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

Methods for measuring somatic mutation and chromosome aberration in humans are currently advancing and provide important new opportunities for biologic dosimetry of nuclear workers. Methods to test somatic mutation in four human genes (hprt, hla-a, glycophorin A, and beta globin) are reviewed briefly and evaluated for their applicability to biological radiation dosimetry of nuclear workers. Two somatic mutation tests can be currently recommended: an HPRT method applied to recently exposed workers and the glycophorin A method applied to workers exposed over their working lifetime. A new method of chromosome analysis using DNA hybridization with chromosome-specific gene libraries allows one to paint single or multiple chromosome pairs in standard metaphase preparations. This method is ideal for rapid and reliable detection of reciprocal translocations, the key lesion for the evaluation of long-term radiation exposure. Both mutational and aberrational approaches should be fostered in the expectation that they will complement other forms of dosimetry and will improve our ability to clarify whether or not significant health effects are dosimetrically related.
 ...
PMID:New approaches for biological monitoring of radiation workers. 235 56

Using either the colony formation assay or flow cytometry, it is feasible to measure the frequency of rare mutant lymphocytes or erythrocytes in human peripheral blood. Accordingly, we have investigated the mutant cell frequencies of the hypoxanthine-guanine phosphoribosyltransferase and T-cell receptor genes in T lymphocytes and of the glycophorin A gene in erythrocytes of several hundred persons aged 0-96 years. The mutant frequency of every one of these genes increased significantly with age. A simple accumulation of mutations in hematopoietic stem cells over time may explain the age-dependent increase in the frequency of glycophorin A mutants. In contrast, a balance between mutant cell generation and loss should be taken into account for the mechanism of the increase of T-cell mutations.
 ...
PMID:Mutation frequency in human blood cells increases with age. 756 69

To assess the potential effect of maternal environments on human embryonic/fetal somatic mutation, we measured the frequencies of hypoxanthine-guanine phosphoribosyltransferase (HPRT, hprt gene), mutant T lymphocytes (Mf), and glycophorin A (GPA) variant erythrocytes (Vf) of both allele-loss (phi/N) and allele-loss-and-duplication (N/N) phenotypes in umbilical cord blood. The mean hprt Mf (1.40 +/- 1.11 x 10(-6), N = 66) and GPA Vf (phi/N 4.0 +/- 2.2 x 10(-6), N = 114; N/N 2.7 +/- 2.0 x 10(-6), N = 91) were significantly lower than those previously reported for adult populations. In addition, the hprt Mf was significantly higher than that of a published study of newborn cord blood samples from a geographically distant population (0.64 +/- 0.41 x 10(-6), N = 45, P < 0.01; t test, P < 0.01, Mann-Whitney U test). An examination of the demographic data from these two populations led to the sampling of 10 additional newborns specifically matched to the published study for maternal socioeconomic status. The hprt Mf (0.70 +/- 0.49 x 10(-6)) of this selected population was consistent with the published report and significantly lower than that of our initial population (P < 0.03, t test; P < 0.01, Mann-Whitney U test). These results indicate that there is an environmental effect related to maternal socioeconomic status on the frequency of embryonic/fetal somatic mutations. Molecular analyses of hprt mutants from this cohort with elevated Mf revealed a significant decrease in the relative contribution of gross structural mutations to the overall Mf (25 of 38, 66% vs. 34 of 41, 83%, P = 0.024, chi 2 test), suggesting that the higher Mf resulted from an elevated level of "point" mutations. No individual maternal demographic or environmental factor was identified as contributing more significantly than other any factor to the observed variability in hprt Mf or GPA Vf.
 ...
PMID:Sensitivity of somatic mutations in human umbilical cord blood to maternal environments. 758 45

