Gene/Protein Disease Symptom Drug Enzyme Compound
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Previous population-based studies have identified subject characteristics that, when combined, can account for approximately 20% of the observed interindividual variation in baseline SCE rates. In the present investigation, a classic twin study design was used to address the issue of the relevance of genetic factors to baseline SCE rates and to identify other demographic, hematologic, and exposure variables predictive of SCE rate. Questionnaire data and peripheral blood samples from 136 monozygotic and 88 dizygotic twins (age range: 25-81 years) were obtained. Among the large number of variables examined, univariate analyses (including ANOVA tests for the categorical variables and Pearson-product moment correlations for the quantitative variables) revealed smoking status, coffee drinking status, sex, white blood cell count, and absolute numbers of lymphocytes and neutrophils to have significant effects on SCE rates. A stepwise multiple regression analysis showed that together, smoking and coffee drinking status entered at the first step accounted for 21% of the observed variance in SCE, with a further 6% being contributed by the demographic and hematologic variables added in subsequent steps. Finally, the twin analyses showed that after adjustment of the data set for smoking and other significant predictors, genetic factors accounted for approximately 30% of the variation in SCE rates. Thus these data support the hypothesis of a significant genetic influence on baseline SCE.
Environ Mol Mutagen 1992
PMID:Genetic and environmental influences on baseline SCE. 163 80

The rodent liver carcinogen, mitogen, and peroxisome proliferator, methylclofenapate (MCP), has been investigated as a chemical mitogen for use in the rat liver micronucleus assay. A series of experiments comparing MCP with the potent mitogen 4-acetylaminofluorene (4AAF) and with 2/3 partial hepatectomy showed unexpected differences between the three treatment regimes as monitored by the expression of micronucleated hepatocytes (MH) in livers initiated with N-nitrosodimethylamine (NDMA). These differences were observed in both the profile of MH induction, as a function of time after mitogenic stimulation, and in the magnitude of response. There was no correlation between the magnitude of MH induction and the degree of mitogenesis triggering the MH induction. It is concluded that the yield of MH observed in a rat liver micronucleus assay is not a simple function of the level of DNA damage induced by the initiating agent (here NDMA). This indicates the need for caution in the interpretation of data obtained in the liver micronucleus assay for chemicals of unknown carcinogenicity. The use of acridine orange as a fluorescent stain for use with isolated hepatocytes is described.
Environ Mol Mutagen 1992
PMID:Mitogenesis, micronuclei, and carcinogenesis in the rat liver: some basic inconsistencies. 163 81

Previous studies have shown that the rat liver carcinogen quinoline is essentially nongenotoxic to the rat liver in vivo. Those studies also established it as a potent mitogen to rat liver. The present experiments have established quinoline as a mitogen to the mouse liver, a tissue in which it is also reported to be carcinogenic. In contrast, quinoline is reported to be noncarcinogenic to the guinea pig liver, and the present data establish it to be essentially nonmitogenic to the guinea pig liver. It is concluded that the mitogenicity of quinoline correlates better with its hepatocarcinogenic properties than does its genotoxicity in vivo.
Environ Mol Mutagen 1992
PMID:Mitogenic activity of quinoline to the rat, mouse, and guinea pig liver: empirical correlations with hepatic carcinogenicity. 163 82

Spontaneous and chemically induced revertant colonies were not observed on plates when a strictly anaerobic environment and anaerobically prepared media were used to perform the Ames histidine reversion assay with each of eight different Salmonella strains. A similar effect was observed when the E. coli tryptophan reverse mutation assay was performed under strictly anaerobic conditions. We provide evidence here that under anaerobic conditions growth inhibitor(s) are formed by the S. typhimurium and E. coli bacteria when the limited histidine and tryptophan, respectively, are depleted from the medium. The inhibitor(s) are nonspecific and inhibit the growth not only of prototrophic bacteria but also of the inhibitor-producing bacteria as measured by neutralized supernatants of growth-limiting minimal liquid cultures. Inhibitor(s) are also formed in stationary phase cultures of Salmonella and E. coli in minimal liquid medium supplemented with excess histidine and tryptophan, respectively. These results suggest that inhibitor formation under anaerobic conditions is a physiological phenomenon which interferes with at least two reverse mutation assays. Whether or not it also interferes with the reverse mutagenesis process remains to be determined.
Environ Mol Mutagen 1992
PMID:Evidence that inhibitor(s) are formed which may interfere with the growth of revertant colonies in the Ames Salmonella and the E. coli tryptophan reverse mutation assays when strictly anaerobic conditions are used. 163 83

