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)

Recent reports by several laboratories indicate that not all non-essential target loci are equally capable of detecting chromosomal mutations. The present study was undertaken to determine if both the tk locus in mouse lymphoma cells and the hgprt locus in Chinese hamster ovary (CHO) cells can be used to quantitate chromosomal mutations. Seven known mutagens for the tk locus were selected. These compounds were evaluated in the mouse lymphoma assay and in a suspension adapted CHO assay for their mutagenicity. In addition to the specific locus mutagenesis analysis, mouse lymphoma and CHO cells were evaluated for the frequency of gross chromosome aberrations. From these investigations, it appears that only those compounds [2-methoxy-6-chloro-9-(3-[ethyl-2-chloroethyl] aminopropylamino)-acridine-dihydrochloride (ICR 170), ethyl methanesulfonate (EMS) and methyl methanesulfonate (MMS)] that induce significant numbers of large-colony thymidine kinase (TK) mutants also induce significant numbers of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) mutants. The four acrylates evaluated (methyl acrylate, ethyl acrylate, trimethylolpropane triacrylate and tetraethyleneglycol diacrylate) induced almost exclusively small-colony TK mutants and very few if any HGPRT mutants. Aberration analysis revealed that both the mouse lymphoma and CHO cells responded to the clastogenicity of the compounds (except for ICR 170 which was not positive in CHO cells) and that neither cell line was clearly more sensitive than the other to the clastogens tested. It is significant that the four acrylates give little or no evidence of genotoxicity when evaluated using selection for HGPRT-deficient mutants, yet are clearly clastogenic to the same cells in the same experiment. These results are consistent with the hypothesis that the hgprt locus may not be useful as a marker to evaluate the clastogenic component of a genotoxic compound. The present study adds to the increasing number of studies that support the view that the hemizygous nature of the hgprt locus permits the recovery of mutations primarily affecting the function of a single gene; whereas the heterozygous nature of the tk locus permits the recovery of both single gene and chromosomal mutations.
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PMID:Differential mutant quantitation at the mouse lymphoma tk and CHO hgprt loci. 268 35

We evaluated the ability of the antitumor agent 4-(9-acridinylamino)-methanesulfon-m-anisidide (amsacrine or m-AMSA) and its congener, o-AMSA, to induce specific-locus mutations at the heterozygous thymidine kinase (tk) locus of L5178Y/TK+/- -3.7.2C mouse lymphoma cells. These cells permit the recovery of mutants due to single-gene or chromosomal mutation. m-AMSA was highly mutagenic at the tk locus, producing approximately 3000 mutants/10(6) survivors at 10% survival; positive dose range 1-10 ng/ml; o-AMSA produced approximately 1500 mutants/10(6) survivors at 10% survival; positive dose range 0.1-2.5 micrograms/ml. Most of the TK mutants were small colonies, which suggests that m-AMSA and o-AMSA induce primarily chromosomal mutations as opposed to single-gene mutations. The potent clastogenicity of these agents was confirmed by cytogenetic analysis for chromosomal aberrations, which showed that m-AMSA (9 ng/ml, 10% survival) and o-AMSA (1 microgram/ml, 10% survival) produced 383 and 179 aberrations, respectively, per 100 metaphases (background = 3-4/100). The large-colony TK mutant frequencies produced by m-AMSA (67 - 112/10(6) survivors; background = 7/10(6); survival = 63 - 16%) were comparable to the published HPRT mutant frequencies produced by m-AMSA in V79 cells. Novobiocin (50 micrograms/ml), an inhibitor of mammalian DNA topoisomerase II and other enzymes, inhibited the mutagenic effects of m-AMSA, suggesting that DNA topoisomerase II (or another enzyme) may play a role in the mutagenic/clastogenic activity of m-AMSA.
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PMID:Mutagenicity of m-AMSA and o-AMSA in mammalian cells due to clastogenic mechanism: possible role of topoisomerase. 283 Apr 52

