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)

The purposes of the present study were: (i) to investigate the potential use of several biomarkers as quantitative indicators of the in vivo conversion of ethylene (ET) to ethylene oxide (EO); (ii) to produce molecular dosimetry data that might improve assessment of human risk from exogenous ET exposures. Groups (n = 7/group) of male F344 rats and B6C3F1 mice were exposed by inhalation to 0 and 3000 p. p.m. ET for 1, 2 or 4 weeks (6 h/day, 5 days/week) or to 0, 40, 1000 and 3000 p.p.m. ET for 4 weeks. N:-(2-hydroxyethyl)valine (HEV), N:7-(2-hydroxyethyl) guanine (N7-HEG) and HPRT: mutant frequencies were assessed as potential biomarkers for determining the molecular dose of EO resulting from exogenous ET exposures of rats and mice, compared with background biomarker values. N7-HEG was quantified by gas chromatography coupled with high resolution mass spectrometry (GC-HRMS), HEV was determined by Edman degradation and GC-HRMS and HPRT: mutant frequencies were measured by the T cell cloning assay. N7-HEG accumulated in DNA with repeated exposure of rodents to 3000 p.p.m. ET, reaching steady-state concentrations around 1 week of exposure in most tissues evaluated (brain, liver, lung and spleen). The dose-response curves for N7-HEG and HEV were supralinear in exposed rats and mice, indicating that metabolic activation of ET was saturated at exposures >/=1000 p.p.m. ET. Exposures of mice and rats to 200 p.p.m. EO for 4 weeks (as positive treatment controls) led to significant increases in HPRT: mutant frequencies over background in splenic T cells from exposed rats and mice, however, no significant mutagenic response was observed in the HPRT: gene of ET-exposed animals. Comparisons between the biomarker data for both unexposed and ET-exposed animals, the dose-response curves for the same biomarkers in EO-exposed rats and mice and the results of the rodent carcinogenicity studies of ET and EO suggest that too little EO arises from exogenous ET exposure to produce a significant mutagenic response or a carcinogenic response under standard bioassay conditions.
Carcinogenesis 2000 Sep
PMID:Biomarkers of exposure and effect as indicators of potential carcinogenic risk arising from in vivo metabolism of ethylene to ethylene oxide. 1096 97

Recently, we have shown a hypermutable response to the food-associated heterocyclic amine 2-amino-1-methyl-6-phenylimidazo-[4,5-b]-pyridine (PhIP) in human cells defective in mismatch repair (MMR). These findings suggest that exogenous compounds such as PhIP may play an important role in the generation of tumors in MMR-defective individuals. The specificity of mutations induced by PhIP exposure at the endogenous HPRT locus was determined in cell lines defective in MMR to better understand the mutagenic effects of PhIP in MMR-defective individuals and to gain insight into the molecular mechanism of carcinogenesis induced by PhIP. Eighty-six induced HPRT mutants from two different cell lines were isolated and sequenced after exposure to 10 microM PhIP. Nineteen (22%) of these mutants contained G:C to T:A transversion mutations, consistent with the promutagenic adduct of PhIP at the C8 position of guanine miscoding with adenine. This level of PhIP-induced G:C to T:A transversions was approximately 4.5-fold higher than spontaneous G:C to T:A frequencies. Additionally, a hotspot for mutation was observed in a run of six guanines in HPRT exon 3, where a total of 23 (27%) of all PhIP-induced mutations occurred. These mutations consisted of transversions, transitions, and frameshift mutations. The increase in mutant frequency at this run of guanines corresponded to a 24-fold elevation above the spontaneous frequency in one cell line and a 3.3-fold increase in the other. These data suggest that PhIP may increase the risk of human carcinogenesis mediated by MMR by increasing mutations at runs of guanine residues. PhIP may thereby promote tumorigenesis by mutating growth-regulating genes that contain runs of guanines in their coding sequences, such as BAX, the insulin-like growth factor II receptor IGFIIR, and even the mismatch repair gene hMSH6.
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PMID:Specificity of mutations induced by the food-associated heterocyclic amine 2-amino-1-methyl-6-phenylimidazo-[4,5-b]-pyridine in colon cancer cell lines defective in mismatch repair. 1098 7

