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

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Query: EC:2.4.2.8 (hypoxanthine-guanine phosphoribosyltransferase)
2,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An autopsied case of the Lesch-Nyhan syndrome did not indicate the specific pathological features except delayed physical development. 2. Xanthine calculi caused by allopurinol administration scattered in the kidneys, brain, thymus, and thyroid glands, but its excretion into urine was not observed during his life. 3. Activities of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) in various tissues indicate complete deficiency, but HGPRT in liver was normal.
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PMID:An autopsy case of the Lesch-Nyhan syndrome: normal HGPRT activity in liver and xanthine calculi in various tissues. 98 65

Nitric oxide (NO.) is a physiological messenger formed by several cell types. Reaction with O2 forms oxides that nitrosate amines at pH values near 7. We now report experiments in which NO. was added to intact human cells and to aerobic solutions of DNA, RNA, guanine, or adenine. TK6 human lymphoblastoid cells were mutated 15- to 18-fold above background levels at both the HPRT and TK gene loci. Xanthine and hypoxanthine, from deamination of guanine and adenine, respectively, were formed in all cases. NO. induced dose-responsive DNA strand breakage. Yields of xanthine ranged from nearly equal to about 80-fold higher than those of hypoxanthine. Yields of xanthine and hypoxanthine from nucleic acids were higher than those from free guanine and adenine. This was most pronounced for xanthine; 0.3 nmol/mg was formed from free guanine vs. 550 nmol/mg from calf thymus RNA. Nitric oxide added to TK6 cells produced a 40- to 50-fold increase in hypoxanthine and xanthine in cellular DNA. We believe that these results, plus the expected deaminations of cytosine to uracil and 5-methylcytosine to thymine, account for the mutagenicity of nitric oxide toward bacteria and mammalian cells.
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PMID:DNA damage and mutation in human cells exposed to nitric oxide in vitro. 155 8

BALB/c mouse thymoma-derived T cell line, CAK4.4 (Thy-1+, L3T4-, Lyt-2-), produced a large amount of TCR-gamma mRNA, a trace amount of TCR-beta mRNA but no detectable level of TCR-alpha mRNA. Another BALB/c mouse thymoma-derived T cell line, CAK1.3 (Thy-1+, L3T4+, Lyt-2+), synthesized a high level of TCR-alpha as well as TCR-beta mRNA but did not produce any amount of TCR-gamma mRNA. HAT-sensitive clones were established from the two T cell lines. Azaguanine-resistant, HPRT- CAK4.4 cells and bromodeoxyuridine-resistant, TK- CAK1.3 cells were fused by electrofusion method and the resultant hybrids were analyzed for expression of TCR genes as well as the changes of their cell surface phenotypes. Transcription of TCR-gamma gene was completely suppressed in all hybrids tested, although Southern blot analysis showed that the hybrids maintained TCR-gamma chain genes derived from both parental cells. TCR-alpha gene transcription occurred normally in one hybrid. In two other hybrids, TCR-alpha gene transcription was strongly suppressed. Treatment of the hybrid cells with 12-O-tetradecanoyl phorbol-13-acetate reversed the suppression of TCR-alpha gene transcription, but TCR-gamma gene transcription was not recovered by the same treatment. However, transcription level of TCR-beta gene was not changed in all hybrids. Our results suggested that the different trans-acting regulatory mechanisms control the transcription levels of TCR-alpha and TCR-gamma genes and that such a transcriptional control may play a crucial role in the determination of orderly appearance of TCR-gamma and TCR-alpha gene products during T cell ontogeny in the thymus.
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PMID:Trans-acting regulatory factors for T cell antigen receptor alpha- and gamma-chain gene expression. 283 44

A microassay requiring as few as 2 X 10(5) cells per assay was developed for systematic analysis of 9 purine enzymes in lymphocytes from equine peripheral blood, spleen, lymph node, thymus and bone marrow. The activities of adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP), adenosine kinase (AK), deoxyadenosine kinase (dAK), deoxycytidine kinase (dCK), 5'-nucleotidase (5'-N), AMP deaminase, hypoxanthine-guanine phosphoribosyl transferase (HGPRT or HPRT), and adenine phosphoribosyl transferase (APRT) were measured by this microassay in lymphocytes from peripheral blood from four different breeds of horses (Arabian, Quarter Horse, Thoroughbred and Shetland Pony). There were no significant differences in the enzyme activities among the various breeds. Peripheral blood lymphocytes (PBL) from foals exhibited enzyme activities similar to those observed for adult animals. All lymphoid tissue contained similar levels of activity for each kinase (AK, dAK and dCK). Spleen had the highest activity for ADA, PNP, 5'-N, and HGPRT. The lowest activity for ADA, APRT, PNP and AMP deaminase was found in thymus. Enzymatic activities that varied the most among the tissue were 5'-N, ADA, APRT, HGPRT and AMP deaminase.
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PMID:Distribution of enzymes of purine metabolism in lymphocytes of horse, Equus caballus. 299 Aug 11

