gene product in the oocyte.

In Drosophila melanogaster the sex-linked gene must(1)101+ is essential for mutagenesis induced by a cross-linking agent: mature sperm mutagenized by nitrogen mustard (HN2) yield high frequencies of induced sex-linked recessive lethals if tested with wild-type oocytes but practically no recessive lethals if tested with homozygous mus(1)101D1 oocytes. In the absence of mus(1)101+ at least some cross-links act as lethal lesions, whereas in the presence of mus(1)101+ some act as premutational lesions. The lack of delayed mutations in mutant oocytes indicates that the lesions are efficiently eliminated and do not lead to mutagenesis in later post-fertilization nuclear divisions. The mutation mus(1)101D1 is not a null allele because, in tests with heterozygotes, it reduces mutagenesis to a lesser extent than a deletion including the mus(1)101 locus. It is a leaky allele with such a reduced activity that, in homozygous condition, mutagenesis is practically absent. In deletion heterozygotes the mus(1)101+ gene is not dosage-compensated.

Alleles↗
PubMed1982

An investigation of the genetic toxicology of irradiated foodstuffs using short-term test systems. III--In vivo tests in small rodents and in Drosophila melanogaster.

Six in vivo genetic toxicity tests were carried out on irradiated or unirradiated cooked chicken, dried dates and cooked fish. The tests were as follows: sex-linked recessive lethal mutations in Drosophila melanogaster (dried dates only), chromosome aberrations in bone marrow of Chinese hamsters, micronucleus test in rats, mice and Chinese hamsters, sister-chromatid exchange in bone marrow of mice and Chinese hamsters and in spermatogonia of mice, and DNA metabolism in spleen cells of Chinese hamsters. None of the tests provided any evidence of genetic toxicity induced by irradiation. However, dried dates, whether irradiated or not, showed evidence of some genetic toxicity in their effect on DNA metabolism in spleen cells and SCE induction in bone marrow. Feeding irradiated fish affected DNA metabolism in the spleen cells of Chinese hamsters. This effect could be interpreted as an induction of an immunoactive compound, although it could also be explained by the persistence of an immunoactive compound due to the removal by irradiation of spoilage organisms that would normally degrade it.

Animals↗
PubMed1981

[The treatment of psoriasis-arthritis with cyclosporin A, a new immunosuppressive agent].

The treatment of psoriasis and psoriatic arthritis by cyclosporin A, a new immunosuppressive agent believed to have a largely selective action on T lymphocytes, is described. Results in 4 cases show that cyclosporin A can bring about a most impressive improvement in psoriatic lesions of the skin and its appendages, but that its effect on the arthropathy is variable. There is still little certainty about the compound's mechanism of action in these conditions. Cyclosporin A may give rise to a whole range of side effects and its use--like that of other immunosuppressants--should therefore be contemplated only in severe and progressive forms of psoriasis and psoriatic arthritis resistant to other forms of treatment except cytostatic drugs.

Aged↗
PubMed1981

[Cyclosporin A--effects and side effects in the treatment of rheumatoid and psoriatic arthritis (author's transl)].

The treatment of rheumatoid arthritis and psoriatic arthritis with cyclosporin A is described. Cyslosporin A is a new selective immunosuppressant which acts primarily on the T lymphocytes. It has already been shown to be effective in preventing rejection following kidney transplantation as well as in preventing graft-versus-host disease. In rheumatoid and psoriatic arthritis, however, its effect was not satisfactory, although rather different in the two conditions; overall only about one third of the patients showed any marked improvement. By contrast, and for reasons which are as yet unexplained, it had a beneficial effect on the cutaneous symptoms of psoriasis. Cyclosporin A had little effect on immune parameters. Side effects--mainly kidney toxicity, gastro-intestinal reactions and hirsutism--were common but reversible. On present evidence its principal indication among rheumatological diseases would seem to be as a treatment for severe, intractable psoriatic arthritis.

Aged↗