Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00492 (hypoxanthine-guanine phosphoribosyltransferase)
 2,385 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A review of the epidemiological and mechanistic data on 1,3-butadiene indicates that this chemical is a human carcinogen for which the mouse is an appropriate model for assessing human cancer risk. Butadiene is carcinogenic at multiple organ sites in laboratory animals, including the induction of lymphomas in mice, while epidemiological studies have consistently found associations between occupational exposure to butadiene and increased mortality from lymphatic and hematopoietic cancers. Activated oncogenes and inactivated tumor suppressor genes in butadiene-induced tumors in mice are analogous to genetic alterations frequently observed in human cancers. Butadiene is metabolized to mutagenic and carcinogenic epoxides in all mammalian species studied, including humans. These metabolites form N7-alkylguanine adducts which have been detected in liver DNA of mice exposed to butadiene and in urine of exposed workers. Increases in hprt mutations were observed in lymphocytes from mice exposed to butadiene and in occupationally exposed humans. The mutational spectra for butadiene and its epoxide metabolites at the hprt locus in mouse lymphocytes are similar to the mutational spectrum of ethylene oxide; all of these chemicals exhibit a high percentage of frameshift mutations. Ethylene oxide, an alkylating agent that also forms an N7-alkylguanine adduct, was recently classified by the International Agency for Research on Cancer as a human carcinogen. Based on these data, we suggest that cancer induction by ethylene oxide and butadiene involve similar molecular mechanisms.
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PMID:Mechanistic data indicate that 1,3-butadiene is a human carcinogen. 785 43

1,3-Butadiene (BD) is a carcinogen in both rats and mice with mice being substantially more sensitive than rats. It is not known if BD poses a carcinogenic risk for humans. Findings from exposure assessment studies indicate that potential industrial exposure to BD in monomer, polymer, and end-user industries is typically < 2 p.p.m. Epidemiologic studies of persons occupationally exposed to BD are inconclusive. In vitro metabolism of BD in rats, mice and human tissues indicate that there are significant quantitative species differences in the metabolic activation of BD to butadiene monoepoxide (BMO) and butadiene diepoxide (BDE) and the detoxication of BMO. Activation/detoxication ratios calculated using in vitro kinetic constants reveal that ratios in mice were 12-fold greater than rats and humans. In rats and mice exposed to BD, concentrations of BMO in blood and tissues of mice were up to 14-fold higher than in rats and BDE was only detected in mice thereby providing a strong argument for why mice are highly sensitive to BD carcinogenicity. The fact that human tissues do not appear to metabolize BMO to BDE to any significant extent suggest that humans may not be sensitive to BD carcinogenicity. In mice, BDE is a more potent carcinogen than BMO. BDE is mutagenic in vitro at the hprt locus in human TK6 lymphoblasts at concentrations that were 100-fold less than the concentration of BMO required to yield a similar mutation frequency. Importantly, the concentrations of BDE that were genotoxic in vitro are nearly identical to the concentrations of BDE measured in blood and tissues of mice exposed to BD by inhalation. BD is genotoxic in mice, but not rats, following inhalation exposure and this is paralleled by species differences in observed tumor susceptibility. BD is not genotoxic in occupationally-exposed workers. The genetic basis for BD carcinogenicity appears to be primarily through induction of point mutations and deletion events mediated via the potent genotoxic metabolite, BDE. The genotoxic endpoints induced by BDE (e.g., deletion and point mutations) rather than BMO (e.g., point mutations) likely represent the underlying mechanism responsible for the striking species differences observed in the genotoxicity and carcinogenicity of BD in mice versus rats.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Epidemiological and mechanistic data suggest that 1,3-butadiene will not be carcinogenic to humans at exposures likely to be encountered in the environment or workplace. 785 44

