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Query: UNIPROT:P06889 (Mol)
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A quantitative structure-activity relationship (QSAR) has been derived for the mutagenic activity of 117 aromatic and heteroaromatic nitro compounds acting on Salmonella typhimurium TA100. Relative mutagenic activity is bilin-early dependent on hydrophobicity, with an optimal log P of 5.44, and is linearly dependent on the energy of the lowest unoccupied molecular orbital of the nitro compound. The dependence of mutagenic activity on hydrophobicity and electronic effects is very similar for TA98 and TA100. Mutagenic activity in TA100 does not depend on the size of the aromatic ring system, as its does in TA9. The effect of the choice of assay organism, TA98 versus TA100, on nitroarene QSAR is seen to be similar to the effect previously found for aminoarenes. Lateral verification of QSARs is presented as a tool for establishing the significance of a new QSAR.
Environ Mol Mutagen 1992
PMID:Quantitative structure-activity relationship investigation of the role of hydrophobicity in regulating mutagenicity in the Ames test: 2. Mutagenicity of aromatic and heteroaromatic nitro compounds in Salmonella Typhimurium TA100. 173 4

Molecular analysis of hypoxanthine-guanine phosphoribosyltransferase (hprt) cDNA from 6-thioguanine-resistant T-lymphocytes cloned from smoking and non-smoking adult donors showed that 35% of these mutants were defective in splicing of hprt mRNA. Among a set of 42 hprt splice mutants, we observed i) complete loss of one or more exons, ii) partial loss of one exon, or iii) inclusion of part of an intron sequence between adjacent exons. Loss of exon 4 was significantly more frequent than of the other exons, suggesting that the sequences that regulate splicing of this exon are either larger than those of the other exons or especially prone to mutation. In order to identify the molecular nature of DNA alterations causing aberrant splicing of hprt mRNA, 17 splice mutants were analyzed in more detail by sequencing the genomic regions flanking the mis-spliced exon. Base pair substitutions or small deletions causing defective splicing were either detected in exon sequences or in splice site consensus sequences of introns. Furthermore, genomic deletions encompassing entire exons were found. In some mutants, the alteration responsible for incorrect splicing could not be identified, suggesting that the target sequence for splice mutations is larger than merely the splice junctions. Molecular characterization of hprt splice mutations will lead to the identification of specific sequences regulating splicing of hprt mRNA and will reveal whether the mutational spectrum in splice mutants is similar to that found in the hprt coding region.
Environ Mol Mutagen 1992
PMID:Molecular analysis of mutations affecting hprt mRNA splicing in human T-lymphocytes in vivo. 173 5

P-Benzoquinone dioxime (BQD) appears to be a sex-specific rat carcinogen inducing tumours of the urinary bladder in female rats. The present paper shows that BQD is a direct-acting mutagen in Salmonella typhimurium TA98, confirming published data. In contrast to this in vitro data, negative results were obtained after oral administration of BQD to female rats in both the bone marrow micronucleus test and the in vivo liver UDS test. BQD did, however, induce a marked effect upon S-phase synthesis in the livers of female rats between 14 and 48 hr after a single oral dose of 250 mg/kg. A similar effect was also observed in the livers of male rats. There was no evidence of hepatotoxicity (in terms of elevated liver enzyme levels) after treatment of female rats with the compound indicating that the increase in cell proliferation was due to a direct mitogenic effect of BQD in this organ. Some liver mitogens have been found to be liver carcinogens; this does not appear to be the case for BQD. Nevertheless, the mitogenic activity of this compound might play a contributory role to the induction of bladder cancer in rats if it also acted as a mitogen in this tissue. Further studies are indicated, measuring genotoxicity and cell-proliferative activity in the bladder in order to further elucidate the mechanism of action of this compound as a rodent carcinogen.
Environ Mol Mutagen 1992
PMID:In vivo genotoxicity studies with p-benzoquinone dioxime. 173 6

The purpose of this study was to assess the cytogenetic effects of two commonly used herbicides, alachlor and atrazine, which are often found together in groundwater. Chromosome damage was examined in bone marrow cells of mice drinking water containing 20 ppm alachlor and/or 20 ppm atrazine, with an immunosuppressive dose of cyclophosphamide used as a positive control. Chromosome damage was also quantified in human lymphocytes exposed in culture to 1.0, 0.1, or 0.01 microgram/ml alachlor and/or atrazine. The in vitro study demonstrated dose related cytogenetic damage not associated with mitotic inhibition or cell death, with damage due to the alachlor-atrazine combination suggesting an additive model. The in vivo study also suggested additive damage due to the alachloratrazine combination after 30 days of treatment, but, unexpectedly, demonstrated less cytogenetic damage and fewer cells with multiple aberrations after 90 days. Also, at 90 days, all treated mice had elevated mitotic indices compared to controls. The fact that the elevated mitotic index was associated with immune suppression in the cyclophosphamide group suggests that death of cells with accumulated chromosomal aberrations resulted in increased bone marrow proliferation, so a higher fraction of cells examined were newer with less damage. Since the alachlor-atrazine combination treated mice showed little systemic toxicity despite bone marrow mitotic indices similar to the cyclophosphamide treated animals, as well as a similar decrease in cytogenetic damage at 90 days compared to 30 days, cell death and replacement must also be involved but cannot completely explain the results.
Environ Mol Mutagen 1992
PMID:Cytogenetic effects of alachlor and/or atrazine in vivo and in vitro. 173 7

