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)

In male BALB/c mice, a combination of individually non-lethal doses of 6-mercaptopurine and endotoxin was significantly lethal. In contrast, mice treated with phenobarbital were resistant to this lethal effect. The high levels of thioinosinic acid in mice that were treated with endotoxin contrasted significantly with the levels in phenobarbital-treated mice. On the other hand, the concentration of hypoxanthine was increased by the administration of phenobarbital and decreased by the administration of endotoxin. The sleeping time and levels of pentobarbital hydroxylase found in endotoxin-treated mice were consistent with the lethality and levels of thioinosinic acid. After mice were treated with endotoxin, their sleeping time was prolonged, which agrees with the course of the stimulatory effects of 6-mercaptopurine anabolism. However, there were no significant differences in hypoxanthine-guanine phosphoribosyltransferase. Furthermore, contrary to expectation, there were significant increases in xanthine oxidase after treatment with endotoxin. Thus, the metabolism of 6-mercaptopurine might be modified by hepatic microsomal enzyme activity.
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PMID:Effects of phenobarbital and endotoxin on the lethality and metabolism of 6-mercaptopurine in male BALB/c mice. 90 14

Pyrroxamide [N-(1-hydroxymethyl-2,3-dihydroxypropyl)-2,2,5,5-tetramethyl pyrrolidine-1-oxyl-3-carboxyamide] is a newly tested nonionic monomeric nitroxyl compound with demonstrated effectiveness for MRI contrast enhancement at doses as low as 10(-3) M. Pyrroxamide and its hydroxylamine metabolic derivative were tested in concentrations from 10(-9) to 10(-2) M with a battery of cytotoxic and mutagenic assays using mammalian Chinese hamster ovary cells. Loci-specific mutation induction was examined at the hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and the Na+/K+ ATPase loci, both in the presence and absence of a liver microsomal metabolic activating mixture (S-9 mix). Cell survival and induction of sister chromatid exchanges also were studied. All tests yielded negative results indicating that pyrroxamide and and hydroxylamine derivative were both noncytotoxic and nonmutagenic at the doses tested.
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PMID:Pyrroxamide, a nonionic nitroxyl spin label contrast agent for magnetic resonance imaging. Mutagenesis and cell survival. 341 40

4-Hydroxynonenal (HNE), a major product of the peroxidation of liver microsomal lipids, was examined for mutagenic activity at the hypoxanthine-guanine phosphoribosyltransferase locus in V79 Chinese hamster lung cells. At concentrations ranging from 10 to 45 microM, HNE induced a dose-dependent increase in the number of mutations to 6-thioguanine resistance, which reached the level of 4.7X baseline at the highest concentration tested.
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PMID:Mutagenicity of 4-hydroxynonenal in V79 Chinese hamster cells. 382 75

The relationship between DNA-adduct formation and mutagenicity of two heterocyclic aromatic amines associated with cooked foods was determined in a CHO cell strain lacking nucleotide excision repair. Cells were exposed to tritiated IQ (2-amino-3-methylimidazo[4,5-f]quinoline) or Trp-P-2 (3-amino-1-methyl-5H-pyrido[4,3-b]indole) supplemented with hamster S9 microsomal fraction for metabolic activation. DNA from nuclei was isolated by DNAase-mediated elution from polycarbonate filters after RNAase and proteinase treatment. The presumed metabolites of both compounds bound to DNA in a dose-dependent fashion. Although the dose required to produce 50% cell killing was 15 times higher for IQ than Trp-P-2, the amount of radioactive material bound to DNA at that dose was about 10-fold lower with IQ. When mutations at the hprt and aprt loci were compared with the estimated levels of adducts, the calculated mutagenic efficiency of the adducts was about 4 mutations per 1000 adducts for both compounds, assuming a target sequence of 1000 base pairs for either locus. We conclude that IQ is acting as a weak mutagen in this system because its extracellular metabolites either do not reach or do not react efficiently with the DNA of the CHO cells.
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PMID:Comparative mutagenic efficiencies of the DNA adducts from the cooked-food-related mutagens Trp-P-2 and IQ in CHO cells. 398 43