Cockayne syndrome (CS) patients are deficient in the transcription coupled repair (TCR) subpathway of nucleotide excision repair (NER) but in contrast to xeroderma pigmentosum patients, who have a defect in the global genome repair subpathway of NER, CS patients do not have an elevated cancer incidence. To determine to what extent a TCR deficiency affects carcinogen-induced mutagenesis and carcinogenesis, CS group B correcting gene (CSB)-deficient mice were treated with the genotoxic carcinogen benzo(a)pyrene (B[a]P) at an oral dose of 13 mg/kg body weight, three times a week. At different time points, mutant frequencies at the inactive lacZ gene (in spleen, liver, and lung) as well as at the active hypoxanthine phosphoribosyltransferase (Hprt) gene (in spleen) were determined to compare mutagenesis at inactive versus active genes. B[a]P treatment gave rise to increased mutant frequencies at lacZ in all of the organs tested without a significant difference between CSB-/- and wild-type mice, whereas B[a]P-induced Hprt mutant frequencies in splenic T-lymphocytes were significantly more enhanced in CSB-/- mice than in control mice. The sequence data obtained from Hprt mutants indicate that B[a]P adducts at guanine residues were preferentially removed from the transcribed strand of the Hprt gene in control mice but not in CSB-/- mice. On oral treatment with B[a]P, the tumor incidence increased in both wild-type and CSB-deficient animals. However, no differences in tumor rate were observed between TCR-deficient CSB-/- mice and wild-type mice, which is in line with the normal cancer susceptibility of CS patients. The mutagenic response at lacZ, in contrast to Hprt, correlated well with the cancer incidence in CSB-/- mice after B[a]P treatment, which suggests that mutations in the bulk of the DNA (inactive genes) are a better predictive marker for carcinogen-induced tumorigenesis than mutations in genes that are actively transcribed. Thus, the global genome repair pathway of NER appears to play an important role in the prevention of cancer.
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PMID:The relationship between benzo[a]pyrene-induced mutagenesis and carcinogenesis in repair-deficient Cockayne syndrome group B mice. 1105 60

Interleukin-8 (IL-8) is a chemokine for neutrophils and an angiogenic factor. Human tumors that express IL-8 may exhibit intense neutrophil infiltration and increased vascularization. Mutatect cells are a murine fibrosarcoma that can be grown as subcutaneous tumors in syngeneic C57BL/6 mice. Since neutrophils are a source of cytotoxic and genotoxic species, we constructed Mutatect cell lines that constitutively express human IL-8 to explore the involvement of neutrophils in tumor biology and genetic instability. An IL-8/neo expression plasmid was stably transfected into Mutatect MC17-51 cells and clone MIL-4 was isolated. Tumors initiated with 5x10(5) MIL-4 cells grew very slowly compared with tumors from pure MC17-51 cells or from 0.5 to 4x10(5) MIL-4 cells mixed with 5x10(5) MC17-51 cells. Over 95% of cells recovered from slow-growing pure MIL-4 tumors lost the transgene as measured by loss of (i) resistance to G418, (ii) expression of IL-8 protein and (iii) IL-8-specific DNA sequences. When tumors from mixed cell types were examined, loss of the transgene did not occur; rather, IL-8 producing cells appeared to have some growth advantage. The neutrophil content of tumors (as measured by myeloperoxidase) was directly proportional to the level of IL-8 expressed at the time tumors were excised. As reported earlier, the frequency of mutations at the hypoxanthine phosphoribosyltransferase locus was also directly proportional to neutrophil content. To explain some of these biological findings, we postulate that early in development of pure MIL-4 tumors, genotoxic/cytotoxic neutrophils are attracted by IL-8, which in turn leads to loss of the transgene and to localized cytotoxicity of IL-8 producing cells. In mixed tumors, where the initial IL-8 concentration may be lower, tumors might become established more readily because fewer neutrophils may be attracted. This relatively simple experimental paradigm has revealed some of the complex biological changes that can occur as a result of IL-8 in tumors.
Carcinogenesis 2001 Feb
PMID:Constitutive expression of interleukin-8 by Mutatect cells markedly affects their tumor biology. 1118 44

Marked differences between the mutagenic efficiency of N-methyl-N-nitrosourea (MNU), a potent carcinogen, methyl methane sulphonate (MMS) and dimethyl sulphate (DMS), both weak carcinogens, have been reported at the hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and ouabain loci in V79 cells. Differences in levels of O6-guanine methylation produced by these alkylating agents, has been interpreted as indicating that O6-methylguanine is the DNA lesion specifically responsible for their mutagenic and carcinogenic effects. Because of the heterogeneity of molecular events which can result in forward mutation this conclusion seems unjustified. The development and characterisation of a reverse assay from 6-thioguanine resistance and HAT medium sensitivity (TG(R) and HAT(S)), to 6-thioguanine sensitivity and HAT medium resistance (TG(S) and HAT(R)) HGPRT(-)-->HGPRT+ in V79 cells, has allowed us to test the above hypothesis in a more specific way. Ethyl methane sulphonate, a weak carcinogen and MNU, both of which produce significant levels of O atom alkylation, were similarly effective mutagens in the reverse direction. At equitoxic doses, DMS was 40-60 fold less efficient. There was however, no quantitative correlation between numbers of revertants induced and measured levels of O6-alkylguanine. From these and other observations it is concluded that O6-alkylguanine is not the only potentially mutagenic lesion in mammalian cells.
Carcinogenesis 1980 Sep
PMID:Evidence for the involvement of lesions other than O6-alkylguanine in mammalian cell mutagenesis. 1121 71

