Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00492 (hypoxanthine-guanine phosphoribosyltransferase)
 2,385 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mutagenic potentials of the human bladder carcinogen 4-amino-biphenyl (ABP) and three of its proximate carcinogenic metabolites, N-hydroxy-4-aminobiphenyl (N-OH-ABP), N-hydroxy-4-acetylaminobiphenyl (N-OH-AABP) and N-acetoxy-4-acetylaminobiphenyl (N-OAc-AABP) were tested on a prime human target cell type for carcinogenesis, human uroepithelial cells (HUC). SV-HUC (PC), a near diploid, clonally derived, nontumorigenic SV40-immortalized human uroepithelial cell line that is transformable to tumorigenicity after exposure to ABP and its metabolites, was used for quantitative mutation assays. The end point used was the induction of mutations in the hypoxanthine-guanine phosphoribosyltransferase (HGPRT) locus, selected using 6-thioguanine resistance (TGr). A single, 24-h exposure of SV-HUC to ABP, N-OH-ABP, N-OH-AABP, or N-OAc-AABP caused a statistically significant, dose-dependent increase in mutation frequency resulting in a 2-30-fold increase in the number of TGr mutants in carcinogen-exposed groups compared to untreated controls. These chemicals were similarly mutagenic towards MC-T11, an SV-HUC-derived low grade tumor cell line that was also shown to be responsive to transformation (in a separate study) by ABP, N-OH-ABP, or N-OH-AABP as judged by the generation of higher grade tumors. In contrast, the mutagenic potencies of ABP and N-OH-ABP were lower when tested on a subclone of SV-HUC (BC) that is refractory to transformation by these chemicals. Thus, these data support a model of transformation in which ABP as well as its metabolites contribute to tumorigenic transformation and neoplastic progression of HUC by inducing mutations in susceptible target cell genes.
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PMID:Induction of thioguanine-resistant mutations in human uroepithelial cells by 4-aminobiphenyl and its N-hydroxy derivatives. 131 36

Recently, we have observed a small (36%), but significant, enhancement of the frequency of 6-thioguanine (6-TG)-resistant T-lymphocytes in blood from smokers. The molecular nature of 43 hypoxanthine-guanine phosphoribosyltransferase (hprt) mutant T-lymphocyte clones from nine smoking individuals was determined to investigate whether the increase in hprt mutant frequency would lead to a changed mutation spectrum. The types and distribution of hprt mutations in smokers was compared with those found in 55 6-TGr T-lymphocyte clones from 12 members of a control group of non-smokers. From this control group 25 hprt mutants were novel, whereas 31 have been described previously. Among smokers and non-smokers, a similar proportion of base substitutions (approximately 35%), mutations causing aberrant splicing (approximately 37%), frameshifts (approximately 16%) and deletions (approximately 9%) was found. In both groups, GC----AT base pair changes were found to be predominant among transitions. However, whereas all types of transversions were about equally represented in non-smokers, GC----TA transversions were not recovered among smokers. Investigation of the distribution of base substitutions over the hprt coding region showed no differences between the two groups. These data provide no clues on the nature of DNA adducts induced by smoking, which are thought to be responsible for the increased mutation frequency at the hprt locus in T-lymphocytes from smokers.
Carcinogenesis 1992 Sep
PMID:Enhanced hprt mutant frequency but no significant difference in mutation spectrum between a smoking and a non-smoking human population. 139 47