Mutant sublines were derived of S49 mouse T-lymphoma cells that were resistant to tritiated deoxyadenosine. Twenty-five isolates that were selected in 1 microCi/ml of the nucleoside were cross-resistant to 6-thioguanine, were sensitive to HAT (hypoxanthine, aminopterin, and thymidine), and contained less than 1% of hypoxanthine phosphoribosyltransferase activity in wild-type cells. One of the mutant clones, S49-dA2, was further subjected to selection in a medium containing 2 microCi/ml tritiated deoxyadenosine and 1 microgram/ml deoxycoformycin, an inhibitor of adenosine deaminase. All resistant subclones were cross-resistant to tubercidin, 6-methylmercaptopurine riboside, and arabinosyladenine. One of the subclones, S49-12, was completely devoid of adenosine kinase and was partially deficient in deoxyadenosine kinase. This subclone, however, contained wild-type levels of deoxycytidine kinase. DEAE chromatography of the wild-type cell extracts revealed two deoxyadenosine phosphorylating activities, one of which coeluted with adenosine kinase and was the enzyme missing in S49-12. The other species phosphorylated both deoxyadenosine and deoxycytidine, of which deoxycytidine was the preferred substrate.
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PMID:Adenosine kinase deficiency in tritiated deoxyadenosine-resistant mouse S49 lymphoma cell lines. 283 56

Cloning of genomic and cDNA sequences of mammalian genes has made it possible to analyze at the molecular level mutations induced by radiation and chemical mutagens. The X-linked HPRT gene is very suitable for these investigations because in addition to the availability of cell culture systems, HPRT mutants can also be obtained directly from the lymphocytes of mouse and man. Recently a new technique has been introduced by Saiki and co-workers which allows the cloning and sequencing of small specific DNA segments from total genomic DNA after in vitro amplification of those segments up to 200,000-fold (Saiki et al., 1985). We have adapted this so-called polymerase chain reaction (PCR) procedure in such a way that the entire mouse HPRT-coding region could be amplified, cloned and sequenced. Instead of genomic DNA, we have used RNA as template in the PCR reactions. This allows us to detect point mutations in HPRT exon sequences in a very efficient way, since the DNA sequence of all 9 exons, which are scattered over 34 kb of DNA, can be obtained from only one amplification experiment. We studied the nature of 3 N-ethyl-N-nitrosourea (ENU)-induced HPRT mutants from cultured mouse lymphoma cells. One contains an A:T----G:C transition, the second an A:T----T:A transversion, whereas the third mutant is the result of abnormal splicing events, probably due to a mutation in the 3' splice site of the first intron.
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PMID:Nucleotide sequence determination of point mutations at the mouse HPRT locus using in vitro amplification of HPRT mRNA sequences. 289 23

The vinyl monomer acrylamide (AA) was studied for its activity in a range of genotoxicity tests, including the Salmonella/microsome test, the fluctuation test using Klebsiella pneumoniae, the test for gene mutations at the TK and HPRT loci in L5178Y mouse lymphoma cells, tests for chromosomal aberrations and SCEs in V79 Chinese hamster cells, the sex-linked recessive lethal (SLRL) and somatic mutation and recombination (SMART) assays in Drosophila melanogaster and the mouse bone marrow micronucleus assay. AA showed genotoxic activity in most systems. The bacterial tests did not respond, in compliance with literature data; also in the Drosophila SLRL test, no significant increase in mutation rate was observed.
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PMID:Mutagenic activity of acrylamide in eukaryotic systems but not in bacteria. 313 22

We evaluated the ability of proflavin to induce specific-locus mutations at the heterozygous thymidine kinase (tk) locus of L5178Y/TK +/- -3.7.2C mouse lymphoma cells, which appears to permit the recovery of mutants due to single-gene and chromosomal mutations. Proflavin was highly mutagenic at the tk locus, producing 724-965 TK mutants/10(6) survivors (background = 56-85/10(6); survival = 29-32%). Most of the mutants were small colonies, which suggested that proflavin may induce chromosomal mutations. The potent clastogenicity of proflavin was confirmed by cytogenetic analysis for chromosomal aberrations. At the highest dose analyzed (1.5 micrograms/ml), proflavin produced 82 aberrations/100 metaphaes (background = 2/100). The large-colony TK mutant frequency produced by proflavin (48-109/10(6) survivors; background = 23/10(6); survival = 57-61%) was similar to published HPRT mutant frequencies produces by proflavin in L5178Y and CHO cells (50-100/10(6) survivors; background = 2-50/10(6); survival = 50-62%). These results lead to the conclusion that proflavin is a potent clastogen and induces a high frequency of small-colony TK mutants; however, it induces a low frequency of HPRT mutants and a low frequency of large-colony TK mutants.
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PMID:Mutagenicity and clastogenicity of proflavin in L5178Y/TK +/- -3.7.2.C cells. 334 81