Allelic loss is an important mutational mechanism in human carcinogenesis. Loss of heterozygosity (LOH) at an autosomal locus is one outcome of the repair of DNA double-strand breaks (DSBs) and can occur by deletion or by mitotic recombination. We report that mitotic recombination between homologous chromosomes occurred in human lymphoid cells exposed to densely ionizing radiation. We used cells derived from the same donor that express either normal TP53 (TK6 cells) or homozygous mutant TP53 (WTK1 cells) to assess the influence of TP53 on radiation-induced mutagenesis. Expression of mutant TP53 (Met 237 Ile) was associated with a small increase in mutation frequencies at the hemizygous HPRT (hypoxanthine phosphoribosyl transferase) locus, but the mutation spectra were unaffected at this locus. In contrast, WTK1 cells (mutant TP53) were 30-fold more susceptible than TK6 cells (wild-type TP53) to radiation-induced mutagenesis at the TK1 (thymidine kinase) locus. Gene dosage analysis combined with microsatellite marker analysis showed that the increase in TK1 mutagenesis in WTK1 cells could be attributed, in part, to mitotic recombination. The microsatellite marker analysis over a 64-cM region on chromosome 17q indicated that the recombinational events could initiate at different positions between the TK1 locus and the centromere. Virtually all of the recombinational LOH events extended beyond the TK1 locus to the most telomeric marker. In general, longer LOH tracts were observed in mutants from WTK1 cells than in mutants from TK6 cells. Taken together, the results demonstrate that the incidence of radi-ation-induced mutations is dependent on the genetic background of the cell at risk, on the locus examined, and on the mechanisms for mutation available at the locus of interest.
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PMID:Different mechanisms of radiation-induced loss of heterozygosity in two human lymphoid cell lines from a single donor. 1122 43

The presence of single nucleotide instability, an increase of spontaneous point mutation rates (MR: number of mutations per cell division) without microsatellite instability, was demonstrated previously in two rat mammary carcinoma cell lines. In this study, spontaneous point MRs were analyzed in human breast cancer cell lines by the fluctuation test using the hypoxanthine-guanine phosphoribosyltransferase (hprt) marker gene. MRs obtained for six breast cancer cell lines, MCF-7, ZR-75-1, T-47D, MDA-MB-231, MDA-MB-468, and BT-474, all of which were proficient in G/T mismatch binding and reported to be negative for microsatellite instability, were 7.6, 4.6, 6.3, 2.2, 5.6, and 19 x 10(-7) mutations/hprt/cell division. Those in normal human mammary epithelial cells and in a colon cancer cell line with proficient mismatch repair, SW480, were 1.6 and 1.4 x 10(-7) mutations/hprt/cell division, respectively. These findings showed that single nucleotide instability was also present in five of the six human breast cancer cell lines and strongly indicates it has important roles in human and rat mammary carcinogenesis.
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PMID:The presence of single nucleotide instability in human breast cancer cell lines. 1169 86

As the primary metabolite of alcohol, acetaldehyde (AA) may be responsible for many pathological effects related to consumption of alcohol, such as esophageal cancer. The spectrum of p53 mutations in esophageal tumors is indicative of the involvement of exogenous agents, such as tobacco smoke. There is, however, no experimental proof for the involvement of alcohol as data on mutational spectrum induced by AA in human genes is completely lacking. The aim of this study is to investigate whether AA leaves mutational fingerprint in the HPRT reporter gene in human peripheral T cells. Pre-existing in vivo HPRT mutants were removed from PHA-stimulated T lymphocytes before in vitro treatment with 2.4 mM AA for 24 h. Following cell growth to allow mutation expression, independent 6-thioguanine-resistant mutants were selected from large numbers of subcultures showing a 3-fold induction of mutant frequency on average. A total of 73 induced and 36 spontaneous mutants were found to carry a missense, nonsense, frameshift or splice mutation. Base substitutions were identified in the coding or splicing sequences of 55 induced and 26 control mutants. The induced base changes were mainly G > A transition (40%, G on non-transcribed strand) followed by A > T transversions (14.5%, A on non-transcribed strand). The control mutants had significantly (P = 0.04) less G > A transition (15.4%) and completely lacked A > T transversions. We also identified 5'-AGG-3' or 5'-AAG-3' as potential target sequences for AA-induced G > A transitions. This specific mutational spectrum induced by AA is consistent with the known formation and persistency of N(2)-ethyl-2'-guanosine adduct and with the predominance of G > A transitions and mutations at A:T base pairs in the p53 gene of esophageal tumors. We conclude that AA may be involved in the pathogenesis of esophageal cancer.
Carcinogenesis 2001 Nov
PMID:Mutational spectrum induced by acetaldehyde in the HPRT gene of human T lymphocytes resembles that in the p53 gene of esophageal cancers. 1169 45