The cell surface antigen associated with the transformed state of cells that could grow in an anchorage-independent manner was analyzed by use of techniques of DNA transfection and hybridomas secreting the monoclonal antibody (MoAb). Spleen cells of C57BL/6 mice immunized with a highly tumorigenic, chemically induced murine cultured colon 36 tumor (C-C36) of BALB/c origin were hybridized with NS-1, a hypoxanthine phosphoribosyltransferase-deficient myeloma line of BALB/c mice. Screening of hybridomas revealed an antibody that reacted with C-C36 and transformed Swiss 3T3 cells growing in soft agar after transfection of 3T3 cells with C-C36 DNA. The hybridomas that did not react with nontransformed 3T3 and the less tumorigenic BALB/c hemangioendothelioma line D10 were then selected. An MoAb was designated "#71295." This MoAb immunoprecipitated the antigen that consisted of 65,000- and 14,000-molecular-weight components with soluble C-C36 membrane antigens. It also reacted with 2 other chemically induced syngeneic colon tumor lines, cultured colon 26 tumor line and cultured colon 51 tumor line, and with fibrosarcoma Meth A. However, #71295 was not found in NS-1, D14, and BALB/c normal thymus, liver, colon, and kidney tissues. In addition, this MoAb could not inhibit the anchorage-independent growth of C-C36 and transformed 3T3 cells. These results suggest that although the molecule defined by #71295 might not be associated with the anchorage independence of cell growth, it could be a newly expressed determinant on the cell surface that is related to the events of cell transformation.
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PMID:Identification of transformation-related antigen by monoclonal antibody on Swiss 3T3 cells induced by transfection with murine cultured colon 36 tumor DNA. 346 94

The usefulness of the 32P-post-labeling/t.l.c. method for quantitative DNA adduct dosimetry was evaluated. 2-Acetylaminofluorene (2-AAF)-DNA adducts from three systems were characterized qualitatively and quantitatively by the 3H-radiolabeled technique with subsequent analysis by h.p.l.c. (pre-labeling method) and by the 32P-post-labeling method. Both methods showed N-acetoxyacetylaminofluorene (N-OAc-AAF) reaction products with calf thymus DNA were predominantly N-(deoxyguanosin-8-yl)-2-acetylaminofluorene (dG-C8-AAF) with some N-(deoxyguanosin-8-yl)-2-aminofluorene (dG-C8-AF) and N-(deoxyguanosin-N2-yl)-2-acetylaminofluorene (dG-N2-AAF). In contrast, Chinese hamster ovary (CHO) cells treated with [3H]N-OAc-AAF gave 80 or 90% dG-C8-AF adducts and 20 or 10% dG-C8-AAF adducts with the post- or pre-labeling method, respectively. Likewise in CHO cells treated with 2-AAF in the presence of rat liver homogenate, approximately 90% dG-C8-AF and 10% dG-C8-AAF adducts were detected using the 32P-post-labeling method. In Salmonella typhimurium strain TA1538 treated with 2-AAF or [3H]2-AAF in the presence of a rat liver homogenate, one adduct, dG-C8-AF, was identified. Similar quantitative results were also obtained with the two methods. However, the 32P-post-labeling method was more sensitive and also eliminated the use of radiolabeled-mutagen treatments. Quantitative DNA adduct dosimetry was applied to AAF-induced mutagenesis in the S. typhimurium and CHO/HPRT mutation assays. A linear and reproducible relationship existed between dG-C8-AF levels and AAF-induced mutants in both systems.
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PMID:The 32P-post-labeling method in quantitative DNA adduct dosimetry of 2-acetylaminofluorene-induced mutagenicity in Chinese hamster ovary cells and Salmonella typhimurium TA1538. 354 38