Pretreatment with sublethal doses of nitrofurantoin induced adaptive response in both Vibrio cholerae and Escherichia coli cells as indicated by their greater resistance to the subsequent challenging doses of the same drug. Adaptive response was maximum corresponding to pretreatment drug concentrations of 0.40 microgram/ml and 0.015 microgram/ml respectively for V. cholerae OGAWA 154 (wild type) and E. coli K-12 AB 2463 (recA-) cells. Adaptive response was inhibited by chloramphenicol (100 micrograms/ml) indicating the need of concomitant protein synthesis. Induction of adaptive response in recA deficient E. coli cells indicated that it was different from the conventional "SOS" response. Melting temperature of DNA of V. cholerae cells subjected to adaptive (0.4 microgram/ml for 1 hr) and challenging (120 micrograms/ml for 1 hr) doses of nitrofurantoin (76 degrees C) was closer to that of native DNA (75 degrees C) vis-a-vis DNA isolated from nonadapted and drug treated cells (77.5 degrees C). Also, DNA isolated from V. cholerae cells subjected to adaptive and challenging doses of the drug revealed the presence of fewer interstrand cross-links (16% reversible DNA) vis-a-vis DNA from nonadapted but drug treated cells (55% reversible DNA). Photomicrographic studies revealed that V. cholerae cells that were nonadapted but drug treated grew into long filamentous forms (4.25 +/- 2.97 micron) whereas those subjected to both adaptive and challenge doses of the drug exhibited much less filamentation (2.08 +/- 0.84 micron) vis-a-vis native cells (1.42 +/- 0.5 micron). Similar results on DNA melting temperature, cross-links in DNA, and filamentation of cells were obtained for E. coli AB 2463 (recA-) cells subjected to adaptive and challenging treatments with nitrofurantoin. Almost equal degree of resistance against nitrofurantoin could be induced in both V. cholerae OGAWA 154 (wild type) and E. coli strain PJ3 (AB 1157 ada-) when these cells were pretreated with nontoxic doses of hydrogen peroxide or nitrofurantoin. Evidence obtained in this work on the nature of the nitrofuratoin induced adaptive response with particular references to the oxidative and/or alkylating DNA damages were discussed. Nitrofuratoin induced adaptive response appeared similar to that elicited by furazolidone in V. cholerae cells and appeared to be directed towards oxidative and not alkylating adaptive repair pathway.
Environ Mol Mutagen 1992
PMID:Adaptive response of Vibrio cholerae and Escherichia coli to nitrofurantoin. 163 84

To study the genotoxic activity of Decemtione (Imidan), this substance was subjected to a series of tests. After preliminary cytotoxicity testing, the capacity of Decemtione to damage human DNA was determined by alkaline elution of DNA and DNA unwinding. Both tests gave positive results, suggesting that Decemtione was able to induce single-strand breaks in DNA. This capacity was higher in the absence and lower in the presence of the S9 fraction. The potential mutagenicity of Decemtione was followed on the basis of its ability to induce resistance to 6-thioguanine in V79 hamster cells. Unlike the induction of single-strand breaks, Decemtione showed, in the absence of the metabolic activation system, a very weak mutagenic effect, which was, however, significantly higher in the presence of the S9 fraction. The ability of the substance to transform diploid cells under in vitro conditions was followed on the basis of morphological transformation of Syrian hamster embryo cells. The results showed that Decemtione, like positive carcinogenes, induced a significant elevation in morphologically transformed colonies of embryo cells. The results suggest a carcinogenic potential of this organophosphate insecticide.
Environ Mol Mutagen 1992
PMID:Decemtione (Imidan)-induced single-strand breaks to human DNA, mutations at the hgprt locus of V79 cells, and morphological transformations of embryo cells. 163 85

