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 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

The initiation of carcinogenesis by carcinogens such as 7r,8t-dihydroxy-9,10t-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE-I) is thought to involve the formation of DNA adducts. However, the diastereomeric diol epoxide, 7r,8t-dihydroxy-9,10c-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE-II), also forms DNA adducts but is inactive in standard carcinogenesis models. We have measured the formation and loss of DNA adducts derived from BPDE-II in a DNA-repair-proficient line of Chinese hamster ovary (CHO) cells, AT3-2, and in two derived mutant cell lines, UVL-1 and UVL-10, which are unable to repair bulky DNA adducts. BPDE-II adducts were lost from cellular DNA in AT3-2 cells with a half-life of 13.8 h; this was about twice the rate found for BPDE-I adducts. BPDE-II adducts were also lost from DNA in UVL-1 and UVL-10 cells, but at a much slower rate. When purified DNA was modified in vitro with BPDE-II and then held at 37 degrees C, DNA adducts were removed at a rate identical to that seen in UVL-1 and UVL-10 cells, suggesting that the loss in these cells was not due to enzymatic DNA-repair processes but to chemical lability of the adducts. Mutant frequencies at the APRT and HPRT loci were measured at BPDE-II doses that resulted in greater than 20% survival, and were found to increase linearly with dose. In the DNA-repair-deficient cells, the HPRT locus was moderately hypermutable compared with AT3-2 cells (about 5-fold); the APRT locus was extremely hypermutable, giving about 25-fold higher mutant fractions in UVL-1 and UVL-10 than in AT3-2 cells at equal initial levels of binding. When we compared the mutational efficiency of BPDE-II at both loci in AT3-2 cells (the mutant frequency in mutants/10(6) survivors at a dose that resulted in one adduct per 10(6) base pairs) with our previous studies of BPDE-1, we found that BPDE-II was 4-5 times less efficient as a mutagen than BPDE-I. This difference in mutational efficiency could be explained in part by the increased rate of loss of BPDE-II adducts from the cellular DNA, part of which was due to an increased rate of enzymatic removal of these lesions compared with the removal of BPDE-I adducts.
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PMID:Differences in the rate of DNA adduct removal and the efficiency of mutagenesis for two benzo[a]pyrene diol epoxides in CHO cells. 172 82

To gain insight into the mechanisms by which mutations are induced in human cells by carcinogens, we have determined the kinds and location (spectrum) of mutations induced in the coding region of the hypoxanthine (guanine) phosphoribosyltransferase (HPRT) gene by (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE). Individual populations of diploid human fibroblasts were treated with BPDE, or were left untreated (control). After a suitable expression period, the progeny cells were selected for resistance to 6-thioguanine. Individual drug-resistant colonies were isolated, and the mRNA in the lysate of 100-400 cells from each colony was copied directly into cDNA using reverse transcriptase. The cDNA of the HPRT gene of 29 unequivocally independent mutants from BPDE-treated populations and 13 from the control populations was amplified 10(11)-fold, and the product was sequenced directly. Twenty-three of the 29 BPDE-induced mutants examined contained a single base pair substitution; four exhibited two base pair substitutions. Eight out of 13 control mutants exhibited base pair substitutions, and four others were missing a complete exon. Thirty of the 32 base pair substitutions in the BPDE-induced mutants involved G.C base pairs, primarily G.C----T.A transversions. The majority (89%) of the base pair substitutions observed in the mutants from the control population involved an A.T base pair. Base substitutions were found throughout the coding region of the gene, but 41% of those seen in mutants from the BPDE-treated population and 44% of those from the untreated population were located in the first half of exon 3.
Carcinogenesis 1991 Jan
PMID:Kinds and location of mutations induced by (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene in the coding region of the hypoxanthine (guanine) phosphoribosyltransferase gene in diploid human fibroblasts. 189 56