The enzymic capacities of the de novo and the salvage pathways for purine nucleotide synthesis were compared in rat in normal, differentiating, and regenerating liver, and in three hepatomas of widely different growth rates. The activities of the key de novo and salvage enzymes were also determined in mouse lung and Lewis lung carcinoma, in human kidney and liver, and in renal cell carcinoma and hepatocellular carcinomas. A precise and reproducible assay was worked out for measuring the activities of adenine phosphoribosyltransferase (EC 2.4.2.7) and hypoxanthine-guanine phosphoribosyltransferase (HGPRT; EC 2.4.2.8) in crude liver and hepatoma systems. Kinetic studies on the salvage enzymes were carried out in the crude 100,000 X g supernatant fluid from normal liver and rapidly growing hepatoma 3924A. In both tissue extracts, Michaelis-Menten kinetics was observed for adenine phosphoribosyltransferase and HGPRT. The reciprocal plots for 5-phosphoribosyl-1-pyrophosphate (PRPP) of liver and hepatoma enzymes gave apparent KmS of 2 microM for adenine phosphoribosyltransferase and 4 microM for HGPRT, showing two orders of magnitude higher affinities for PRPP than that of the rate-limiting enzyme of de novo purine synthesis, amidophosphoribosyltransferase (EC 2.4.2.14) (Km = 400 to 900 microM). The apparent Km values for adenine of liver and hepatoma adenine phosphoribosyltransferase were 0.6 to 0.9 microM, respectively. For both liver and hepatoma HGPRT, the reciprocal plots for hypoxanthine and guanine yielded the same Km of 3 microM. The specific activities of purine phosphoribosyltransferases were markedly higher than that of amidophosphoribosyltransferase in rat thymus, spleen, testis, bone marrow, colon, liver, kidney cortex, lung, heart, brain, and skeletal muscle, but were lower in the small intestine. In hepatomas and regenerating and differentiating liver, the activities of the salvage enzymes were 2.1- to 32-fold higher than that of amidophosphoribosyltransferase. The purine phosphoribosyltransferase activities were also higher than that of amidophosphoribosyltransferase in Lewis lung carcinoma (8.2- to 32-fold), human renal cell carcinoma (3.5- to 22-fold), and hepatocellular carcinoma (3.4- to 30-fold). The high activities and the high affinity to PRPP of the purine phosphoribosyltransferases might explain the lack of linkage of the behavior of these enzymic activities with proliferation in normal, regenerating, differentiating, or neoplastic tissues. In contrast, the specific activity of the amidophosphoribosyltransferase, which is lower than that of the salvage enzymes, is linked with transformation as it is increased in all examined tumors.4
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PMID:Enzymic capacities of purine de Novo and salvage pathways for nucleotide synthesis in normal and neoplastic tissues. 632 16

The lymphocyte hypoxanthine-guanine phosphoribosyltransferase (Hprt) assay is frequently used as a biomarker for the exposure of both humans and laboratory animals to potentially carcinogenic agents. To obtain information concerning the sensitivity of the rat Hprt lymphocyte assay toward aromatic amine carcinogens, male F344 rats were fed 0.02% 2-acetylaminofluorene (2-AAF) for 1 month and then returned to control diet for 2 months. At 4, 27, 48, 62, and 90 days after the initiation of 2-AAF-feeding, the frequency of mutants in the Hprt gene was determined. In addition, DNA was isolated from liver nuclei, spleen lymphocytes, bone marrow, and thymus, and DNA adducts were analyzed by 32P-postlabeling. 2-AAF feeding resulted in a significant induction of 6-thioguanine-resistant T-lymphocytes and the mutant frequency continued to increase after the 2-AAF feeding was stopped. The same major DNA adduct, N-(deoxyguanosin-8-yl)-2-aminofluorene, was detected in liver, spleen lymphocytes, bone marrow, and thymus. DNA adduct levels were greatest in the tumor target tissue (liver) but occurred in all T-lymphocyte compartments, being highest in spleen lymphocytes. The DNA adduct levels were highest at the end of the 1-month 2-AAF feeding period and decreased rapidly in all tissues. The data indicate that the Hprt lymphocyte mutagenesis assay detects arylamine carcinogens, but with relatively low sensitivity.
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PMID:Hprt lymphocyte mutant frequency in relation to DNA adduct formation in rats fed the hepatocarcinogen 2-acetylaminofluorene. 1050 13