Chromium(VI) compounds exert their genotoxicity and mutagenicity by complex metabolic reducing pathways that generate a variety of reactive forms of chromium and free radicals. To investigate the molecular nature of chromium-induced mutations, we characterized the entire coding region of the hypoxanthine (guanine) phosphoribosyltransferase (hprt) gene of 27 independent mutants derived from chromium(VI) oxide (CrO3)-treated Chinese hamster ovary-K1 cells, by direct sequencing of PCR-amplified cDNA. Among these mutants, 10 consisted of single base substitutions, five contained two base substitutions, one had four base substitutions, six were splicing mutations, and five exhibited single base pair insertions or deletions. All of the base substitutions and most of the frameshift mutations observed were located at A/T-rich sequences. More than 90% of the base substitutions (22/24) occurred in A.T base pairs. Among them, T-->A and T-->G transversions (18/22) predominated. The mutational hotspots for single and double base substitutions were the 3' thymidine of 5'PuT and thymidines of 5'ATTT sequences respectively. This mutational specificity was also observed in CHO-K1 cells treated with two other chromium(VI) compounds, namely K2Cr2O7 and PbCrO4. Strand bias was noticed in chromium mutagenicity, since 77% of T base substitutions occurred on the non-transcribed strand. This highly sequence-specific mutation spectrum suggests that a particular form of chromium may directly interact with DNA at these hotspot sequences.
Carcinogenesis 1992 Nov
PMID:Mutational specificity of chromium(VI) compounds in the hprt locus of Chinese hamster ovary-K1 cells. 142 75

The spontaneous hprt mutant clone SP5, derived from V79 Chinese hamster cells, was shown to exhibit a duplication of approximately 2 kb, including exon 2 and its flanking intron sequences, inserted into the intron 1 sequence of the hprt gene. The most striking feature of SP5 is that this clone is quite unstable, demonstrating an extremely high spontaneous reversion frequency. Molecular analysis of 25 independent revertant clones of SP5 indicated that they arose after precise deletion of the duplicated fragment in the hprt gene. Reversion of SP5 could be induced by agents which damage DNA by different mechanisms, but there was no correlation with induction of the forward mutations. Based on these results, we suggest that intrachromosomal recombination must be responsible for the spontaneous reversion of SP5. Genetic recombination in somatic cells has been suggested to be involved in the multistep process of carcinogenesis. Since the ability to induce intrachromosomal recombination in yeast has been shown to be highly correlated with non-mutagenic as well as mutagenic carcinogens, it is of great interest to investigate similar systems in mammalian cells. The SP5 cell line may be unique for such a purpose, since this mutant clone contains an endogenic marker for studying the process of intrachromosomal recombination.
Carcinogenesis 1992 Apr
PMID:Reversion of the hprt mutant clone SP5 by intrachromosomal recombination. 157 14

DNA sequence was determined in 21 mutants induced at the hprt locus of Chinese hamster ovary (CHO) cells by 1-nitrosopyrene, a metabolite of the tumorigenic environmental pollutant 1-nitropyrene. Following cDNA synthesis using RNA from each of the mutants, the hprt protein-coding region was amplified by the polymerase chain reaction (PCR) and subjected to direct DNA sequence analysis. Sixteen primary mutations were found: seven were G:C----T:A transversions, five were G:C----A:T transitions, two were single basepair insertions, one was a single basepair deletion, and one was a complex mutation involving substitutions at two A:T basepairs. The simple basepair substitution mutations preferentially occurred with one or two purines 3' to the mutated dG, and mutations in exons 1-4 disproportionately occurred with the mutated dG on the nontranscribed DNA strand. In addition, 12 of the mutants produced one or more cDNA PCR products with partial or complete exon deletions. Seven mutants with multiple PCR products had point mutations in one of the products; exon deletions in the other product(s) removed these point mutations. A group of solvent control mutants had a different distribution of basepair substitution mutations and a lower proportion of cDNAs with exon deletions than that found for the 1-nitrosopyrene-induced mutants. The results indicate a specificity for the induction of mutations in the hprt gene of CHO cells by 1-nitrosopyrene with respect to both the types of mutations produced and their location in the hprt gene. Also, the elimination of point mutations in many of the cDNA PCR products with exon deletions suggests that mutations in the protein-coding sequence affect hprt mRNA processing.
Carcinogenesis 1992 May
PMID:DNA sequence analysis of 1-nitrosopyrene-induced mutations in the hprt gene of Chinese hamster ovary cells. 158 93

