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)

Treatment of cultures of spontaneously immortalized human epidermal cells with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) sensitized them to carcinogen toxicity. While the tryptophan pyrolysis product 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and the mycotoxin sterigmatocystin were highly toxic to the cultures at moderate concentration (1 microgram/ml), the potency of each agent was increased > or = 10-fold in the presence of TCDD. A toxicity increase was also evident in the several-fold stimulation by TCDD of protein and DNA adducts formed by Trp-P-1. In contrast, the cells were insensitive to toxicity from 3-amino-1-methyl-5H-pyrido[4,3-b]indole. DNA damage mediated by Trp-P-1 was capable of producing inheritable effects, as judged by the induction of hprt mutants in a TCDD-stimulated fashion. Northern blotting showed that TCDD strongly stimulated expression of P4501A1 and 1B1 in the cells, enzymes important for xenobiotic metabolism. These findings demonstrate the potential usefulness of SIK cultures as a model for studying keratinocyte responses to carcinogens activated by TCDD-induced cytochromes P450.
Carcinogenesis 1995 Sep
PMID:2,3,7,8-Tetrachlorodibenzo-p-dioxin sensitization of cultured human epidermal cells to carcinogenic heterocyclic amine toxicity. 755 73

The V-E5 cell line, a mutant V79 Chinese hamster cell line, was used to study the effect of chromosomal instability on the spectrum of gene mutations and chromosome aberrations induced by the anthracycline antibiotic adriamycin (AM). V-E5 cells showed hypersensitivity to the cytotoxic effects of AM when compared to the parental cell line. AM caused both, chromosome-type aberrations and chromatid-type aberrations in V-E5 cells. Under the same experimental conditions, gene mutations were induced at the hprt locus which mainly represented deletion mutations. The spectrum of AM-induced chromosomal aberrations and gene mutations did not show any peculiarities in comparison to normal V79 cells. It is concluded that the genomic instability in V-E5 cells does not influence the pathways leading to chromosome aberrations and gene mutations after AM treatment.
Mutat Res 1995 Sep
PMID:The pattern of adriamycin-induced mutations in V-E5 Chinese hamster cells with chromosomal instability. 756 8

3-Chloro-4-(chloromethyl)-5-hydroxy-2(5H)-furanone (CMCF), a chlorine disinfection by-product in drinking water, was mutagenic in the Salmonella/his (Ames) assay for both base-pair substitution strains (TA1535, TA100, TA102) and frameshift strains (TA97, TA98) with the highest mutagenic response observed in strain TA100 (1292 revertants/microgram). The presence in TA100 of pKM101 plasmid, which enhances error-phone DNA repair, greatly increased susceptibility to CMCF mutagenicity relative to the isogenic strain TA1535 lacking pKM101. In the Chinese hamster ovary (CHO) cell hprt (6-thioguanine resistance) locus assay, the mutagenicity of CMCF (1.04 mutants/10(6) clonable cells per microgram/ml) was barely detectable because of the low mutagenicity/cytotoxicity ratio. From the present experiments it appears that CMCF acts in a manner similar to that of another drinking water mutagen, 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX). However, CMFC appears to be a less potent mutagen in vitro than MX.
Mutat Res 1995 Sep
PMID:Salmonella and mammalian-cell mutagenicity of 3-chloro-4-(chloromethyl)-5-hydroxy-2(5H)-furanone. 756 15

The growth inhibitory mechanisms of mizoribine, an immunosuppressive imidazole nucleoside used clinically to inhibit rejection reactions after renal transplantation and in the treatment of systemic lupus erythematosus and rheumatoid arthritis, were studied in human and murine cells. We found that (a) human cells were 20- to 60-fold more resistant than murine cells to both mizoribine and its aglycone, (b) adenine phosphoribosyltransferase (APRT)-deficient human cells were resistant to aglycone but not to mizoribine, (c) hypoxanthine phosphoribosyltransferase (HPRT)-deficient human cells were at least 100-fold more sensitive to both mizoribine and aglycone, and (d) the decrease in intracellular GTP broadly paralleled the cytotoxicity in each case. Therefore, data obtained from studies using non-human tissues should be interpreted carefully before clinical application. Results indicate that the growth inhibitory effect of the aglycone but not of mizoribine is mediated by APRT, and depletion of guanine nucleotides is responsible for the effects of both drugs. Our data also suggest that the drugs may reduce mutant HPRT-deficient somatic cells in vivo, and may cause enhanced adverse reactions in HPRT-deficient individuals. The drug may have altered effects in patients receiving other purine or pyrimidine analogs.
Biochem Pharmacol 1995 Sep 28
PMID:Differential cytotoxic effects of mizoribine and its aglycone on human and murine cells and on normal and enzyme-deficient human cells. 757 67