Fibulin-1 is an extracellular matrix protein induced by estradiol in estrogen receptor (ER) positive ovarian cancer cell lines. Alternative splicing of fibulin-1 mRNA results in four different variants named A, B, C and D that may have distinct biological functions. We studied the relative expression of fibulin-1 mRNA variants and their estrogen regulation in human ovarian cancer cells. In ovarian tissues and cancer cell lines, fibulin-1C and -1D are the predominant forms, whereas fibulin-1A and -1B are weakly expressed. We developed a competitive PCR assay based on coamplification of fibulin-1C and -1D to study the relative expression of these fibulin-1 variants in human ovarian samples. In ovarian cancer cell lines and ovarian cancer samples, there was a marked increase in the fibulin-1C:1D and fibulin-1C:HPRT mRNA ratios as compared to normal ovaries. In the BG1 estrogen receptor positive ovarian cancer cell line, fibulin-1C mRNA was induced by estradiol in a dose- and time-dependent manner. Since others and we have previously shown an increased expression of ERalpha as compared to ERbeta in ovarian cancer cells, we investigated whether ERalpha or ERbeta is involved in this induction. For this aim, MDA-MB-231 breast cancer cell line, which expresses both low basal levels of ERs and fibulin-1, was infected with recombinant ERalpha or ERbeta encoding adenovirus and treated with estradiol. Fibulin-1C was induced by estradiol in ERalpha- but not ERbeta-infected cells, suggesting that fibulin-1C induction is mediated through ERalpha. In ovarian tumors, a trend towards a correlation between fibulin-1C and ERalpha expression levels was noted. In conclusion, this study showed an increased fibulin-1C:-1D mRNA ratio in ovarian cancer cells as compared to normal ovaries. This finding suggests that the C variant may be involved in ovarian carcinogenesis. Fibulin-1C overexpression may thus be a clue for the understanding of a putative role of estrogens in ERalpha promoted ovarian tumor progression.
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PMID:Estrogen induction and overexpression of fibulin-1C mRNA in ovarian cancer cells. 1185 Aug 27

Mother-to-child transmission of the human immunodeficiency virus is substantially reduced by prenatal and postnatal treatment with anti-retroviral nucleoside analogues; however, the long-term consequences of these drug interventions are not known. The nucleoside analogue zidovudine (3'-azido-2',3'-dideoxythymidine; AZT) is carcinogenic in mice when administered transplacentally or neonatally, and this may be due to a genotoxic mechanism. Since single-drug treatment with AZT is being superseded by multidrug combinations, we have investigated the induction of mutations and micronuclei in mice treated neonatally with AZT, lamivudine (3'-thia-2',3'-dideoxycytidine; 3TC), or a combination of the two drugs. B6C3F(1)/Tk+/- mice were treated daily from days 1-8 of age with 200 mg AZT/kg/day, 200 mg 3TC/kg/day, or a mixture of 200 mg AZT + 200 mg 3TC/kg/day (AZT/3TC). One and 2 days after the last dose, bone marrow was collected to assess the induction of micronuclei in polychromatic erythrocytes; 3 weeks following treatment, the induction of mutants was determined in the hypoxanthine-guanine phosphoribosyltransferase (Hprt) and thymidine kinase (Tk) genes of spleen lymphocytes. AZT and AZT/3TC, but not 3TC, caused a significant increase in micronuclei, with the response being greatest one day after the last dose. None of the drugs induced mutations in the Hprt gene, while AZT and AZT/3TC, but not 3TC, caused a significant increase in the Tk mutant frequency. The increase in Tk mutants by AZT and AZT/3TC was associated with loss of the wild-type (Tk+) allele (loss of heterozygosity). These data suggest that AZT, but not 3TC, is genotoxic in neonatal mice, and that 3TC does not alter significantly the responses observed with AZT alone.
Carcinogenesis 2002 Sep
PMID:Frequency of Tk and Hprt lymphocyte mutants and bone marrow micronuclei in B6C3F(1)/Tk+/- mice treated neonatally with zidovudine and lamivudine. 1218 83


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