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)

We have investigated the activity of insoluble and soluble lead compounds in inducing mutagenesis, cell transformation and sister chromatid exchange in mammalian cells. Insoluble lead sulfide, readily phagocytized, was more than four times as toxic to V79 cells on a microM basis, than two moderately soluble lead compounds although the exposure time for the soluble salts was five times longer. These findings demonstrate the importance of different cellular mechanism(s) of metal uptake and bioavailability. Both insoluble lead sulfide and more soluble lead nitrate were mutagenic at the HPRT locus in V79 cells. Although less mutagenic at the higher concentrations, lead nitrate at a concentration of 500 microM enhanced the mutation frequency greater than 6-fold above background following a 5-day exposure. Although the mechanism(s) by which lead induces mutations is unknown, failure of both compounds to induce SCE and DNA single-strand breaks, detectable by alkaline elution, suggests that lead-induced mutations may not be a result of direct damage to DNA but may occur via indirect mechanisms including disturbances in enzyme functions important in DNA synthesis and/or repair, or in DNA-helical structure. Lead acetate also transformed SHE cells in a dose-response fashion following a 48-h exposure. Our results indicate that lead compounds may be genotoxic by an indirect mechanism, and lend support to the view that lead is a carcinogen.
Carcinogenesis 1988 Oct
PMID:Genetic toxicology of lead compounds. 316 50

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.
Carcinogenesis 1987 Apr
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

Chinese hamster cells of the mutant strain W27-1 which is hypersensitive to UV and monofunctional alkylating agents were transfected with human DNA ligated to the bacterial xanthine-guanine phosphoribosyltransferase (gpt) gene. Selection was performed for resistance to mycophenolic acid and finally for survival after treatment with high doses of methyl methanesulfonate. A gpt+ transfectant was generated (T38-2-7) which acquired resistance to methyl methanesulfonate and cross-resistance to N-methyl-N'-nitro-N-nitrosoguanidine at levels comparable with the parental (wild-type) strain CHO-9. T38-2-7 cells were not more resistant, however, to UV, mitomycin C and N-hydroxyethyl-N-chloroethylnitrosourea than the mutant W27-1. The transfectant contains integrated human DNA and was shown to be deficient for the O6-methylguanine-DNA methyltransferase. The results indicate that the transfected DNA specifically complemented the defect underlying alkylation hypersensitivity of W27-1 cells or that a gene was transfected which is generally inactive in CHO cells and which causes alkylation resistance.
Carcinogenesis 1987 Dec
PMID:Correction of alkylation hypersensitivity of CHO-W27-1 cells by transfection with human DNA. 367 16

In this study, we determined the wavelength dependence of u.v.-induced pyrimidine dimer formation, cell killing and mutation induction in human diploid skin fibroblasts. Pyrimidine dimers were quantified using the T4 endonuclease V assay, cell killing was measured as loss of colony forming ability and mutation induction was detected at the HPRT locus. U.v. irradiation was performed with monochromatic light of four different wavelengths (254, 297, 302 and 365 nm) and with polychromatic light of a Philips TL-01 lamp (predominantly 312 nm). The relative wavelength dependence for cell killing and mutation induction did not correlate with that for dimer formation. Toxicity and mutagenicity per equivalent initial dimer load increase with increasing wavelength. The relative wavelength dependence for cell killing and mutation induction is essentially the same, except at 365 nm.
Carcinogenesis 1986 Nov
PMID:The wavelength dependence of u.v.-induced pyrimidine dimer formation, cell killing and mutation induction in human diploid skin fibroblasts. 376 30

We have previously described the induction by r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) of 8-azaguanine resistant (AGr) Chinese hamster V79 cell mutants, 40% of which were found to contain material which cross-reacted (CRM) with antiserum to hypoxanthine-guanine phosphoribosyltransferase (HPRT) and whose AGr phenotype we ascribed to missense mutation (Brookes et al., 1982). We now report that we have been unable to demonstrate by Southern blotting any change in the HPRT gene in 11 CRM-negative mutants. We have, moreover, found HPRT mRNA of normal size and amount in most of these mutants. Examination of the revertants of one mutant indicates the probable occurrence of changes within an amino acid codon in the genesis of mutant and revertant. Our results suggest that BPDE functions primarily as a point mutagen.
Carcinogenesis 1984 Jul
PMID:On the nature of the mutations induced by the diolepoxide of benzo[a]pyrene in mammalian cells. 632 42

Combined cultures of human hepatocytes and human fibroblasts constitute a system composed entirely of normal human cells that can be used to investigate the mutagenicity of chemicals requiring metabolic activation. Addition of diethylnitrosamine (DEN) to this system resulted in mutations at the hypoxanthine-guanine phosphoribosyltransferase locus of the human fibroblasts. In separate experiments with cultures of hepatocytes alone, DEN induced unscheduled DNA synthesis (UDS) in the human hepatocytes. A comparative analysis of UDS and hepatocyte-mediated mutagensis indicates a great degree of similarity between the human and previously studied rat hepatocytes in their response to DEN in vitro.
Carcinogenesis 1983
PMID:Human hepatocyte-mediated mutagenesis and DNA repair activity. 640 71