As part of a major study to evaluate the mutagenicity of chemicals produced during the cooking of foods, we examined the responses of bacteria and cultured Chinese hamster cells to the compounds Trp-P-2 (3-amino-1-methyl-5H-pyrido[4,3-b]indole) and IQ (2-amino-3-methylimidazo[4,5-f]quinoline), constituents identified in cooked beef and fish. In the Ames/Salmonella tester strain TA1538, both compounds were confirmed to be extremely potent mutagens that were active at levels below 1 ng/plate in the presence of hamster-liver S9 microsomal fraction. 50-fold higher doses of both compounds were required for mutagenicity in the uvr+ tester strain TA1978. Trp-P-2 also behaved as a strong mutagen in CHO cells using the standard exogenous activation with hamster-liver S9 fraction. At concentrations below 1 microgram/ml it produced dose-dependent increases in cell killing, mutations at the hprt and aprt loci, sister-chromatid exchanges, and chromosomal aberrations. An excision-repair-deficient strain was about 2-fold more sensitive than the normal CHO cells with respect to these genotoxic effects of Trp-P-2. IQ had unexpectedly weak activity for all genetic endpoints in the CHO cells, and it produced clear-cut responses only in the repair-deficient cells and only above a concentration of 10 micrograms/ml. The toxicity that was observed with IQ was not affected by the repair capacity of the cells and was not associated with chromosomal aberrations, indicating that damage to cellular structures other than nuclear DNA was likely the predominant pathway for cell killing. Because the culture conditions normally used for CHO cell exposure were shown to be competent in producing bacterial mutagenicity with IQ, it was concluded that the active metabolite of IQ was present in the medium but was somehow ineffective in reaching the DNA of CHO cells and/or reacting with it. These results suggest that the relative mutagenic potency of compounds in Salmonella may bear no direct relationship to relative mutagenicity in CHO cells, emphasizing precaution in attempting to extrapolate microbial data to mammalian somatic cells. This study illustrates the use and merits of a multi-endpoint assay for genetic damage in CHO cells, the utility of using CHO cells that are defective in excision repair of DNA, and the importance of comparative testing between bacterial and mammalian systems.
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PMID:Comparative genotoxic effects of the cooked-food-related mutagens Trp-P-2 and IQ in bacteria and cultured mammalian cells. 634 52

Aryl hydrocarbon (benzo[a]pyrene) hydroxylase inducibility by benzo[a]anthracene was studied in 29 somatic cell hybrid clones, developed by fusing mouse spleen or peritoneal cells from four different inbred strains with hypoxanthine phosphoribosyltransferase-deficient Chinese hamster E36 cells. Karyotype analysis plus 25 markers assigned to 16 autosomes and the X chromosome were examined. In 28 of the 29 clones, the presence or absence of inducibility is associated with the presence or absence, respectively, of mouse chromosome 17. Liver microsomal aryl hydrocarbon hydroxylase induction by 3-methylcholanthrene or benzo[a]anthracene was assessed in appropriate backcrosses with the Mus musculus molossinus, M. m. castaneus, MOR/Cv, PL/J, SM/J and DBA/2J inbred strains and in 13 NX8 recombinant inbred lines. Twenty-seven biochemical genetic markers representing all but four autosomes were tested for possible linkage with the hydroxylase inducibility, and no linkage was found. The hepatic Ah receptor was quantitated in 26 BXD recombinant inbred lines; the Ah phenotype did not match exactly any of the more than 70 genes with established strain distribution patterns representing 12 autosomes and at least five unlinked markers. It is concluded that a major gene controlling aryl hydrocarbon hydroxylase inducibility by benzo[a]anthracene is located on chromosome 17. Because there is no significant linkage with any of three biochemical markers in the upper third of the chromosome, we conclude that the inducibility gene is located in the distal 40% of mouse chromosome 17. Whether this trait represents the Ah locus, i.e., the gene encoding the cytosolic Ah receptor, will require further study.
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PMID:Aryl hydrocarbon hydroxylase induction by benzo[a]anthracene: regulatory gene localized to the distal portion of mouse chromosome 17. 654 99