Previous work showed that WTK1 human lymphoblastoid cells are radioresistant but more sensitive to X-ray-induced mutation than the closely related line TK6. In addition, WTK1 cells contain a mutant p53 while in TK6 cells p53 is wild-type. In this work, we examined the spectra of 68 X-ray-induced and 56 spontaneous mutants at the hemizygous hprt locus in WTK1 cells. The induced spectra were classified by Southern blot and multiplex polymerase chain reaction (PCR); there were 19 point mutations (28%) with an unaltered Southern blot or PCR pattern, 26 (38%) partial deletions or rearrangements and 23 (34%) complete gene deletions. The spontaneous spectrum included 25 (45%) point mutations, 22 (39%) partial deletions and 9 (16%) complete gene deletions. These spectra of mutations were compared to those of TK6 cells. Although distinct differences in the spectra of mutations at the tk locus were reported previously, overall there is no significant difference in the spectra of X-ray-induced or spontaneous mutations at the hprt locus in these two cell lines. While there was an increase in the proportion of large-scale changes that occurred at tk after X irradiation, the spectrum of mutations at the hprt locus shows all classes of mutations increasing proportionately in WTK1 cells. However, the proportion of internal partial deletion mutations at the hprt locus was about 2 times more frequent in WTK1 than in TK6 cells.
Radiat Res 1995 Sep
PMID:Spectra of spontaneous and X-ray-induced mutations at the hprt locus in related human lymphoblast cell lines that express wild-type or mutant p53. 765 62

The influence of the dietary antioxidants vitamin C, alpha- and beta-carotene, lycopene, lutein/zeaxanthin, phytofluene, beta-cryptoxanthin, retinol and alpha- and gamma-tocopherol on the hypoxanthine phosphoribosyltransferase (hprt) mutant frequency in human peripheral T lymphocytes was investigated. Twenty-five male non-smokers and 27 male smokers in the age range 50-59 years were recruited. Smokers showed a significantly higher mutant frequency compared with non-smokers (X1.5, P < 0.01). In addition, there was a significant positive relationship between hprt mutant frequency and the number of cigarettes that individuals reported smoking daily (P < 0.01). Smokers showed significantly lower levels of plasma vitamin C and the carotenoid alpha-carotene than non-smokers (P < 0.01 and P < 0.05 respectively). Both hprt mutant frequency and lymphocyte plating efficiency were weakly inversely associated with plasma vitamin C levels (P < 0.07 and P < 0.06 respectively) suggesting that vitamin C may be protective against mutation at the hprt locus. This relationship was markedly stronger in smokers (P < 0.01).
Mutat Res 1995 Sep
PMID:The influence of smoking and diet on the hypoxanthine phosphoribosyltransferase (hprt) mutant frequency in circulating T lymphocytes from a normal human population. 766 69