A prospective, longitudinal study was performed to test the hypothesis that environmental factors (e.g., diet or cigarette smoking) modulate genetic damage caused by treatment for breast cancer and render these women more susceptible to developing second malignancies. A total of 107 women (49 with breast cancer, 52 with benign breast masses, and 6 normal women) were enrolled. This report describes initial studies at the time of enrollment and disease presentation. Mutant frequency at the hprt locus and cloning efficiency of peripheral blood lymphocytes did not differ significantly among the 3 groups. Mutant frequency increased with age, with a history of cigarette smoking, and with the number of years that current smokers used cigarettes. There was no correlation in women with benign masses between mutant frequency and the incidence of chromosome aberrations (28 women) or sister chromatid exchanges (23 women). A maternal history of breast cancer did not influence mutant frequency. There was no significant relationship between dietary intake of vitamins A, B12, C and E, folacin, selenium, calcium, caffeine, or multivitamin pills, and mutant frequency. Serum folate levels in the deficient range were associated (P = 0.02) with elevated mutant frequencies, whereas SCE rates inversely correlated with serum vitamin B12 levels. These results confirm the importance of age and, less so, cigarette smoking as factors that influence mutant frequency and suggest that a micronutrient, folic acid, may modify genetic damage at the hprt locus. To the extent that somatic mutation contributes to carcinogenesis, these environmental factors may enhance the risk of developing malignant transformation.
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PMID:Factors influencing mutation at the hprt locus in T-lymphocytes: studies in normal women and women with benign and malignant breast masses. 160 Sep 53

The reaction product of N-methyl-N-nitrosourea (MNU) with DNA, O6-methylguanine (O6-MeG), is responsible for the mutagenic and carcinogenic effects of this carcinogen. These involve activation of the H-ras proto-oncogene in rat mammary tumors by MNU, with a high frequency of GC to AT transitions in codon 12 of this gene. The present study aimed to investigate the types and position specificities of mutations induced by MNU in another gene, the hprt gene of V79 Chinese hamster cells. Furthermore, since processes involved in the expression of genetic damage, e.g. the state of the DNA precursor pool, have been suggested to be important factors in carcinogenesis, the mutagenic specificity of MNU was also studied in the presence of an imbalanced nucleotide pool. Isolation of independent hprt mutant clones from three groups treated in different manners was performed. Two different doses of MNU and a low dose of MNU in combination with hydroxyurea (HU) were employed. Comparison of the results with the two doses of MNU did not indicate any shift in mutation specificity. The majority of the mutations induced by MNU were base substitutions, mostly transitions of GC to AT showing high affinity for the middle base in 5'-purine-G-N-3' sequences (15/18) in the nontranscribing strand, suggesting a difference in repair capacity for the two strands. The relatively high frequency of the base substitutions resulting in splicing defects is explained by the presence of a consensus sequence (5'-purine-g-N-3') in the splice sites of the hprt gene. The results from the HU/MNU group showed a few more GC to TA transversions, though not statistically significant, which may be caused by a shift from miscoding to non-coding recognition of the O6-MeG lesion. The same reactive decomposition products formed from MNU are also formed from a variety of other carcinogenic compounds, e.g. N-methyl-N'-nitro-N-nitrosoguanidine, dimethylnitrosamine, nitrosocimetidine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, suggesting that our findings concerning the mutagenic specificity of MNU in mammalian cells are valid also for these other compounds as well.
Carcinogenesis 1991 Oct
PMID:Site specificity of N-methyl-N-nitrosourea-induced transition mutations in the hprt gene. 193 71