Reactive oxygen species produced by normal cellular metabolism have been considered to play a causative role in spontaneously occurring genomic instability and carcinogenesis. To study the genotoxic consequences of an enhanced flux of metabolically produced reactive oxygen species, cells may be exposed to hyperoxia (elevated concentrations of oxygen), a condition known to generate high levels of microscopically visible chromosomal damage. Here we assess the mutagenic potential of normobaric hyperoxia in several mammalian cells lines (CHO-K1-BH4 and AS52 Chinese hamster cells and TK6 human lymphoblastoid cells) using different target genes, including hprt, xprt and tk. Exposure of cell cultures to hyperoxia to 10-40% clonogenic cell survival, failed to induce mutations at the hprt and xprt loci. In human TK6 cells, hyperoxia failed to induce normal growing tk mutants, but efficiently induced slow growing tk mutants. The latter type of mutant is supposed to result from very large deletions or mutlilocus events. Our results suggest that elevated levels of endogenous activated oxygen species are inefficient in inducing point mutations or small deletions, but tend to generate gross rearrangements. Mammalian cells under oxidative stress thus exhibit a hyper-recombination phenotype. The carcinogenic impact of metabolic oxygen radical fluxes may thus be based on enhanced mitotic recombination rates, leading to tumor suppressor gene inactivation through 'loss of heterozygosity'.
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PMID:Mutagenicity of metabolic oxygen radicals in mammalian cell cultures. 800 Dec 23

Chronic inhalation of carbon black can produce carcinomas in rat lungs. At present the mechanisms underlying the rat lung tumor response to carbon black are unknown, although a significant role for inflammation and cell proliferation has been postulated. To investigate the processes which may contribute to development of rat lung tumors after carbon black exposure, we characterized the effects of subchronic inhalation of carbon black by rats on mutagenesis in alveolar epithelial cells, pulmonary inflammation, inflammatory cytokine/growth factor expression, and lung histopathology. Briefly, rats were exposed for 6 hr/day, 5 days/week for up to 13 weeks to 1.1, 7.1, and 52.8 mg/m3 carbon black and the effects on the lung were characterized after 6.5 and 13 weeks of exposure and 3 and 8 months of recovery. Endpoints characterized after carbon black exposure included mutation in the hprt gene of alveolar epithelial cells, changes in bronchoalveolar lavage fluid markers of lung injury and inflammation, expression of mRNA for the chemokines, MIP-2 and MCP-1, and lung histopathology. Lung burdens of carbon black were also determined. After 13 weeks of exposure to 1.1, 7.1, and 52.8 mg/m3 carbon black, lung burdens were 354, 1826, and 7861 micrograms carbon black, respectively. The lung clearance of carbon black appeared impaired after exposure to 7.1 and 52.8 mg/m3 carbon black, with the effects being more pronounced at the higher exposure level. Subchronic inhalation of 1.1 mg/m3 carbon black did not elicit any detectable adverse lung effects. A significant increase in hprt mutation frequency in alveolar epithelial cells was detected immediately after 13 weeks of exposure to 7.1 and 52.8 mg/m3 carbon black as well as after 3- and 8-month recovery periods for the group exposed to 52.8 mg/m3. No increase in hprt mutation frequency was observed for epithelial cells obtained from rats exposed to 1.1 mg/m3 carbon black. The observation that genotoxic effects (i.e., mutations) on alveolar epithelial cells occurred only after carbon black exposures which resulted in significant inflammation and epithelial hyperplasia supports the hypothesis that inflammatory cell-derives oxidants and increased cell proliferation play a role in the pathogenesis of rat lung tumors in response to carbon black.
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PMID:Pulmonary inflammatory, chemokine, and mutagenic responses in rats after subchronic inhalation of carbon black. 861 46

Colon cancer and an increasing number of other cancers have been found to exhibit instability of DNA microsatellite sequences. Such tumors have been designated as replication errors (RER) tumors. However, as microsatellites are only rarely found within coding regions of the genome, instability of these sequences cannot directly contribute to carcinogenesis. Recently, we have shown RER colon cancers also demonstrate a marked 100-fold increase in mutation rates measured within an expressed gene, hprt, suggesting the mutator phenotype in these tumors extends beyond microsatellite sequences. To determine whether the RER phenotype indeed destabilizes non-repetitive DNA sequences we have sequenced hprt gene mutations recovered from the RER colon cancer cell line RKO. Greater than 10% of hprt mutants proved to be a single 3 bp deletion located in a nonrepetitive ATTAT sequence motif. Additionally, 1-4 bp deletions or insertions were found to be randomly located throughout the hprt gene. Lastly, one third of hprt mutations proved to be transitions or transversions. The microsatellite instability demonstrated in RKO is thus a global mutator phenotype which destabilizes DNA sequences both inside and outside of repetitive sequence elements and which augments base substitutions as well as frameshifts. These findings extend the characteristics of mutations associated with RER tumors and suggest additional mechanisms by which mutator phenotypes may alter oncogenes and tumor suppressor genes.
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PMID:Diverse hypermutability of multiple expressed sequence motifs present in a cancer with microsatellite instability. 862 58