Mutations in mammalian genomes are the result of several mutagenic processes that are intrinsic to cell metabolism. Analysis of the mutation spectrum of a chromosomal gene is a valuable tool for assessing the contribution of these mechanisms to mutagenesis in the cell. We have studied the specificity of mutations induced by various mutagens in a cDNA hprt gene integrated in a chromosome of a mouse cell line. To understand the mechanisms underlying mammalian cell mutagenesis, we compiled a list of more than 250 sequenced hprt mutations that arose spontaneously or were induced by mutagens, and compared it with the published mutation data. There are at least two distinct processes of mutagenesis in eukaryotic cells: one is mispairing, while another is errors in translesion synthesis. The alkylating agent methylnitrosourea causes G:T mispairing; consequently, most mutations it induces are G to A transitions. The second process can occur spontaneously or be caused by exposure to X-rays, Trp-P2, a tryptophan pyrolysate, or acetylaminofluorene. A variety of premutagenic lesions are produced in DNA by these mutagens, but spectra of the mutations resemble each other, especially in the high frequency of deletions at the sites of short direct repeats. The slippage--misalignment mechanism accounted well for the greater part of the observed deletions. A similar spectrum of mutations was observed in the tumor suppressor gene APC from colorectal tumors; about 40% are deletions at the sites of short repeats. These findings led us to propose that slippage--misalignment is an ubiquitous mechanism of mutagenesis and is responsible for a significant proportion of spontaneous mutations in mammalian cells.
Mutagenesis 1994 Sep
PMID:Slippage--misalignment: to what extent does it contribute to mammalian cell mutagenesis? 783 71

Spectra of N-ethyl-N-nitrosourea (ENU)-induced mutations differ widely among various in vitro and in vivo mutational systems. To investigate possible reasons for these differences, a mutational system is needed in which the same target gene is used for comparison in the same type of cells in vitro and in vivo. In the present study, this was achieved by analysing at the molecular level 35 hprt mutant rat fibroblast clones obtained from cell populations exposed in vitro to ENU and comparing the mutational spectrum with the previously determined spectrum of ENU-induced hprt mutants in the same target cells exposed in vivo. Twenty-eight mutants contained a single base pair alteration in the hprt coding sequence. Most of these changes were found at AT base pairs (19/28), the AT to TA transversion being the most frequent kind of mutation (12/19), which is probably caused by O2-ethylthymine. Transversions at AT base pairs showed all mutated T's to be located in the nontranscribed strand of the hprt gene, suggesting a strand specific fixation of mutations induced by O2-ethylthymine, which appears to be a general feature of ENU- and ENNG-induced hprt mutations in mammalian cells. GC to AT transitions, probably caused by O6-ethylguanine, were detected at a lower frequency (7/28). This in vitro mutational spectrum was very similar to that of the same target cells exposed in vivo to ENU. A comparison of the mutational spectra in AGT-proficient and AGT-deficient rodent cells exposed to ethylating agents showed that in contrast to the situation in AGT-proficient rat fibroblasts, GC to AT base pair changes (and not AT to TA) are the predominant mutations in AGT-deficient hamster cells.
Mutagenesis 1994 Sep
PMID:AT base pairs are the main target for mutations at the hprt locus of rat skin fibroblasts exposed in vitro to the monofunctional alkylating agent N-ethyl-N-nitrosourea. 783 75

A large number of hprt-mutants were obtained by treating human lymphoblast cells (TK6) with 5 microM K2Cr2O7 for 5 hr and selecting by growth in 6-thioguanine. A combination of high fidelity polymerase chain reaction (PCR) and denaturing gradient gel electrophoresis (DGGE) allowed us to measure mutant frequencies as a function of DNA sequence. Chromium(VI) induced four hotspots in a 104 bp domain of hprt exon 3. Substitutions at G:C base pairs were the predominant mutations. One of the chromium-induced hotspots was located at the same position as previously determined hydrogen peroxide and benzo(a)pyrene diol epoxide hotspots.
Environ Health Perspect 1994 Sep
PMID:Use of denaturing-gradient gel electrophoresis to study chromium-induced point mutations in human cells. 784 3

Lesch-Nyhan syndrome is a rare anomaly consisting of a deficiency in the production of hypoxanthine phosphoribosyltransferase that leads to the overproduction of purine and the accumulation of uric acid. Major manifestations include mental retardation and self-destructive behavior resulting in self-mutilation through biting and scratching. Because no medical treatment exists to alleviate the symptoms of self-mutilation, direct dental intervention is the only way these behaviors can be affected. A unique case of this type involving two male identical twins is reported.
Oral Surg Oral Med Oral Pathol 1994 Sep
PMID:Lesch-Nyhan syndrome. A case report. 797 May 91


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