Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UNIPROT:P00492 (hypoxanthine-guanine phosphoribosyltransferase)
2,385 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1,3-Butadiene (BD) is an indirect alkylating agent that has greater cancer potency in the mouse than in the rat. The purpose of the present study was to compare the mutagenic potency of BD at the hprt locus of T-lymphocytes of exposed mice and rats and to determine whether mutations induced in this marker gene can be used as a quantitative indicator for species differences in susceptibility to cancer. To this end, experiments were conducted to define the effects of exposure duration and the time elapsed after exposures on the frequency of hprt mutations (Mf) in T-cells from female B6C3F1 mice and F344 rats of similar age (4-5 weeks) when exposed to BD by inhalation. The accumulation of hprt mutations in T-cells from thymus was assessed in animals necropsied 2 weeks after exposure to 0 or 1250 ppm BD for 1 or 2 weeks, while the time course for the appearance of hprt mutant T-cells (i.e., the phenotypic expression and cell migration) in thymus and spleen was evaluated in animals necropsied at weekly/biweekly intervals up to 10 weeks after exposure for 2 weeks. At necropsy, T-cells were isolated from thymus and spleen and cultured in the presence of IL-2, concanavalin A, and 6-thioguanine (Walker and Skopek, Mutat. Res., 288, 151-162, 1993). BD exposures of 1 and 2 weeks led to mutagenic effects in mouse thymus, with the average Mfs being 3- and 5-fold greater than background values, respectively. In rat thymus, there was only a 1.7-fold increase in Mfs after 2 weeks of BD exposure. In the mutant expression experiment, hprt Mfs in thymus and spleen of both species increased for several weeks post-exposure and then declined. Hprt Mfs in thymus reached maximum levels at 2 weeks post-exposure in mice (Mfs = 11.3 +/- 2.4 x 10(-6)) and at 3 weeks post-exposure in rats (4.9 +/- 1.2 x 10(-6)), while hprt Mfs in spleen reached peak levels at 5 weeks post-exposure in mice (19.7 +/- 1.9 x 10(-6)) and 4 weeks post-exposure in rats (10.1 +/- 1.8 x 10(-6)). Background Mfs for mouse and rat thymus and spleen ranged from 1.6 +/- 0.3 x 10(-6) to 3.0 +/- 1.1 x 10(-6). Statistical analyses of the hprt Mf data for spleen demonstrated that, under these exposure conditions, the mutagenic potency of BD (represented by the difference in the areas under the phenotypic expression curves of treated versus control animals) was 5-fold greater in mice than in rats. The magnitude of the species differences in mutagenic potency, observed after 2 weeks of BD exposure, resembles the species differences in metabolism more closely than the species differences in cancer potency.
Carcinogenesis 1998 Jun
PMID:Comparison of the mutagenic potency of 1,3-butadiene at the hprt locus of T-lymphocytes following inhalation exposure of female B6C3F1 mice and F344 rats. 966 40

Genome-wide demethylation has been suggested to be a step in carcinogenesis. Evidence for this notion comes from the frequently observed global DNA hypomethylation in tumour cells, and from a recent study suggesting that defects in DNA methylation might contribute to the genomic instability of some colorectal tumour cell lines. DNA hypomethylation has also been associated with abnormal chromosomal structures, as observed in cells from patients with ICF (Immunodeficiency, Centromeric instability and Facial abnormalities) syndrome and in cells treated with the demethylating agent 5-azadeoxycytidine. Here we report that murine embryonic stem cells nullizygous for the major DNA methyltransferase (Dnmt1) gene exhibited significantly elevated mutation rates at both the endogenous hypoxanthine phosphoribosyltransferase (Hprt) gene and an integrated viral thymidine kinase (tk) transgene. Gene deletions were the predominant mutations at both loci. The major cause of the observed tk deletions was either mitotic recombination or chromosomal loss accompanied by duplication of the remaining chromosome. Our results imply an important role for mammalian DNA methylation in maintaining genome stability.
...
PMID:DNA hypomethylation leads to elevated mutation rates. 973 4