The frequency of clonable 6-thioguanine-resistant (6-TGr) splenic T cells increased moderately with age in female BALB/c mice ranging in age from 3 to 32 months; however, the correlation between the frequency of clonable 6-TGr cells and age was weak. Those clonable 6-TGr T cells were deficient in hypoxanthine/guanine phosphoribosyltransferase (HGPRT) activity and sensitive to hypoxanthine/aminopterin/thymidine medium, as in the case of HGPRT-deficient L5178Y mouse lymphoma cells. When splenic T cells of individual aging mice were assessed simultaneously for the frequency of clonable 6-TGr T cells and for their ability to produce interleukin 2 or to proliferate in response to mitogenic stimulation, an inverse correlation was observed. These results indicate that the frequency of 6-TGr T cells is more closely related to physiologic age than chronologic age. This would mean that the frequency could be used as an index of physiologic age and that the T cells could serve as a cellular model relating gene alterations to physiologic age.
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PMID:Frequency of 6-thioguanine-resistant T cells is inversely related to the declining T-cell activities in aging mice. 348 21

Acrylamide was tested without exogenous activation in L5178Y/TK+/- -3.7.2C cells for mutation at the thymidine kinase locus and for clastogenicity. Acrylamide gave a positive induced mutagenic response (approximately 70 mutants/10(6) survivors) when tested at 600-650 micrograms/ml. The highest dose tested (850 micrograms/ml) resulted in an induced mutant frequency of approximately 380 mutants/10(6) survivors (survival = 13%). Acrylamide induced almost exclusively small-colony mutants, indicating that it might be acting by a clastogenic mechanism. As predicted, acrylamide was clastogenic, inducing both chromatid and chromosome breaks and rearrangements. A clearly positive clastogenic response was observed at both the 750 micrograms/ml and 850 micrograms/ml doses, which showed 16 and 64 aberrations per 100 cells, respectively (background = 3 aberrations per 100 cells). These studies indicate that the L5178Y/TK+/- mouse lymphoma assay can detect some chromosomal mutagens (clastogens) that show little activity in other single gene mutation assays, the CHO/HPRT and Salmonella.
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PMID:Mutagenicity and clastogenicity of acrylamide in L5178Y mouse lymphoma cells. 356 69

A clonogenic assay to quantify thioguanine (TG)-resistant (TGr) spleen lymphocytes in the mouse has been developed to support studies of in vivo mutation affecting the hypoxanthine phosphoribosyltransferase (hprt) locus. Lymphocytes are cultured in 96-well microtiter plates for 9 days with proliferation initiated by the mitogen concanavalin A and supported thereafter by conditioned medium containing interleukin-2. Lymphocytes are plated at high densities (4-8 X 10(5)/well) with TG and irradiated L5178Y lymphoma cells (10(4)/well) to detect the presence of TGr cells. To determine the cloning efficiency without TG lymphocytes are plated at a low density (10/well) with irradiated L5178Y cells and irradiated lymphocytes (4-8 X 10(5)/well). Proliferation of cells is detected by [3H]thymidine incorporation and scintillation spectrometry. Spontaneous frequencies of TGr clones are independent of TG dose from 0.2 to 10 micrograms/ml and independent of cell density over the range cited. The TGr clones tested have less than 10% hypoxanthine incorporation in vivo relative to unselected clones and have stable phenotypes in the absence of selection. The spontaneous frequency of TGr cells ranged from 1 to 3 X 10(-6). In vivo treatment of mice intraperitoneally with ethylnitrosourea 15 days prior to in vitro culture resulted in a linear dose-related increase of TGr cells, with 70.2 mg/kg inducing a frequency of TGr cells of 2 X 10(-5).
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PMID:A method to quantify spontaneous and in vivo induced thioguanine-resistant mouse lymphocytes. 387 11

Methyl bromide is commonly used as a soil fumigant in greenhouses. In the framework of a toxicological evaluation, it was tested for possible genotoxic properties in two bacterial test systems (the fluctuation test using Klebsiella pneumoniae and the plate test using Salmonella typhimurium TA100 and TA98), two systems using mammalian cells in vitro (forward mutations at the TK and HPRT loci in L5178Y mouse lymphoma cells and unscheduled DNA synthesis in primary rat-liver cells) and in the sex-linked recessive lethal test using Drosophila melanogaster. Methyl bromide was active in all tests except the DNA-repair assay. The results indicate a relatively low mutagenic efficiency of the compound, as expected from its alkylating properties.
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PMID:Mutagenicity of methyl bromide in a series of short-term tests. 391 60


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