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

Lonidiamine is a novel indazole-carboxylic acid with antitumour properties; it has been studied for potential mutagenicity in a comprehensive battery of tests. In assays for the induction of gene mutations in prokaryotes (Ames test) and eukaryotes (induction of HPRT mutations in CHO cells), negative results were obtained. There was no evidence of the induction of chromosomal damage in cultured mammalian cells in vitro. No mutagenic activity was observed in tests for chromosomal damage in vivo, in somatic cells (micronucleus test) or in germinal cells (dominant lethal test). These negative results are consistent with observations indicating that lonidamine affects cellular energy processes, rather than the mechanisms of cell division. The lack of mutagenic properties suggests that lonidamine may present significant advantages in treatment of some tumours, offering a reduced risk of resistant clones, secondary cancer and heritable genetic damage.
Carcinogenesis 1990 Sep
PMID:Lonidamine: a non-mutagenic antitumor agent. 240 Oct 42

Over the last few decades, free radicals have been increasingly implicated in biological processes including radiation effects, ageing, carcinogenesis, initiation and progression of various diseases, toxicity of chemicals and drugs. In this field Radiation Biology has played an important role in the development of both technical and cultural background, because it was very soon recognized the radical nature of processes following exposure to ionizing radiation. Several studies have pointed out the importance of both radicals, reacting with cellular targets, and endogenous thiols, mainly represented by glutathione, in controlling radiation responses of living cells. Experimental supports for such a role mainly rest on observations made on cell lines depleted of glutathione content because of a genetic defect or as result of a pharmacological manipulation. We present a study on the influence of endogenous and exogenous thiols on the correlation between lethal and mutational damage in mammalian cells. Survival (S) and induction of HPRT- mutation (M) were measured in cells irradiated with X-rays either after treatment with BSO or in the presence of MEA or GSH. In control experiments log of S is linearly correlated to M. Incubation with 1 mM BSO reduces cellular GSH content and produces an increase in radiosensitivity with regard to both lethal and mutagenic effects. In the presence of MEA a concentration dependent radioprotective effect can be observed on both end-points. GSH added to cells immediately or 90 min before irradiation only displays a slight protective effect on lethality. The yield of mutant cells is not significantly affected when GSH is added immediately before irradiation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The role of thiols in lethal and mutational radiation damage. 275 Nov 90

V79 Chinese hamster cells were cultured in the presence of 3-methylcholanthrene-diolepoxide (10r,9t-dihydroxy-7,8t-epoxy-tetrahydro-3-methylcholanthrene, MCDE) and mutants were selected in medium containing 6-thioguanine (TG). Of 22 TG-resistant mutants examined, 18 were devoid of HPRT (hypoxanthine-guanine phosphoribosyltransferase, EC 2.4.2.8) activity. Two mutants had suffered a total and one a partial gene deletion. The 1.6-kb HPRT mRNA was not detected in these three mutants nor in two others. The remaining mutants did not, however, have a readily demonstrable lesion.
Carcinogenesis 1985 Oct
PMID:On the mechanism of induction of resistance to 6-thioguanine in Chinese hamster V79 cells by 3-methylcholanthrene-diolepoxide. 299 1

Mouse mammary tumor virus (MMTV) has long been implicated in mouse mammary carcinogenesis, and it is now well established that the long terminal repeat (LTR) contains regulatory sequences responsible for glucocorticoid-mediated induction of viral RNA. However, we have demonstrated previously that androgens as well as glucocorticoids can regulate MMTV RNA in the S115 mouse mammary tumor cell line. To determine if androgens act directly on the LTR in these cells, plasmids were constructed with the MMTV LTR joined to the coding sequences of genes not normally expressed in the cells. Following transfection of these chimeric genes into S115 cells, we show that the expression of the genes is regulated by both androgens and glucocorticoids. Furthermore, hormonal regulation is also conferred by the LTR on the neighboring guanine phosphoribosyltransferase (gpt) gene. Thus, androgens can act on the LTR of MMTV when the appropriate receptors are present in the cells, and this interaction can influence the expression of additional adjacent genes.
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PMID:Androgen regulation by the long terminal repeat of mouse mammary tumor virus. 302 50


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