To establish a cause-effect relationship between the human mismatch repair pathway deficiency and the observed phenotypes, a hMSH2 deficient HeLa cell line (HeLa-MSH2-) was established by transfecting the HeLa cells with an antisense RNA expression plasmid. The expression plasmid was constructed by inserting an 851 bp fragment of hMSH2 cDNA into the polyclonal site of the vector pREP9 in a reversed orientation. The production of the mismatch binding protein, hMSH2, was inhibited in HeLa-MSH2- cells, as demonstrated by Western blotting and band shift assay of its whole cell extract. The growth rate of this cell line was not different from the parental HeLa cells soon after transfection. However, the rate was faster after 10 subcultures. The spontaneous mutation frequency at the hypoxanthine phosphoribosyltransferase (HPRT) locus increased markedly, but no N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) tolerance appeared in this cell line. Our results clearly demonstrated several molecular events happened after the inhibition of a major mismatch recognition protein, hMSH2, in the mismatch repair pathway, mimicking carcinogenesis processes.
...
PMID:Molecular events after antisense inhibition of hMSH2 in a HeLa cell line. 975 96

The spectrum of mutations was determined at the hypoxanthine-guanine phosphoribosyltransferase (hprt) locus in the human uterine tumor cell line HEC-1-A which is defective in the mismatch repair gene hPMS2. The mutation frequency at the hprt locus in HEC-1-A was about two orders higher than that in wild type repair-proficient cells. The fifty-eight mutations detected were exclusively point mutations, with frameshifts of one base deletion/addition predominating (66%) the remaining were base substitutions. All the frameshift mutations occurred at sites of monotonous repeating sequences, including six consecutive guanine bases site which was the hot spot for the addition of one G that contributed 60% of the total mutations. Although the observed specificity of mutations in HEC-1-A apparently resembled that of the hMLH1-deficient cell line HCT116 [Ohzeki, S., Tachibana, A., Tatsumi, T., Kato, T., 1997. Spectra of spontaneous mutations at the hprt locus in colorectal carcinoma cell lines defective in mismatch repair. Carcinogenesis, 18, 1127-1133.], the pronounced increase of +/-1 bp frameshifts and the reduced incidence of C-->T transitions at the CpG site suggest that the hPMS2 gene product may have an additional function in the mismatch repair process independent of it's role in the hMutLalpha heterodimer.
...
PMID:Specificity of mutations in the PMS2-deficient human tumor cell line HEC-1-A. 983 64

Dihydrodiol epoxides (DEs) are important carcinogenic metabolites of polycyclic aromatic hydrocarbons (PAHs). The metabolic formation of four stereoisomeric DEs (a pair of optically active diastereomers termed as syn- and anti-form) is possible. Glutathione tranferases (GSTs) have been demonstrated to catalyze the detoxification of DEs. Purified GSTs display remarkable differences in catalytic efficiencies towards bay- and fjord-region DEs along with a high degree of regio- and stereoselectivity. Here we determined to which extent heterologously expressed human GSTP1-1, a major GST isoform in lung, affects the mutagenicity of stereoisomeric bay-region DEs of benzo[a]pyrene in Chinese hamster V79 cells. To evaluate the influence of sterical crowding in the substrate on the activity of GSTP-1, the study was extended to the strongly mutagenic fjord-region (-)-anti-DEs of benzo[c]phenanthrene and dibenzo[a,l]pyrene. GSTP1-1,reduced preferentially the mutagenicity (studied at the hprt locus) of (+)-anti and (+)-syn-DEs of benzo[a]pyrene (by 66 and 67%) as compared with the corresponding (-)-anti- and (-)-syn-enantiomers (by 15 and 13%). These results are in line with previous studies on the enantioselectivity of purified GSTP1-1 towards the DE isomers of benzo[a]pyrene and benzo[c]phenanthrene showing that enantiomers with (R)-configuration at the benzylic oxiranyl carbon are better substrates than those with (S)-configuration. Interestingly, the (-)-anti-DEs of benzo[c]phenanthrene and dibenzo[a,l]pyrene were efficiently detoxified by GSTP-1-1 in the constructed cell line (reduction of mutagenicity by 66 and 64%). This study demonstrates that differences in the caalytic activity seen for purified GST towards individual mutagens do not necessarily reflect the detoxification of DEs by the same enzyme in a living cell and provides further evidence that specific human GSTs play a role in the detoxification of DEs of PAHs.
Carcinogenesis 1998 Nov
PMID:Detoxification of optically active bay- and fjord-region polycyclic aromatic hydrocarbon dihydrodiol epoxides by human glutathione transferase P1-1 expressed in Chinese hamster V79 cells. 985 12