The frequency of sister chromatid exchanges (SCEs) was determined in Hodgkin's disease (HD) patients prior to therapy, following radiotherapy, and following combined radiotherapy and chemotherapy. The frequency of hprt- mutants in these patients has been reported previously. The frequency of SCEs and hprt- mutants in the same individuals were compared. In non-HD controls the mean SCE frequency and the mean of high SCE frequency cells (HFCs) were significantly increased by smoking, while mutant frequency (MF) showed no effect. Untreated HD patients had mean SCEs, mean HFCs and mean MFs that were higher than non-MD controls. In treated patients, mean SCE and HFC frequencies were lower than untreated patients and non-HD controls, while their MFs were significantly elevated. Overall, SCE frequency was not correlated with MF in control or HD patient groups, suggesting that these biomarkers may reflect, in this case, fundamental biological differences between these processes.
Carcinogenesis 1991 Nov
PMID:Sister chromatid exchange frequency in Hodgkin's disease patients with elevated in vivo hprt mutant frequencies. 193 1

The effects of cigarette smoke condensate (CSC) and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) on gap junction structure, quantity and function were investigated. Gap junction morphology was studied in rotary-shadowed freeze-fracture replicas of primary chick embryo hepatocytes. CSC (24 micrograms/ml) induced a strong decrease of gap junction areas; within 6 h the areas were reduced by greater than 60%. In the first 3 h of exposure, TPA (100 ng/ml) also reduced gap junction areas, but in the next 3 h a partial recovery was observed. Protoplasmic fracture face centre-to-centre particle spacings were used as a measure for gap junction coupling. CSC had a slow (although not significant) reducing effect on particle spacings, while TPA induced a reduction from 10.6 nm (control) to 10.0 nm within 3 h, indicating a reduction of coupling. Gap junctions were quantified in thin sections of cultured chick embryo hepatocytes, V79 fibroblasts, and co-cultivated hepatocytes and V79 cells. CSC did not influence gap junction numbers in any of these cultures, while TPA treatment caused a disappearance of gap junctions between hepatocytes and between hepatocytes and V79 cells in the first 12 h of cultivation. In the following 36 h a slow recovery could be observed. Gap junctions between V79 cells had already disappeared within 30 min. Metabolic co-operation between hepatocytes and hypoxanthine-guanine phosphoribosyltransferase-deficient V79 cells was quickly and continuously blocked by CSC over 27 h, whereas the phorbol ester induced a transient block. The dissimilar effects of these compounds on both gap junction structure and function indicate that they act via different mechanisms. The finding that CSC did not inhibit phorbol ester protein kinase C binding and did not activate this protein kinase in vitro supports this hypothesis.
Carcinogenesis 1990 Jun
PMID:Effects of cigarette smoke condensate and 12-O-tetradecanoylphorbol-13-acetate on gap junction structure and function in cultured cells. 211 59

We have used the pZipHprtNeo shuttle vector to determine the types of DNA sequence alterations induced by a potent carcinogen 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P2). The shuttle vector contains a human cDNA hprt as the target gene and is stably integrated into a chromosome of the mouse cell line VH12. After Trp-P2 treatment, 59 independent HPRT- mutant clones of VH12 were isolated and altered sequences of the mutant hprt- cDNA genes were determined. Mutations induced by Trp-P2 comprised a variety of events; base substitutions, frameshifts, deletions and complex. Frameshifts were the most frequent mutational events (51%), and base substitutions were the next most frequent (30%) followed by deletions (14%). Examination of the DNA sequence context in the mutant genes revealed that approximately 70% of mutations induced by Trp-P2 occurred at G:C sites and thymine residues were the suggested target for the remainder of mutations. The results seem consistent with the previously reported finding that in vivo, metabolically activated Trp-P2 specifically binds to the C8 position of guanine residues in DNA to form C8G-Trp-P2 adducts (Hashimoto et al., Mutat, Res., 105, 9-13, 1982). As for molecular mechanisms, we showed that slippage and slippage misalignment could predict the generation of a large portion of Trp-P2-induced mutations found in the cDNA gene.
Carcinogenesis 1990 May
PMID:Mutational specificity of the carcinogen 3-amino-1-methyl-5H-pyrido[4,3-b]-indole in mammalian cells. 233 11


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