Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Preferential breakage of chromosomes at specific sites (so-called "fragile sites") has been observed to occur spontaneously, and has been induced by some metal salts and chemicals. Furthermore, a heterochromatic region of the long arm of the Chinese hamster ovary (CHO) X-chromosome is known to be susceptible to a disproportionately high frequency of spontaneous breakage; unless there is physical displacement of chromatin the resulting achromatic lesions are not scored as structural aberrations. We have encountered such anomalous breakage associated with C-band positive regions of the chromosomes of a CHO-K1 cell line following exposure of the cells to toxic doses of U-68,553B and in this report present evidence that the apparent breaks are due to undercondensed heterochromatin (UH) and evidence that the phenomenon appears to occur at higher frequency in a particular cell line of Chinese hamster. This finding has important implications on the assessment of potential risk due to exposure to the drug. Such apparent breaks at sites of UH in chromosome 1 was not observed in an alternate CHO cell line (CHO-WBL) which supports the notion that the UH associated achromatic lesions in the CHO-K1 line may be a cell line specific phenomenon. Furthermore, careful electron microscopy of the chromosomes revealed chromatin fibers connecting the apparently broken chromosomes. The UH was not observed in the presence of added metabolic activation (S9), and thus the significance of the phenomenon in risk assessment is further reduced. The data presented here provide evidence that sites of UH occur preferentially at locations of C-band positive constitutive heterochromatin in CHO cells; we believe that this is the first report of induced fragile sites in rodent cells in vitro documented in this way. In addition, evidence is presented that U-68,553B lacks the ability to induce breakage in vivo in rodents and lacks the ability to induce chromosome breakage in human peripheral lymphocytes in vitro. Therefore, it is concluded that the positive results with CHO-K1 cells treated with U-68,553B are unlikely to be predictive of a genotoxic hazard. This is a specific example of the importance of careful followup to an in vitro result in risk assessment.
Environ Mol Mutagen 1992
PMID:Chromosomal breakage following treatment of CHO-K1 cells in vitro with U-68,553B is due to induction of undercondensation of heterochromatin. 139 8

The nitrosamine contaminant, N-nitroso-N-methyl-p-aminobenzoic acid, 2-ethylhexyl ester (NPABAO), of the major sunscreen ingredient Padimate O (4-N,N'-dimethylamino-benzoic acid, 2-ethylhexyl ester) was synthesized and tested for mutagenicity in the Salmonella typhimurium and mouse lymphoma L5178Y TK +/- assays. In contrast to the previously reported positive responses in S. typhimurium tester strains TA100 and TA1535 [Loeppky et al., 1991], there were no increases in the number of revertants with strains TA98, TA100, TA1535, and TA1538 in either the Salmonella plate incorporation [Ames et al., 1975] or preincubation [Yahagi et al., 1977] assays. Additional testing with Salmonella, following the modified preincubation procedure [Rogan, 1990] that gave the initial positive response, was also negative. Data from the mouse lymphoma assays were also uniformly negative. During synthesis of NPABAO, small amounts of 4-N,N'-dimethylamino-3-nitrobenzoic acid, 2-ethylhexyl ester (DMANBAO) can be formed. To determine whether the reported positive mutagenicity response of NPABAO could be the result of trace amounts of DMANBAO in the NPABAO, that compound was also synthesized and tested for mutagenicity with Salmonella. Positive responses were obtained with tester strains TA98 and TA 1538 but not with TA100 and TA1535, indicating that DMANBAO was not responsible for the increase in revertants originally reported.
Environ Mol Mutagen 1992
PMID:Evaluation of the mutagenicity of an N-nitroso contaminant of the sunscreen Padimate O: N-nitroso-N-methyl-p-aminobenzoic acid, 2-ethylhexyl ester (NPABAO). 139 9

Sodium/copper chlorophyllin (CHL) is a water-soluble derivative of chlorophyll that exhibits antimutagenic activity in several short-term genotoxicity assays and inhibits carcinogen-DNA binding in vivo. The effect of CHL pretreatment on the excretion of mutagens in the urine and feces of male Sprague-Dawley rats has been studied using the Salmonella mutagenicity assay. Animals were given 1 percent CHL in the drinking water for 2 days before administering a single dose of 2-amino-3-methylimidazo-[4,5-f]quinoline (IQ) by oral gavage. Rats pretreated with CHL had higher levels of mutagens in the urine and feces compared with animals given IQ alone; 48 hr after IQ administration, the total mutagenic dose excreted was < 4% in controls vs. 18% in rats given CHL. Mutagenicity required the presence of an activation system, was unaffected by treatment with beta-glucuronidase or arylsulfatase, and in both the urine and feces was accounted for by increased elimination of unmetabolized parent compound. The results support the view that CHL may operate in vivo as a "desmutagen" or interceptor molecule, interacting with IQ in the gut and tissues, and reducing carcinogen bioavailability.
Environ Mol Mutagen 1992
PMID:Chlorophyllin-enhanced excretion of urinary and fecal mutagens in rats given 2-amino-3-methylimidazo[4,5-f]quinoline. 139 10