The SOS chromotest was applied for the detection of antimutagens. To raise SOS induction, the bacteria were treated with the mutagens, UV, 4-nitroquinoline N-oxide (4NQO), N-methyl-N'-nitro-N-nitroso-guanidine (MNNG), or benzo[a]pyrene (B[a]p). The inhibitory effects of L-ascorbic acid, glutathione, vanillin, 5-fluorouracil (5-FU), 5-chlorouracil (5-CU), cobaltous chloride, sodium selenite and sodium arsenite, which are known as antimutagens, were investigated with their addition either simultaneously or post treatment time. It became clear that the SOS chromotest was very useful for the detection of antimutagens.
Environ Mol Mutagen 1991
PMID:Evaluation of the SOS chromotest for the detection of antimutagens. 164 15

Many human genetic diseases, including some cancers, are characterized by consistent chromosome abnormalities, such as deletions and translocations. Analyses of these mutations often prove crucial to the eventual cloning and characterization of the gene(s) responsible for the disease. Two methods for analyzing these chromosome abnormalities have been developed in recent years: somatic cell hybridization and pulsed field gel electrophoresis (PFGE). Somatic cell hybridization is a technique for segregating an aberrant chromosome from its normal homologue in a cell derived from an unrelated species, which is usually a rodent. Panels of such hybrids dividing a given chromosomal region into increasingly smaller units can be constructed and used specifically to map DNA probes into those units. PFGE can then be used to define precise physical distances between such an array of chromosome abnormalities. Demonstrations of these analytic techniques are presented, using as an example chromosomal abnormalities involving human chromosome band 11p13, the locus for the Wilms' tumor, aniridia, genitourinary abnormality, and mental retardation (WAGR) syndrome.
Environ Mol Mutagen 1991
PMID:Molecular analysis of chromosomal rearrangements using pulsed field gel electrophoresis and somatic cell hybrids. 166 Aug 7

The glutathione transferase mu gene (GST1) and the debrisoquine hydroxylase gene (CYP2D6) are known to be polymorphic in the human population and have been associated with increased susceptibility to cancer. Smokers with low lymphocyte GST mu activity are at higher risk for lung cancer, while low debrisoquine hydroxylase activity has been correlated with lower risk for lung and bladder cancer. Phenotypic characterization of these polymorphisms by lymphocyte enzyme activity (GST) and urine metabolite ratios (debrisoquine) is cumbersome for population studies. Recent cloning and sequencing of the mutant alleles of these genes has allowed genotyping via the polymerase chain reaction (PCR). Advantages of PCR approaches are speed, technical simplicity, and minimal sample requirements. This article reviews the PCR-based methods for detection of genetic polymorphisms in human cancer susceptibility genes.
Environ Mol Mutagen 1991
PMID:Detection of DNA sequence polymorphisms in carcinogen metabolism genes by polymerase chain reaction. 168 53

BALB/c-3T3 cells were employed to examine the genotoxic potential of a variety of known chemical carcinogens. BALB/c-3T3 cells displayed a dose-dependent transformation response to a variety of carcinogens (polycyclic hydrocarbons, methylating agents, ethylating agents, aflatoxin B1 [AFB1], and 4-nitroquinoline-N-oxide [4-NQO]). When the ability of these compounds to induce mutagenesis to resistance to the cardiac glycoside ouabain (OUAR) was examined, we found the short chain alkylating agents to be particularly effective mutagens, causing biologic effects at doses below those necessary to induce a transformation response. In contrast, the polycyclic hydrocarbons which were potent transforming agents were weaker, albeit significant, mutagens for the OUAR locus in this system, while AFB1 was quite weak. Further studies were performed with 5-azacytidine (5-AZA) and the nongenotoxic carcinogen cinnamyl anthranilate (ClN). 5-AZA was a potent transforming agent, but failed to cause mutagenesis. ClN similarly caused in vitro transformation. When a series of eight structurally diverse compounds were examined in both the BALB/c-3T3 and C3H10T1/2 mouse fibroblast transformation systems, the BALB/c-3T3 system was shown to be sensitive to a wide variety of potential carcinogens, whereas the C3H10T1/2 system proved routinely sensitive only to the polycyclic hydrocarbons.
Environ Mol Mutagen 1990
PMID:Induction of mutagenesis and transformation in BALB/c-3T3 clone A31-1 cells by diverse chemical carcinogens. 169 71


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