Toluenediamines have been of toxicological concern because of their industrial use as intermediates in polyurethane synthesis and because of the potential of their release from degradation of the Microthane polyesterurethane covering of some breast implants. In this study, we have assessed the extent of DNA damage in rats treated with a carcinogenic toluenediamine isomer, 2,4-toluenediamine (2,4-TDA), under conditions that result in tumor induction, and in rats implanted with Microthane polyesterurethane foam. Time and dose-dependent formation of adducts was observed in DNA from the liver and mammary gland of rats fed 10, 40, 80 and 180 ppm 2,4-TDA for up to 6 weeks. In assays conducted 1 to 32 weeks after the start of treatment, no adducts were detected in the DNA of T-lymphocytes isolated from the spleens of animals fed 40 or 180 ppm 2,4-TDA, nor was there an increase in mutations at the hprt locus in these lymphocytes. In rats fed 40 or 180 ppm, 2,4-TDA for 6 weeks, adducts were detectable in DNA isolated from liver and mammary gland for 26 to 43 weeks after termination of the treatment. No DNA damage, as assessed by both DNA adduct measurement and induction of T-lymphocyte hprt mutations, was observed in rats up to 42 weeks after receiving subcutaneous implants of polyesterurethane foam (67 or 267 mg/kg). Although 2,4-TDA is clearly capable of damaging DNA, the results of this study are consistent with the conclusion that Microthane foam-containing implants present a minimal risk of genotoxicity through release and subsequent metabolic activation of 2,4-TDA. The study also indicates that DNA adduct formation and mutation induction in lymphocytes are inadequate biomonitors for measuring exposure to toluenediamines.
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PMID:Assessment of DNA adducts and the frequency of 6-thioguanine resistant T-lymphocytes in F344 rats fed 2,4-toluenediamine or implanted with a toluenediisocyanate-containing polyester polyurethane foam. 862 27

We have determined the frequency and spectrum of spontaneous mutations at the hprt locus in LoVo, HCT116, LS180 and DLD-1 colon carcinoma cell lines exhibiting microsatellite genetic instability. Each cell line has a different mutator gene. LoVo and HCT116 cells have mutated hMSH2 and hMLH1 genes, respectively, which account for the majority of hereditary non-polyposis colorectal cancer (HNPCC). LS180 cells are wild type for these genes and also for hPMS1 and hPMS2 mismatch repair genes. DLD-1 cells harbor a mutated GTBP mismatch binding factor and a mutated DNA Polymerase delta. The mutation rate at the hprt locus was several hundred fold higher in these cell lines relative to control cell lines without microsatellite instability. The mutations were frameshifts (deletions and insertions of a single nucleotide in short repeats) and single base substitutions (transversions and transitions). Some mutations were shared by these four cell lines. However, every cell line also exhibited a distinctive spectrum of mutations suggesting that each mutator gene induces a particular mutator phenotype. These results also suggest that the frequency and spectrum of somatic mutations in tumor cells of the microsatellite mutator phenotype may have diagnostic applications to discriminate among the diverse underlying mutator genes.
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PMID:Differences in the spectrum of spontaneous mutations in the hprt gene between tumor cells of the microsatellite mutator phenotype. 864 58

Radon exposure has been linked to lung carcinogenesis in both human and animal studies. Studies of smoking and nonsmoking uranium miners indicate that radon alone is a risk factor for lung cancer at the levels encountered by these miners, although the possibility exists that other substances in the mine environment affect the radon-induced response. The relevance of data from mines to the lower-exposure home environment is often questioned; still, a recent study of miners exposed to relatively low radon concentrations demonstrated a statistically significant increase for lung and laryngeal cancer deaths. In two major series of experiments with rats, the primary carcinogenic effect found was respiratory tract tumors, and evidence for an inverse exposure-rate effect was also noted. Although this inverse dose-rate effect also has been described in underground miner studies, it may not similarly apply to radon in the home environment. This observation is due to the fact that, below a certain exposure, cells are hit once or not at all, and one would not expect any dose-rate effect, either normal or inverse. Because some chromosome aberrations persist in cycling cells as stable events, cytogenetic studies with radon are being performed to help complete the understanding of the events leading to radon-induced neoplasia. Radon has been found to induce 13 times as much cytogenetic damage (as measured by the occurrence of micronuclei) than a similar dose of 60Co. A wide variety of mutation systems have demonstrated alpha-particle mutagenesis; recent investigations have focused on the molecular basis of alpha-induced mutagenesis. Gene mutations are induced by radon in a linear and dose-dependent fashion, and with a high biological effect relative to low-LET irradiation. Studies of the hprt locus show that approximately half of the alpha-induced mutations arise by complete deletion of the gene; the remaining mutations are split between partial deletions, rearrangements, and events not detectable by Southern blot or PCR exon analysis. Although other mutation systems do not show the same spectra as observed in the hprt gene (suggesting that the gene environment affects response), DNA deletions or multilocus lesions of various size appear to be predominant after radon exposure. As data emerge regarding radon-induced changes at the chromosomal and molecular level, the mechanisms involved in radon carcinogenesis are being clarified. This information should increase the understanding of risk at the low exposure levels typically found in the home.
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PMID:Genetic, cytogenetic, and carcinogenic effects of radon: a review. 869 77