Somatic cell gene mutations arising in vivo in humans provide biomarkers for genotoxicity. Four assays, each measuring changes in a different "recorder" gene, are available for detecting mutations of the hemoglobin (Hb) and glycophorin A (gpa) genes in red blood cells and the hypoxanthine-guanine phosphoribosyltransferase (hprt) and HLA genes in T-lymphocytes. Mean adult background mutant frequencies have been established; i.e., approximately 4 x 10(-8) (Hb), 5-10 x 10(-6) (hprt), 10-20 x 10(-6) (gpa) and 30 x 10(-6) (HLA). All the assays have now been used in studies of individuals exposed to physical and/or chemical genotoxic agents, and all have shown elevated values following exposures; examples are presented. In addition to quantitation, the lymphocyte assays allow molecular analyses of in vivo mutations, the definition of background and induced mutational spectra, and the search for unique changes for characterizing specific mutagens. The HPRT system currently has the largest database in this regard. Approximately 15% of adult background hprt mutations are due to gross structural alterations (primarily deletions) having random breakpoints; 85% result from "point" changes detected only by sequencing. In contrast, a specific intragenic deletion due to DNA cleavage at specific sites characterizes fetal hprt mutations, implicating a developmental mistake in their genesis. (This kind of developmental mistake in other genes is frequently observed in lymphoid malignancies.) Mutational spectra are just beginning to be defined for induced hprt mutations, e.g., ionizing radiation produces large deletions.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Somatic cell gene mutations in humans: biomarkers for genotoxicity. 814 16

The purpose of this study was to evaluate the intercorrelation between three genetic assays in 112 subjects. The group was pooled from two originally separate but homogeneous subgroups of 56 persons each. Procedures included assays for hprt mutant frequencies, micronuclei in human lymphocytes, and mutations at the glycophorin A (gpa) loci. We found no statistically significant or biologically important intercorrelations among the three biomarkers. We did, however, observe significant correlations between log(e) hprt mutant frequency and cloning efficiency (inverse correlation for these 2 variables), age and log(e) hprt mutant frequency, an inverse relationship between cloning efficiency and age, and an important differential sex effect favoring a greater micronuclei frequency in females than males. No significant correlations between the covariates of interest and glycophorin A variant frequencies NN or NO were observed. Using multivariable linear regression, age was found to account for the majority of the variability in hprt mutant frequency (greater than sex and/or smoking); for micronuclei data, only sex contributed a statistically significant and biologically important proportion to the total variation. We conclude that despite observing no significant intercorrelations between the three assays performed simultaneously from the same individuals in a large population database, a significant correlation between age and hprt mutant frequency and an inverse association between cloning efficiency and hprt do exist; furthermore, we verified the strong differential sex-specific effect on micronucleus frequencies.
 ...
PMID:Intercorrelations and sources of variability in three mutagenicity assays: a population-based study. 860 Mar 59

Somatic cell gene mutation arising in vivo may be considered to be a biomarker for genotoxicity. Assays detecting mutations of the haemoglobin and glycophorin A genes in red blood cells and of the hypoxanthine-guanine phosphoribosyltransferase and human leucocyte antigenes in T-lymphocytes are available in humans. This MiniReview describes these assays and their application to studies of individuals exposed to genotoxic agents. Moreover, with the implementation of techniques of molecular biology mutation spectra can now be defined in addition to the quantitation of in vivo mutant frequencies. We describe current screening methods for unknown mutations, including the denaturing gradient gel electrophoresis, single strand conformation polymorphism analysis, heteroduplex analysis, chemical modification techniques and enzymatic cleavage methods. The advantage of mutation detection as a biomarker is that it integrates exposure and sensitivity in one measurement. With the analysis of mutation spectra it may thus be possible to identify the causative genotoxic agent.
 ...
PMID:Somatic mutation detection in human biomonitoring. 882 95

