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 used liposomes to deliver DNAase I inside normal Syrian hamster embryo (SHE) cells. We showed the entrance of DNAase I inside the cell by dose-dependent cytotoxicity; and the entrance of DNAase I into the nucleus by the induction of chromosomal aberrations and somatic mutation at the HPRT locus (but not at the Na+/K+ ATPase locus). The induction of neoplastic transformation in cultures treated by DNAase I-in-liposomes was manifested by increased saturation density, colony formation at low seeding density, colony formation in 1% serum and 0.3% agar, and tumorigenicity in 100% of injected animals. The acquisition of anchorage-independent growth became apparent only after 39-57 posttreatment population doublings. Thus damage to DNA alone can initiate the neoplastic transformation process; but for full expression of the neoplastic phenotypes, a long progression time is required for the acquisition of anchorage-independent growth and tumorigenicity.
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PMID:DNAase I encapsulated in liposomes can induce neoplastic transformation of Syrian hamster embryo cells in culture. 650 50

As part of the International Workshop on Standardization of Genotoxicity Test Procedures, in Melbourne, 27-28 February 1993, various international guidelines were examined with respect to protocol issues in the area of mammalian cell gene mutation assays. The working group on mammalian cell gene mutation assays discussed a wide range of protocol issues related to study design; in most cases the recommendations are reasonably consistent with existing guidelines. Agreement was reached on several issues as follows. The upper limit of concentration for testing non-toxic substances should be 10 mM or 5 mg/ml, whichever is lower. For testing toxic substances the criteria of an acceptable upper limit of concentration should yield 10-20% survival. Any of several established mammalian cell mutation assays (L5178Y TK+/-, CHO/HPRT, AS52/XPRT, V79/HPRT) can be used to evaluate mutagenesis in mammalian cells; the ouabain (Na/K-ATPase) system is not an acceptable mutation assay for routine evaluation of mutagenesis in mammalian cells. Ability to recover small colonies must be convincingly demonstrated when using the L5178Y TK+/- mouse lymphoma assay. In the mouse lymphoma assay (L5178Y TK+/-), colonies in positive controls and at least two (if available) representative positive doses of the test compound should be sized if a positive response is seen; in the event of a negative response due to the test compound, colony sizing of the positive control is necessary to validate the conduct of the assay. Testing both in the presence and absence of S9 metabolic activation is necessary. It was not possible to come to a firm conclusion about the length of treatment. There was a general agreement that extended treatment times (> 2 cell cycles) often bear more disadvantages than advantages and should only be used with adequate justification. It is not necessary to repeat clear positive or clear negative tests when the assay has been adequately performed; this recommendation differs significantly from the UK guidelines. If treatment groups are not replicated, the numbers of doses tested should be increased; this recommendation differs significantly from the UK guidelines. Each laboratory should establish a historical database for the performance of a given assay in that laboratory.
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PMID:Mammalian cell gene mutation assays working group report. 751 37

The genotoxic effects induced by the monofunctional nitrosourea derivative streptozotocin (STZ) were investigated in Chinese hamster ovary cells, parental (CHO-9) and its mutant hypersensitive to alkylating agents, designated EM-C11. The ability of this compound to induce chromosomal aberrations, cell killing, sister-chromatid exchanges (SCEs) and mutations was evaluated on these two cell lines. The mutant cells were found to be slightly more sensitive to the killing effects of STZ than the parental cell line. EM-C11 cells also showed higher levels of STZ-induced chromosomal aberrations than CHO-9 cells, but appeared to be equally sensitive to induction of SCEs. The frequencies of STZ-induced mutations, measured as resistant Na+/K(+)-ATPase and HPRT mutants, revealed a higher sensitivity of EM-C11 to the mutagenic effects of this compound.
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PMID:Streptozotocin-induced chromosomal aberrations, SCEs and mutations in CHO-9 parental cells and in EM-C11 mutant cell line. 752 88