Etoposide is one of the most widely used antineoplastics. Unfortunately, the same treatment schedules associated with impressive efficacy are associated with an increased risk of secondary acute myeloid leukemia (AML), which has prompted its withdrawal from some treatment regimens, thereby potentially compromising efficacy against the original tumor. Because etoposide-associated AML is characterized by site-specific illegitimate DNA recombination, we studied whether etoposide could directly cause site-specific deletions of exons 2 and 3 in the hprt gene. Human lymphoid CCRF-CEM cells were treated with etoposide for 4 hours, and DNA was isolated after subculturing. The deletion of exons 2 and 3 from hprt was assayed by a quantitative polymerase chain reaction (PCR) method. In the absence of etoposide treatment, the frequency of deletions of exons 2 and 3 was very low (5.05 x 10(-8)). After exposure to 10 mumol/ L etoposide, the frequency of the exon 2 + 3 deletion was increased immediately after and at 24 hours after etoposide treatment (65 to 89 x 10(-8)) and increased to higher levels (128 to 173 x 10(-8)) after 2 and 6 days of subculture (P < .001 overall). The frequency of the exon 2 + 3 deletion assessed at 6 days of subculture after 4 hours of 0, 0.25, 1, 2.5, 5, and 10 mumol/L etoposide treatment increased with etoposide concentration, ie, 5.05 x 10(-8), 89.2 x 10(-8), 108 x 10(-8), 142 x 10(-8), 163 x 10(-8), and 173 x 10(-8), respectively (P < .0001). Sequencing of a subset of amplified products confirmed the presence of DNA sequences at the breakpoints consistent with V(D)J recombination. By contrast, exon 2 + 3 deletions after etoposide treatment in the myeloid cell lines KG-1A and K562 showed no evidence of V(D)J recombinase in their genesis. We conclude that etoposide can induce the illegitimate site-specific action of V(D)J recombinase on an unnatural DNA substrate after a single treatment in human lymphoid cells.
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PMID:Etoposide causes illegitimate V(D)J recombination in human lymphoid leukemic cells. 882 41

Self-incompatible het-6OR/het-6PA partial diploids of Neurospora crassa were selected from a cross involving the translocation strain, T(IIL-->IIIR)AR18, and a normal sequence strain. About 25% of the partial diploids exhibited a marked increase in growth rate after 2 weeks, indicating that "escape" from het-6 incompatibility had occurred. Near isogenic tester strains with different alleles (het-6OR and het-6PA) were constructed and used to determine that 80 of 96 escape strains tested were het-6PA, retaining the het-6 allele found in the normal-sequence LGII position; 16 were het-6OR, retaining the allele in the translocated position. Restriction fragment length polymorphisms in 45 escape strains were examined with probes made from cosmids that spanned the translocated region. Along with electrophoretic analysis of chromosomes from three escape strains, RFLPs showed that escape is associated with deletion of part of one or the other of the duplicated DNA segments. Deletions ranged in size from approximately 70 kbp up to putatively the entire 270-kbp translocated region but always included a 35-kbp region wherein we hypothesize het-6 is located. The deletion spectrum at het-6 thus resembles other cases where mitotic deletions occur such as of tumor suppressor genes and of the hprt gene (coding for hypoxanthine-guanine phosphoribosyl-transferase) in humans.
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PMID:Escape from het-6 incompatibility in Neurospora crassa partial diploids involves preferential deletion within the ectopic segment. 888 17


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