A survey of glycophorin A (gpa) in vivo somatic cell mutation in a population of 394 healthy people from 8 to 77 years of age (mean age +/- SD 41 +/- 15 years) revealed a subset of 37 individuals with stably elevated allele-loss and/or allele-loss with duplication variant erythrocyte frequencies (Vf) exceeding 30 x 10(-6). These 37 individuals with gpa outlier Vf are significantly older (P < 0.001) than the remainder of the larger study population from which they were drawn reflecting a highly significant increase in the prevalence of these individuals in the population beyond age 40 years. A study of hpt mutant frequencies (Mf) in the peripheral blood T-lymphocytes of 27 of these individuals, together with 15 matched control individuals with unremarkable gpa Vf, was undertaken to determine if these subjects also displayed elevated mutation frequencies at this independent locus indicative of globally elevated somatic mutation. The hprt Mf in these 27 subjects (geometric mean 11.5 x 10(-6)(dispersion interval 5.8 x 10(-6) to 22.8 x 10(-6)) was not significantly different from that observed in the 15 controls (geometric mean 12.1 x 10(-6)(dispersion interval 5.7 x 10(-6) to 25.5 x 10(-6)). These Mf are higher than typically reported values reflecting the older age distribution of these individuals (arithmetic mean age +/- SD 53 +/- 12 and 50 +/- 16 years for the subjects and controls, respectively). Taken together, these data suggest that several genetic mechanisms may be responsible for producing the gpa outlier Vf observed in these subjects. The observation that hprt Mf were not increased indicates that the majority did not arise by a genome-wide increased rate of somatic mutation detectable at both loci. The fixation and subsequent expansion of 'jackpot' mutations at the gpa locus occurring early in embryonic/fetal development also does not appear to be a predominant mechanism. Some cases may result from a stable over-representation of gpa variant cells, perhaps associated with a marked age-dependent decrease in the number of contributing erythroid stem cells in the bone marrow. The subset that displays elevated allele-loss with duplication Vf involving both gpa alleles may represent individuals with increased rates of somatic recombination. Elevations arising by this mechanism are not detected in the hprt assay, but could be confirmed using a autosomal locus in vivo somatic cell mutation endpoint such as the hla-a assay. Of primary biological significance, these results demonstrate that genetics/stochastic processes leading to the loss of heterozygosity of somatic cells occur ubiquitously in humans and in some individuals this level of somatic mosaicism can approach a frequency of 10(-3) at the gpa locus in erythroid lineage cells.
 ...
PMID:Human in vivo somatic mutation measured at two loci: individuals with stably elevated background erythrocyte glycophorin A (gpa) variant frequencies exhibit normal T-lymphocyte hprt mutant frequencies. 954 37

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.
 ...
PMID:Genotoxic markers among butadiene polymer workers in China. 1060 34

We examined a spectrum of genotoxic and other outcomes in 41 butadiene-polymer production workers and 38 nonexposed controls, in China, to explore the role of butadiene in human carcinogenesis. Among butadiene-exposed workers, median air exposure was 2 ppm (6-h TWA), due largely to intermittent high-level exposures. Compared to 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 percent of white blood cells were moderately correlated with greater THBVal levels (Spearman's rho=0.32, P=0.07). Among butadiene-exposed workers, several serum cytokines correlated with THBVal adduct levels. 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.
 ...
PMID:Markers for carcinogenicity among butadiene-polymer workers in China. 1139 6

The goals of this study were to assess three biomarkers of genetic effect for their individual and collective ability to detect and estimate radiation exposure in Russian Chernobyl clean-up workers. Work assignments were planned to limit dose to 0.25 Gy. The three biomarkers employed were chromosome translocations detectcd in lynmphocytes by florescence in situ hybridisation (FISH), and mutation at two genes, glycophorin A (GPA) in red blood cells detected by flow cytometry and hypoxanthine phosphoribosyltransferase (HPRT) in lymphocytes detected by selective cell culture. Samples were Obtained from 1992 to 2000. The time between exposure at Chernobyl and sample acquisition was > or =5 years. The lymphocyte assays detected an elevation over controls in average outcomes it clean-up workers: translocation rates were 46% higher when adjusted for age and smoking and HPRT mutant frequencies were were 16% higher when adjusted for age. The G PA assay did not detect an exposure effect. The results indicate that measuring frequency of translocations by FISH is preferred for low dose radiation, retrospective biochemistry.
 ...
PMID:Evaluation of three somatic genetic biomarkers as indicators of low dose radiation effects in clean-up workers of the Chernobyl nuclear reactor accident. 1176 59


1 2 Next >>