A strain of Chinese hamster ovary cells that is deficient in nucleotide excision repair, strain UV5, was compared with the normal parental CHO cells in terms of cytotoxicity and mutagenesis after exposure to several chemical carcinogens that are known to produce bulky, covalent adducts in DNA. Induced mutations were measured at the hprt locus using thioguanine resistance and at the aprt locus using azaadenine resistance. The compounds tested that required metabolic activation (using rat or hamster microsomal fractions) were 7,12-dimethylbenz(a)anthracene, 3-methylcholanthrene, benzo(a)pyrene, aflatoxin B1, 2-acetylaminofluorene, and 2-naphthylamine. The direct-acting compounds (+/-)-r-7,t-8-dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene, N-acetoxy-2-acetylaminofluorene, and N-OH-2-naphthylamine were also studied. For all compounds except 2-naphthylamine and its active metabolite, the repair-deficient cells were significantly more sensitive to killing than the normal CHO cells. Mutation induction at both loci was also more efficient in UV5 cells in each instance where enhanced cytotoxicity was observed. By using tritium-labeled N-acetoxy-2-acetylaminofluorene, normal and mutant cells were shown to bind mutagen to their nuclear DNA with similar efficiency, and a greater amount of adduct removal occurred in the normal cells. From this study it is concluded that the use of excision repair-deficient CHO cells provides enhanced sensitivity for detecting mutagenesis and that a positive differential cytotoxicity response gives an indication of repairable, potentially lethal genetic damage.
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PMID:Hypersensitivity to cell killing and mutation induction by chemical carcinogens in an excision repair-deficient mutant of CHO cells. 665 96

Somatic cell hybrid clones were derived from the fusion of hypoxanthine phosphoribosyltransferase (HPRT; EC 2.4.2.8)-deficient mouse cells and two different human fibroblast strains, each carrying an X chromosome-autosome translocation. One of these had an X/11 translocation [46,X,t(X;11)(p21;q13)] and the other had an X/19 translocation [46,X,t(X;19)(q22;q13)]. The structurally normal human X chromosome is the late-replicating (genetically inactive) chromosome in these two cell strains; the rearranged X chromosome is early replicating (genetically active). One primary hybrid clone carrying both the translocated X chromosome and the structurally normal X chromosome was isolated in hypoxanthine/aminopterin/thymidine medium from each of these two cell fusion experiments. These clones were then selected in medium containing 8-azaguanine to achieve the loss of the active human HPRT locus. Five subclones from the cell hybrid with the X/11 translocation failed to express two known human X-chromosome markers [glucose-6-phosphate dehydrogenase (G6PD; EC 1.1.1.49) and phosphoglycerate kinase (PGK; EC 2.7.2.3)] but did express human microsomal steroid sulfatase (STS; sterol-sulfate sulfohydrolase, EC 3.1.6.2). Three of these were cytogenetically analyzed and found to contain a structurally normal human X chromosome but not the X/11 translocation. Two subclones were isolated in 8-azaguanine from the hybrid with the X/19 translocation. Cytogenetic analysis of these two clones showed the presence of a structurally normal human X chromosome; the X/19 translocation was not present. They did not express human G6PD, PGK, or HPRT but did express human STS. These results indicate that human STS is expressed from a locus on the inactive human X chromosome and support our earlier finding that the STS locus escapes X-inactivation in man.
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PMID:Expression of an X-linked gene from an inactive human X chromosome in mouse-human hybrid cells: further evidence for the noninactivation of the steroid sulfatase locus in man. 693 82