In the yeast Saccharomyces cerevisiae, the mutS homolog protein products MSH3 and MSH6, each in cooperation with MSH2, play well-defined and specific roles in the repair of DNA mismatches and nucleotide loops. The discrete functions of the human homologs hMSH3 and hMSH6 are less clear and current evidence suggests that the substrate specificity of these proteins may be less strict. To determine the role of MSH3 in mammalian mismatch repair, we employed MSH3-deficient Chinese hamster ovary (CHO) cell lines. No significant changes in mutation rate were detected in the MSH3-deficient strain and there were no differences in sensitivity to DNA-damaging agents. Further analysis of hprt mutants did not show a MSH3-dependent shift in the mutant spectrum. Interestingly, thorough examination of four dinucleotide microsatellite regions revealed instability at only one locus in one of the MSH3-deficient cell lines. These data support the idea of a high degree of redundancy in the function of the MutS homologs MSH3 and MSH6, at least with respect to the control of microsatellite instability.
Carcinogenesis 1999 Feb
PMID:MSH3 deficiency is not sufficient for a mutator phenotype in Chinese hamster ovary cells. 1006 56

Apoptosis plays a crucial role in maintaining genomic integrity by selectively removing the most heavily damaged cells from the population. Under that premise, the dysregulation of apoptosis may result in an inappropriate survival of mutated cells. This study demonstrates that ectopic expression of Bcl-2 effectively suppresses benzene-active metabolites, 1,4-hydroquinone- and 1, 4-benzoquinone-induced apoptosis in human leukemic HL-60 cells, as evidenced by morphological changes and DNA fragmentation. Although reactive oxygen species production largely contributes to the benzene metabolites-induced apoptotic cell death, Bcl-2 fails to attenuate the benzene metabolites-elicited increase of reactive oxygen species in HL-60 cells, as confirmed by flow cytometry analysis. These data suggest that Bcl-2 prevents benzene metabolites-induced apoptosis at the downstream of oxidative damage events. This study also determines the level of 8-hydroxydeoxyguanosine (8-OH-dGua), an indicator for oxidative DNA damage, in neo- and Bcl-2-overexpressing HL-60 cells after treating with 1,4-hydroquinone or 1,4-benzoquinone. Interestingly, our results indicate that a majority of the 8-OH-dGua is efficiently removed in neo control cells within 3 to 6 h, whereas only 25 to 35% of 8-OH-dGua is repaired in Bcl-2 transfectants even for 24 h. Similarly, another oxidative DNA base, thymine glycol, failed to repair and was retained in genomic DNA of Bcl-2 transfectants. The above findings suggest that Bcl-2 may retain benzene metabolites-induced oxidative DNA damage in surviving cells. Indeed, the failure of repairing 8-OH-dGua and thymine glycol in benzene metabolites-treated Bcl-2 survivors increases the number of mutation frequencies at the hprt locus. Results in this study thus provide a novel benzene-induced carcinogenesis mechanism by which up-regulation of Bcl-2 protein may promote the susceptibility to benzene metabolites-induced mutagenesis by overriding apoptosis and attenuating DNA repair capacity.
...
PMID:Suppression of apoptosis by Bcl-2 to enhance benzene metabolites-induced oxidative DNA damage and mutagenesis: A possible mechanism of carcinogenesis. 1022 May 68

Cocaine is a widely abused drug. Recently, it has been shown to induce teratogenesis in both humans and animals. Cocaine-induced teratogenicity has been associated with reactive oxygen species (ROS), which are generated by cytochrome P450 during cocaine biotransformation. Since ROS have been reported to induce genotoxicity, it is of interest to know whether cocaine and/or its metabolites are also genotoxic. In this study, Chinese hamster ovary K1 cells were employed as a model system to investigate the genetic toxicity of cocaine in the presence or absence of rat liver S9 fraction. Cocaine-induced cytotoxicity was potentiated when S9 was present, indicating the cytochrome P450 metabolism plays a role in cocaine-mediated cytotoxicity. Cocaine treatments per se induced a few chromosome aberrations while treatments of cocaine plus S9 caused a significant increase in chromosome aberrations. In contrast, cocaine induced micronuclei (MN) formation and hypoxanthine-guanine phosphoribosyltransferase mutation only in the presence of S9. Therefore, cocaine itself is at best a weak clastogen, whereas metabolite(s) of cocaine is/are truly inducer(s) of clastogenesis and mutagenesis. Cocaine treatments alone also induced a significant increase in sister chromatid exchange frequency but the addition of S9 did not affect the results. Free radical scavengers, including superoxide dismutase and catalase, efficiently decreased the frequency of cocaine plus S9-induced MN, implying that ROS are indeed important components in cocaine-induced genotoxicity. The observation that non-toxic doses of cocaine can inhibit intercellular metabolic cooperation suggests that cocaine may also be a tumor promoter. Our data supports that cocaine could possess genotoxicity in addition to its well-known neurotoxicity and teratogenicity.
Carcinogenesis 1999 Jul
PMID:Genetic toxicity of cocaine. 1038 89