A murine keratinocyte cell-mediated mutagenesis assay was characterized and examined as an in vitro model system for studying the biotransformation of promutagens/procarcinogens by mouse skin. The assay used living cultured newborn SENCAR keratinocytes for the metabolic activation of promutagens and Chinese hamster lung V-79 fibroblasts for detection of resulting mutagens. Mutations at, or affecting, the hypoxanthine-guanine phosphoribosyltransferase locus were scored by resistance to 6-thioguanine. The relative mutagenicities of several polycyclic aromatic hydrocarbons (PAHs) in the cell-mediated assay correlated with the in vivo skin tumorigenicity of the PAHs determined in a two-stage carcinogenesis protocol. Metabolic activation of the promutagenic PAHs to ultimate mutagens was dependent upon the presence of the cultured keratinocyte feeder layer. 7,8-Benzoflavone, a potent inhibitor of 7,12-dimethylbenz[a]anthracene (DMBA)-dependent initiation in mouse skin, inhibited DMBA-dependent mutagenesis in the cell-mediated assay in a concentration responsive manner. The non-PAH promutagens, dimethylnitrosamine (DMN) and sterigmatocystin (STC) were both activated by cultured keratinocytes to cytotoxic derivatives. DMN was neither mutagenic in the cell-mediated assay nor tumorigenic in mouse skin when tested in a two-stage carcinogenesis protocol. STC was weakly mutagenic and tumorigenic in mouse skin.
Carcinogenesis 1983
PMID:Keratinocyte cell-mediated mutagenesis assay: correlation with in vivo tumor studies. 683 37

Cocultures were established of a cell line deficient in hypoxanthine-guanine phosphoribosyltransferase (PG-19; HPRT-) and a mouse epidermal cell line (HEL-37; HPRT+). The cocultures were incubated in a medium containing hypoxanthine, aminopterin and thymidine (HAT). HPRT- cells die in HAT medium unless rescued by metabolic cooperation with HPRT+ cells. The extent of cell death was measured by the release of radioactivity from PG-19 cells previously labelled with [3H]thymidine, and expressed as the lytic index. The lytic index was significantly increased (decreased metabolic cooperation) by tumor-promoting phorbol esters but not by non-promoting esters. The enhanced lytic index was obtained when promoters were incubated with cocultures for 10 h in a total incubation time of 48 h.
Carcinogenesis 1981
PMID:Tumor promoter inhibition of intercellular communication between cultured mammalian cells. 727 7

The influence of phorbol-related tumour promoters and non-promoters on metabolic cooperation between wild-type and mutant Chinese hamster cells has been studied. The recovery, in medium containing 8-azaguanine, of hypoxanthine phosphoribosyl transferase-deficient (HPRT-) V79 cells co-cultured with an excess (2 x 10(6) per 9 cm petri-dish) of wild-type cells was determined in the presence and absence of each compound. Under the latter conditions (solvent treatment only) metabolic cooperation consistently reduced the cloning efficiency of HPRT- cells to approximately 10% of that in cultures without wild-type cells. However, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), the most potent known tumour promoter, almost totally reversed the effect of wild-type cells on mutant recovery when included in the medium at concentrations as low as 1 nM. TPA also markedly enhanced the expression, in crowded cultures, of HPRT- mutants induced by the carcinogen N-methyl-N-nitrosourea. This property was not shared by other phorbol esters which are inactive as tumour promoters, or by polycyclic aromatic hydrocarbons, but was exhibited to a lesser degree by mezerein, a diterpene ester of significant but weaker promoting activity than TPA. Confirmation that the effect of TPA on mutant expression is the result of inhibition of metabolic cooperation was obtained in experiments using autoradiography, which showed that low doses are able to block the transfer of [3H]-uridine nucleotides from prelabelled V79 cells to unlabelled V79 cells in contact. These findings have prompted us to formulate a working hypothesis for the mode of action of TPA in vivo as a tumour promoter based on its interference with this type of intercellular communication.
Carcinogenesis 1981
PMID:Inhibition of metabolic cooperation between mammalian cells in culture by tumor promoters. 727 9

Nitric oxide (NO) is a cellular messenger which is mutagenic in bacteria and human TK6 cells and induces deamination of 5-methylcytosine (5meC) residues in vitro. The aims of this study were: (i) to investigate whether NO induces 5meC deamination in codon 248 of the p53 gene in cultured human bronchial epithelial cells (BEAS-2B); and (ii) to compare NO mutagenicity to that of ethylnitrosourea (ENU), a strong mutagen. Two approaches were used: (i) a novel genotypic assay, using RFLP/PCR technology on purified exon VII sequence of the p53 gene; and (ii) a phenotypic (HPRT) mutation assay using 6-thioguanine selection. BEAS-2B cells were either exposed to 4 mM DEA/NO (Et2N[N2O2]Na, an agent that spontaneously releases NO into the medium) or transfected with the inducible nitric oxide synthase (iNOS) gene. The genotypic mutation assay, which has a sensitivity of 1 x 10(-6), showed that 4 mM ENU induces detectable numbers of G --> A transitions in codon 248 of p53 while 5-methylcytosine deamination was not detected in either iNOS-transfected cells or cells exposed to 4 mM DEA/NO. Moreover, ENU was dose-responsively mutagenic in the phenotypic HPRT assay, reaching mutation frequencies of 24 and 96 times that of untreated control cells at ENU concentrations of 4 and 8 mM respectively; by contrast, 4 mM DEA/NO induced no detectable mutations in this assay, nor were any observed in cells transfected with murine iNOS. We conclude that if NO is at all promutagenic in these cells, it is significantly less so than the ethylating mutagen, ENU.
Carcinogenesis 1995 Sep
PMID:Nitric oxide and ethylnitrosourea: relative mutagenicity in the p53 tumor suppressor and hypoxanthine-phosphoribosyltransferase genes. 755 56


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