Testosterone, testosterone propionate, 17 beta-trenbolone and progesterone, which represent the main endogenous and synthetic androgens and a progestin, were evaluated for possible cell transformation and genetic effects in Syrian hamster embryo (SHE) cells. Cell growth was reduced by treatment with the steroids at 10-30 micrograms/ml in a dose-related manner. Testosterone and testosterone propionate were less toxic than the other two steroids. Testosterone, testosterone propionate and progesterone induced morphological transformation of SHE cells with similar transformation frequencies. The most potent effects were observed with testosterone propionate, which induced cell transformation at 1-30 micrograms/ml in a dose-related manner. Testosterone and progesterone transformed cells only at the highest dose (30 micrograms/ml). 17 beta-Trenbolone did not induce a statistically significant level of cell transformations at any dose tested (up to 30 micrograms/ml). The transformation frequencies induced by testosterone, testosterone propionate and progesterone were less than one-half that induced by benzo[a]pyrene at 1 microgram/ml. None of these steroids induced significant increases in frequencies of chromosome aberrations or aneuploidy. Gene mutations were not observed for testosterone at the HPRT or Na+/K+ ATPase locus. Because these steroids are also associated with carcinogenic activity in vivo, these in vitro findings provide a model and new insights into the study of the mechanisms of androgen- and progestin-induced cell transformation.
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PMID:Effects of testosterone, testosterone propionate, 17 beta-trenbolone and progesterone on cell transformation and mutagenesis in Syrian hamster embryo cells. 778 50

6-Sulfooxymethylbenzo[a]pyrene (SMBP) is an ultimate and reactive form of 6-hydroxymethybenzo[a]pyrene (HMBP), which is converted into SMBP by the mediation of sulfotransferase. SMBP and HMBP with metabolic activation were mutagenic to S. typhimurium TA98 and TA100. The number of mutation per plate in strain TA98 was proportional to the concentrations of SMBP ranging from 0.2 to 1.0 nmol/plate, whereas that in strain TA100 was decreased at concentrations above 0.6 nmol/plate. The mutation frequencies by HMBP was also increased in a dose dependent manner in both strains. Furthermore, SMBP and HMBP were highly mutagenic and cytotoxic to Chinese hamster lung fibroblast (V79) cells. A dose-dependent increase in mutation frequencies at both hypoxanthine:guanine phosphoribosyltransferase (HGPRT) and sodium/potassium-ATPase (Na/K-ATPase) loci were found in V79 cells treated with SMBP and HMBP. The cytotoxicity of SMBP was increased with the increasing concentrations up to 2.5 microM, where the survival frequency and growth rate were decreased to almost 40% and 30% of the control value, respectively. The survival frequencies of V79 cells by HMBP were also decreased in a dose dependent manner up to 180 microM as similar to those of SMBP but the effects were less remarkable. SMBP was progressively accumulated in V79 cells, reaching plateau in just 30 min. A dose dependent increase in complex formation with DNA or proteins was observed by treatment with SMBP. The mutagenicity and cytotoxicity of SMBP and HMBP may be derived from their binding capacity to DNA in V79 cells and S. typhimurium.
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PMID:Mutagenicity of 6-sulfooxymethylbenzo[a]pyrene in Salmonella typhimurium and Chinese hamster V79 cells. 954 51

The JAK2(V617F) mutation is frequently observed in classical myeloproliferative disorders, and disease progression is associated with a biallelic acquisition of the mutation occurring by mitotic recombination. In this study, we examined whether JAK2 activation could lead to increased homologous recombination (HR) and genetic instability. In a Ba/F3 cell line expressing the erythropoietin (EPO) receptor, mutant JAK2(V617F) and, to a lesser extent, wild-type (wt) JAK2 induced an increase in HR activity in the presence of EPO without modifying nonhomologous end-joining efficiency. Moreover, a marked augmentation in HR activity was found in CD34(+)-derived cells isolated from patients with polycythemia vera or primitive myelofibrosis compared with control samples. This increase was associated with a spontaneous RAD51 foci formation. As a result, sister chromatid exchange was 50% augmented in JAK2(V617F) Ba/F3 cells compared with JAK2wt cells. Moreover, JAK2 activation increased centrosome and ploidy abnormalities. Finally, in JAK2(V617F) Ba/F3 cells, we found a 100-fold and 10-fold increase in mutagenesis at the HPRT and Na/K ATPase loci, respectively. Together, this work highlights a new molecular mechanism for HR regulation mediated by JAK2 and more efficiently by JAK2(V617F). Our study might provide some keys to understand how a single mutation can give rise to different pathologies.
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PMID:JAK2 stimulates homologous recombination and genetic instability: potential implication in the heterogeneity of myeloproliferative disorders. 1851 59


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