Earlier studies have shown that the profile of mutations induced by (+)-7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (+)-BPDE at the hypoxanthine (guanine) phosphoribosyltransferase (hprt) gene of Chinese hamster V79 cells was dependent on the concentration of (+)-BPDE. In the present study, we examined the effect of the concentration of (+)-BPDE on its mutational profile at the hprt gene in repair-deficient V-H1 cells (a derivative of V79 cells) to explore the role of DNA repair in the dose-dependent mutational profile of (+)-BPDE. Independent hprt mutant clones were isolated after exposing V-H1 cells to dimethylsulfoxide (DMSO) or to low (4-6 nM; 95% cell survival) or high (40-48 nM; 31% cell survival) concentrations of (+)-BPDE in DMSO. The mutation frequencies for the DMSO control and for the low and high concentration groups were 0.1, 2.1 and 32.9 mutant colonies/10(5) survivors, respectively. The profile of mutations at the hprt gene was characterized for 148 (+)-BPDE-induced mutant clones and the results from the present study were compared with those obtained earlier with V79 cells. The data indicated that: (i) V-H1 cells were approximately 9-fold more sensitive to the cytotoxic effects of (+)-BPDE than V79 cells; (ii) the mutation frequency in V-H1 cells was similar to that observed in V79 cells following exposure to similar concentrations of (+)-BPDE; (iii) (+)-BPDE-induced mutations at guanine on the transcribed strand of the hprt gene were common in V-H1 cells but were extraordinarily rare in V79 cells; (iv) (+)-BPDE-induced mutations at adenine on the transcribed strand of the hprt gene were common in both V-H1 and V79 cells; (v) although exposure of V79 cells to different doses of (+)-BPDE resulted in a dose-dependent mutational profile at the hprt gene, this was not observed in V-H1 cells. Our observations indicate a defect in the transcription-coupled repair of (+)-BPDE-DNA adducts in V-H1 cells and that the repair activity deficient in V-H1 cells is essential for the dose-dependent mutational profile observed with (+)-BPDE in V79 cells.
Carcinogenesis 1999 Dec
PMID:Characterization of the mutational profile of (+)-7R,8S-dihydroxy-9S, 10R-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene at the hypoxanthine (guanine) phosphoribosyltransferase gene in repair-deficient Chinese hamster V-H1 cells. 1059 Feb 20

While 1,3-butadiene is carcinogenic in rodents, cancer causation in humans is less certain. We examined a spectrum of genotoxic outcomes in 41 butadiene polymer production workers and 38 non-exposed controls, in China, to explore the role of butadiene in human carcinogenesis. Because in vitro studies suggest that genetic polymorphisms in glutathione S-transferase enzymes influence genotoxic effects of butadiene, we also related genotoxicity to genetic polymorphisms in GSTT1 and GSTM1. Among butadiene-exposed workers, median air exposure was 2 p.p.m. (6 h time-weighted average), due largely to intermittent high level exposures. Compared with unexposed subjects, butadiene-exposed workers had greater levels of hemoglobin N-(2,3,4-trihydroxybutyl)valine (THBVal) adducts (P < 0.0001) and adduct levels tended to correlate, among butadiene-exposed workers, with air measures (P = 0.03). Butadiene-exposed workers did not differ, however, from unexposed workers with respect to frequency of uninduced or diepoxybutane-induced sister chromatid exchanges, aneuploidy as measured by fluorescence in situ hybridization of chromosomes 1, 7, 8 and 12, glycophorin A variants or lymphocyte hprt somatic mutation. Also among the exposed, greater THBVal levels were not associated with increases in uninduced sister chromatid exchanges, aneuploidy, glycophorin A or hprt mutations. Butadiene-exposed workers had greater lymphocyte (P = 0.002) and platelet counts (P = 0.07) and lymphocytes as a percentage of white blood cells were moderately correlated with greater THBVal levels (Spearman's phi = 0.32, P = 0.07). Among butadiene-exposed workers, neither GSTM1 nor GSTT1 genotype status predicted urinary mercapturic acid butanediol formation, THBVal adducts, uninduced sister chromatid exchanges, aneuploidy or mutations in the glycophorin A or hprt genes. Overall, the study demonstrated exposure to butadiene in these workers, by a variety of short-term and long-term measures, but did not show specific genotoxic effects, at the chromosomal or gene levels, related to that exposure.
Carcinogenesis 2000 Jan
PMID:Genotoxic markers among butadiene polymer workers in China. 1060 34


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---