1,3-Butadiene (BD), an important chemical used mainly in the production of synthetic rubber, is a potent carcinogen in mice, a weak carcinogen in rats, and a suspected carcinogen in humans. To provide a better understanding of the mutagenic mechanisms involved in interspecies differences in BD-induced carcinogenesis, studies were conducted in rodents to test two hypotheses: (a) the mutagenic potency of BD at the hypoxanthine-guanine phosphoribosyltransferase (hprt) locus of T lymphocytes (T cells) can be used to quantify interspecies differences in BD-induced carcinogenicity in exposed rodents and (b) comparison of the mutagenic potency and specificity of BD and racemic mixtures of two epoxy metabolites, 1,2-epoxy-3-butene (BDO) and 1,2,3,4-diepoxybutane (BDO2), at the hprt locus of T cells can be used to define the relative contribution of each intermediate to observed BD mutagenicity in each species. The first hypothesis was investigated by determining the effects of exposure duration and elapsed time after exposures on hprt mutant frequencies (MFs) in T cells from thymus and spleen of female B6C3F1 mice and F344 rats (4 to 5 weeks old). In this study, rodents were exposed by inhalation to 0 or 1,250 parts per million (ppm) BD for up to 2 weeks, or to 0 or 625 ppm BD for up to 4 weeks (with all exposures 6 hours/day, 5 days/week). The second hypothesis was examined by defining the effects of exposure concentration and elapsed time after exposures on the hprt MFs in splenic T cells from mice and rats exposed by inhalation to BD (0, 20, 62.5, or 625 ppm), BDO (0, 2.5, or 25 ppm), or BDO2 (0, 2, or 4 ppm) for 4 weeks (all exposures 6 hours/day, 5 days/week). The hprt MFs were measured weekly or biweekly using the T cell cloning assay for up to 10 weeks after the last exposure. The mutagenic potency of BD (represented by the difference in the areas under the mutant T cell "manifestation" curves [or the "change in MFs over time"] of exposed versus control animals) was significantly greater in mice (4.4-fold) than in rats following 2 weeks of exposure to 1,250 ppm BD. Mutagenic potency in mice was 8.5-fold greater than that in rats following 4 weeks of exposure to 625 ppm BD. These hprt MF data provide the first evidence that BD is mutagenic in the rat, albeit the mutagenic response was significantly less than that observed in similarly exposed mice. In addition, the MF data from the two exposure-duration studies indicate that both exposure concentration and exposure duration are important in determining the magnitude of the mutagenic response to BD. The relative contribution of BDO versus BDO2 to overall BD mutagenicity was evaluated by exposing mice and rats to carefully chosen concentrations of BD and racemic mixtures of BDO and BDO2 (that is, 62.5, 2.5, and 4.0 ppm, respectively) and comparing the mutagenic potency of each compound when comparable blood levels of metabolites were achieved. The resulting MF data indicate that (+/-)-BDO2 is a major contributor to the mutagenicity of BD in mice at lower BD exposure levels (< or = 62.5 ppm), whereas other metabolites and stereochemical configurations are responsible for mutations in BD-exposed rats and for the incremental mutagenic effects at higher exposure levels in mice. Molecular analysis of hprt cDNA from expanded T cell clones from control and BD-exposed mice demonstrated an increased frequency of large deletions in exposed animals (p = 0.016), presumably associated with in situ formation of (+/-)-BDO2, meso-BDO2, or both. Results of these mutagenicity experiments, along with data from collaborative studies of DNA adducts from the same animals, should provide a better understanding of the interspecies variation in carcinogenic response to BD and improve the extrapolation of rodent data to the estimation of cancer risk in exposed persons.
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PMID:1,3-butadiene: cancer, mutations, and adducts. Part III: In vivo mutation of the endogenous hprt genes of mice and rats by 1,3-butadiene and its metabolites. 1092 40

Quantitative and semi-quantitative analysis of gene transcripts requires normalization to RNA-input and/or invariantly expressed house-keeping genes. Currently, only a limited choice of reference genes exists, such as GAPDH(1), beta-actin, or HPRT, whose transcription levels may be less stable than previously thought. We used the meta-database NC-GED, which we had derived from 1968 published murine expression profiles to identify genes with (i) low inter-tissue expression variability and (ii) great stability over 312 conditions, such as experimental drug treatment, age or differentiation. We identified 276 novel genes with "house-keeping" characteristics, including many genes for ribosomal proteins, and aryl-hydrocarbon receptor-interacting protein. Most genes yielded medium to strong fluorescence intensity on the arrays, a relative measure for their cellular expression. We validated the invariant expression levels of eight of the house-keeper candidates in lymph nodes, thymus, liver, kidney and brain of four different mouse strains. In addition, comparative analysis showed the superiority of multiple over single standardization. Caution against established reference genes is justified. The new panel of reference genes is useful for a flexible selection of reference genes in gene expression studies.
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PMID:A toolbox of novel murine house-keeping genes identified by meta-analysis of large scale gene expression profiles. 1879 95


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