The question of how many and which short-term tests (STT) are necessary for a satisfactory characterization of the genotoxic properties of chemicals is still open. The answer is important for both basic mutagenicity research and risk assessment. This paper, aimed at giving a rational answer to the problem, analyzes with multivariate statistical methods the data generated by the International Program for the Evaluation of Short-Term Tests for Carcinogens (IPESTTC). Although it has been found that this data base has a limited reliability for assessing the ability of STTs to predict carcinogenicity, the IPESTTC results are an important source of information on the relationships among different assays, and their ability to identify genotoxic chemicals. A scale of genotoxicity of the chemicals was established by studying with factor analysis their results in 20 IPESTTC tests. The next step of the analysis consisted in the identification of the STT batteries which are the most able to reproduce the genotoxicity scale based on the entire set of STTs. Different batteries were ranked according to their ability to quantify genotoxicity. As a general conclusion, this study indicated that an articulated range of STTs is necessary, and it is not possible to use only one assay (e.g., Salmonella) as an exhaustive indicator of genotoxicity.
Environ Mol Mutagen 1992
PMID:Rational approach to the quantification of genotoxicity. 173 8


Environ Mol Mutagen 1992
PMID:Environmental Mutagen Society, 23rd annual scientific meeting. Reno, Nevada, March 15-19, 1992. Abstracts. 173 92

An overview of the application of various molecular techniques to the analysis of genomic DNA is presented. For the analysis of small-scale changes, the polymerase chain reaction (PCR), colony probe hybridization, mismatch hybridization, and denaturing gradient gel electrophoresis (DGGE) are providing information on mutations within prokaryotic and eukaryotic genes. For large-scale changes, fluorescence in situ hybridization (FISH), pulsed-field gel electrophoresis (PFGE), Southern blotting, multiplex PCR, hybridization of linked probes, and restriction enzyme mapping are permitting analysis of genomic alterations that are larger than point mutations but below the resolution of standard cytogenetic analysis. Many of these techniques, either alone or in combination, produce DNA that can be subjected to DNA sequence analysis, which provides the most detailed information regarding genomic changes.
Environ Mol Mutagen 1991
PMID:Workshop overview: new molecular techniques in genome analysis. 174 81


Environ Mol Mutagen 1991
PMID:Presentations from the twenty-second annual meeting of the Environmental Mutagen Society. April 6-11, 1991. 174 82

A rapid method for determining the DNA sequences of Salmonella typhimurium hisD3052 revertants is presented. DNA colony hybridization was used to analyze revertants previously studied by Isono and Yourno [Proc Natl Acad Sci USA 71:1612-1617, 1974]. Synthetic oligodeoxyribonucleotide probes (18-mers) were able to distinguish sequences that differed by a single base pair. Mutant his sequences not identified by probing analysis were amplified using polymerase chain reaction (PCR) and directly sequenced. The combined use of DNA-colony hybridization and direct sequencing offers a precise and rapid means for the molecular characterization of hisD3052 revertants.
Environ Mol Mutagen 1991
PMID:Analysis of Salmonella typhimurium hisD3052 revertants: the use of oligodeoxyribonucleotide colony hybridization, PCR, and direct sequencing in mutational analysis. 174 83

Our studies of mutational mechanisms in mammalian cells use the AS52 Chinese hamster ovary cell line. AS52 mutants can be selected as 6-thioguanine resistant colonies and mutations are studied at a chromosomally integrated gpt locus. Mutant gpt sequences are amplified using the polymerase chain reaction (PCR) to distinguish deletions from putative point mutations. PCR is efficiently performed from a few thousand lysed cells or from isolated genomic DNA. Amplified mutant PCR fragments carrying putative point mutations are further characterized by localizing the site of the mutation using chemical modification. A heteroduplex molecule consisting of one wild-type and one mutant DNA strand is generated. A base mismatch will be produced at the site of the mutation. Mismatched cytosine or thymine residues are sensitive to modification by hydroxylamine or osmium tetroxide, respectively. The modified DNA heteroduplex is then sensitive to piperidine cleavage. If one strand is 32P-end labeled, then the cleavage product can be separated on a denaturing acrylamide sequencing gel and visualized using autoradiography. Thus, the site of a mutation can be localized to a specific region of the gene, thereby simplifying the DNA sequence analysis and facilitating the rapid generation of mutational sequence spectra.
Environ Mol Mutagen 1991
PMID:Rapid localization of point mutations in PCR products by chemical (HOT) modification. 174 84


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