The inhibitory effects of beta-carotene on cyclophosphamide (CPA)-induced chromosomal aberrations in mouse bone marrow cells were investigated. Male Balb C mice, 8-10 weeks old, were treated with beta-carotene (0.5, 1.0, 2.0, 5.0, 10, 25, 50, 100, and 200 mg/kg) or with corn oil (0.05 ml/10 g b.w.) by gavage for 5 consecutive days. Four hours after the last treatment with or without beta-carotene, the animals were intraperitoneally injected with CPA and killed 24 hr later for cytological preparations and analysis. The results obtained show that beta-carotene provides significant protection against the clastogenicity of CPA. The maximum reduction in the frequency of aberrant metaphases (26.9%) and in total number of chromosomal aberrations were observed when beta-carotene was used at 50 mg/kg. Nevertheless, no direct dose-response relationship was detected, suggesting that beta-carotene might act through different mechanisms at different doses. The results obtained in animals studies have served as part of the basis for the human intervention studies now underway to determine if beta-carotene does indeed function as a chemopreventive agent in human nutrition.
Environ Mol Mutagen 1992
PMID:Beta-carotene as a modulator of chromosomal aberrations induced in mouse bone marrow cells. 139 11

Dichloromethane (DCM) vapour by inhalation is carcinogenic to rodents and is an in vivo rodent cell clastogen and a bacterial mutagen. It has been suggested that the bacterial mutagenicity of DCM is mediated by glutathione (GSH) conjugation. The involvement of endogenous and exogenous GSH in the conversion of DCM to a bacterial mutagen has been studied in a vapour phase protocol using wild-type and GSH-deficient (NG54; gsh) Salmonella typhimurium TA100 strains in the presence and absence of various rat liver fractions. The effect of the duration of exposure was also investigated in these Salmonella strains and in E. coli WP2 uvrA pKM101. Dose- and time-related increases in revertants occurred with all metabolic activation systems used (without exogenous metabolic activation; with Aroclor-induced rat liver S9, microsomes, or cytosol fractions), with minor quantitative differences among the 3 strains. Mutagenicity was marginally highest in the presence of cytosol at the highest DCM concentrations. Strain NG54 gsh, which contains approximately 25% of the TA100 level of GSH/microgram protein, was slightly less responsive to DCM-induced mutagenicity than TA100. Addition of 0.33 mumoles/plate of GSH had little effect on the mutagenic responses of TA100 or NG54 in the presence or absence of S9. In these 2 strains, exogenous S9 produced small increases in mutagenicity at the highest concentrations of DCM (2 and 4% v/v). These results suggest that if an interaction between DCM and GSH is required for the activation of DCM to a bacterial mutagen, it occurs at low levels of endogenous GSH and is not significantly affected by GSH supplementation.
Environ Mol Mutagen 1992
PMID:The role of glutathione in the bacterial mutagenicity of vapour phase dichloromethane. 139 12


Environ Mol Mutagen 1992
PMID:Effect of permethrin on the induction of sister chromatid exchanges and micronuclei in cultured human lymphocytes. 139 13

In recognition of the need for a more comprehensive data base for genetic risk assessment of human exposure to mutagenic agents in the environment, a model system was developed for specific-locus studies in Neurospora crassa. This lower eukaryotic organism permits the utilization of microbial techniques for recovery of large numbers of specific-locus mutations at two closely linked loci as well as their subsequent genetic analysis. In particular, this assay makes possible exploratory experiments with different environmental mutagens to obtain data on a wide variety of experimental conditions. Such data make it possible to study induction kinetics and mutational spectra in a manner that is not as yet feasible in higher eukaryotic organisms. The adenine-3 (ad-3) specific-locus assay was modeled after the 2-gene, morphological specific-locus assay in the dilute-short-ear region of the mouse, and it also detects forward-mutations at two closely linked loci, namely, ad-3A and ad-3B. Because ad-3 mutations are recovered by a direct method, based on the accumulation of a reddish-purple pigment in the vacuoles of the mycelium rather than their requirement for adenine, this system is both a morphological and biochemical specific-locus assay. The use of the ad-3 assay system in experiments with different environmental mutagens has provided precise dose-response curves not only for inactivation, but also the overall induction of ad-3 mutations. Genetic characterization of these ad-3 mutations by a series of 3 rapid and simple genetic tests permits the identification of 18 subclasses of gene/point mutations, and 12 subclasses of multilocus deletion mutations. These subclasses also include 3 different classes of multiple-locus mutations with separate sites of recessive lethal damage either in the immediately adjacent regions or elsewhere in the genome. In summary, this specific-locus assay provides a capability that is unique among eukaryotic organisms for the recovery and analysis of genetic damage at 2 closely linked loci.
Environ Mol Mutagen 1992
PMID:Development of a specific-locus assay in the ad-3 region of two-component heterokaryons of Neurospora: a review. 142 6