The induction of mutations by nitrosamines in the hprt locus of V79 Chinese hamster cells was examined after metabolic activation in a co-cultivation system using either freshly isolated rat hepatocytes or H4IIE rat hepatoma cells and the results obtained were compared with systems which employ the rat liver microsomal fraction (S9-mix). This study was also designed as a first approach to investigating the induction of point mutations by tobacco-specific nitrosamines in mammalian cells in order to obtain information about the significance of these compounds in connection with the carcinogenicity of tobacco smoke. The mutagenicity of two tobacco-specific nitrosamines, 4-(methylnitroso)-1-(3-pyridol)-1-butanone (NNK) and N'-nitrosonornicotine (NNN), were investigated and compared to two extensively investigated nitrosamines, i.e. dimethylnitrosamine (DMN) and diethylnitrosamine (DEN). DMN was activated to mutagenic species by primary hepatocytes at mumolar concentrations, i.e. 1/100 of the concentrations required for mutagenesis by DEN and NNK. NNN was not activated to mutagenic species by liver S9 or primary hepatocytes. The findings shown here on the mutagenicities of NNK and NNN with liver preparations are in agreement with their relative carcinogenic potencies. When the established liver cell line H4IIE was used for metabolic activation, DMN and was found to be mutagenic, whereas the results for NNN were borderline and for DEN and NNK were without effect. The fate of these compounds via different metabolic pathways is discussed in terms of systems for detection of mutagenic metabolites and type of mutation induced.
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PMID:Comparison of co-cultivation of V79 cells with rat hepatocytes and rat H4IIE hepatoma cells for studying nitrosamine-induced hprt gene mutations. 796 67

6-Nitrochrysene can be activated to genotoxic derivatives by two major metabolic pathways: nitroreduction to N-hydroxy-6-aminochrysene, and a combination of ring-oxidation and nitroreduction that involves the intermediate formation of trans-1,2-dihydro-1,2-dihydroxy-6-aminochrysene (6-AC-1,2-dihydrodiol). The DNA adduct formed from this latter pathway was evaluated by reacting individual deoxynucleoside 5'-monophosphates with 6-AC-1,2-dihydrodiol in the presence of liver microsomal enzymes from 3-methylcholanthrene-pretreated rats. Binding was greatest to deoxyguanosine monophosphate and the major deoxyguanosine (dG) adduct co-chromatographed with the single major adduct formed from the microsome-catalyzed reaction of 6-AC-1,2-dihydrodiol with DNA. In order to characterize the mutational changes associated with the 6-AC-1,2-dihydrodiol pathway, we analyzed the mutational spectrum produced by 6-AC-1,2-dihydrodiol in the hypoxanthine-guanine phosphoribosyltransferase (hprt) gene of CHO-K1 cells. cDNA was synthesized from the RNA of 28 6-thioguanine-resistant mutants, the hprt coding region amplified by the polymerase chain reaction, and the DNA products directly sequenced. Twenty independent primary mutations were found: 12 G:C-->T:A transversions, three G:C-->C:G transversions, one G:C-->A:T transition, one A:T-->T:A transversion, two -1 frameshift mutations in sequences containing consecutive guanines, and one 11 bp deletion. All G:C basepair substitutions had the mutated dG on the non-transcribed strand and 86% of the G:C basepair substitutions had one purine 3' to the mutated dG. The pattern of 6-AC-1,2-dihydrodiol-induced basepair substitutions was distinct from the pattern observed in solvent control mutants. These results are consistent with the formation of a promutagenic dG adduct from a metabolite of 6-AC-1,2-dihydrodiol.
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PMID:Trans-1,2-dihydro-1,2-dihydroxy-6-aminochrysene is metabolized to form a major adduct with deoxyguanosine and produces mutations in the hprt gene of Chinese hamster ovary cells at G:C basepairs. 822 62


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