Data from experiments on the induction of specific-locus mutations in model systems are utilized in genetic risk assessment to estimate potential adverse effects in the human population. In such assessments with radiation or chemical mutagens, the following information is required: (1) spontaneous and induced forward-mutation frequencies, (2) dose-response curves for the overall induction of specific-locus mutations, (3) genetic characterization of spontaneous and induced mutations, and (4) dose-response curves for the different genotypic classes. Specific-locus assays in most eukaryote assay systems provide only portions of the information required for genetic risk assessment. In recognition of the need for a more comprehensive data base, a model system was developed for specific-locus studies in Neurospora crassa. The adenine-3 (ad-3) specific-locus assay was modeled after the 2 gene, morphological specific-locus assay in the dilute-short-ear region of the mouse, and it detects forward-mutations at two closely linked loci: ad-3A and ad-3B. The ad-3 assay system has provided precise dose-response curves not only for inactivation, but also the overall induction of ad-3 mutations. The utilization of this assay in experiments with radiation or chemical mutagens has provided a data base on the induction and genetic characterization of specific-locus mutations that is unique among eukaryotic organisms. In this assay, gene/point mutations, multilocus deletion mutations, and 3 different classes of multiple-locus mutations can be identified. The latter consist of specific-locus mutations associated with recessive lethal mutations located either closely linked to the ad-3 region or elsewhere in the genome. The overall data base on the heterozygous effects of X-ray-induced ad-3 mutations demonstrates that such effects are allele specific, genotype specific, and locus specific. There are probably a variety of mechanisms by which the heterozygous effects of individual allelic mutations at different genetic loci can be affected. In conclusion, unless the frequencies of all of the different classes of induced specific-locus mutations are determined, and utilized in genetic risk assessment exercises, the risk of human exposure to environmental mutagens may be grossly underestimated.
Environ Mol Mutagen 1992
PMID:Characteristics of spontaneous and induced specific-locus mutation in the ad-3 region of Neurospora crassa: utilization in genetic risk assessment. 142 7

To study mechanisms for dominance of phenotype, eight ENU- and four X-ray-induced mutations at the alcohol dehydrogenase (Adh) locus were analyzed for partial dominance in their interaction with normal alleles. All ENU and one of the X-ray mutations were single base substitutions; the other three X-ray mutations were 9-21 base deletions. All but one of the 12 mutant alleles were selected for this study because they produced detectable mutant polypeptides, but seven of the 11 producing a peptide could not form dimers with the normal peptide and the enzyme activity of heterozygotes was about half that of normal homozygotes. Four mutations formed dimers with a decreased catalytic efficiency and two of these were near the limit of detectability; these two also inhibited the formation of normal homodimers. The mutant alleles therefore show multiple mechanisms leading to partial enzyme expression in heterozygotes and a wide range of dominance ranging from almost complete recessive to nearly dominant. All amino acid changes in mutant peptides that form dimers are located between amino acids 182 and 194, so this region is not critical for dimerization. It may, however, be an important surface domain for catalyzation.
Environ Mol Mutagen 1992
PMID:Mechanisms for dominance: Adh heterodimer formation in heterozygotes between ENU or X-ray induced null alleles and normal alleles in Drosophila melanogaster. 142 8

The SOS chromotest is a simple short-term genotoxicity assay measuring the induction of gene sfiA in Escherichia coli K-12. The recent availability of SOS tester strains with additional mutations in DNA repair or protection systems allows testing of DNA damaging compounds for genotoxic specificity. E. coli PQ300 differs from the standard SOS tester strain PQ37 in that it contains an additional mutation in gene oxyR that renders it more sensitive to oxidative genotoxins. The generation of reactive oxygen intermediates (ROI) by hydroperoxides (H2O2, t-butyl hydroperoxide, cumene hydroperoxide), gamma-radiation, glucose oxidase, and xanthine oxidase resulted in a more vigorous SOS response in strain PQ300 compared to strain PQ37. PQ300 was also more sensitive than PQ37 for the detection of reducing agents such as ascorbic acid, cysteine, and glutathione, which also alter the redox status of the bacterial cells. However, intercalating agents (adriamycin, bleomycin, and mitomycin C) and the UV- and radiomimetic compound 4-nitroquinoline-1-oxide whose DNA damaging potential are known also to involve ROI did not show significant differences between strains PQ37 and PQ300. It is concluded that the oxyR-deficient strain PQ300 is useful for detecting certain classes of genotoxins that change the oxidative/antioxidative balance of tester bacteria in the SOS chromotest.
Environ Mol Mutagen 1992
PMID:Assessment of oxidative DNA damage in the oxyR-deficient SOS chromotest strain Escherichia coli PQ300. 142 9


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