Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ouabain resistance (ouar) and 6-thioguanine resistance (6-TGr) mutation frequencies were measured in Chinese hamster ovary cells after treatment with N-ethyl-N-nitrosourea (ENU) for varying periods of time. Maximal mutation frequency at the Na+/K+ ATPase gene locus (ouar mutations) was attained within 5 min of exposure, whereas the mutation frequency at the hypoxanthine guanine phosphoribosyltransferase locus (6-TGr mutations) continued to increase up to 60 min, following the theoretical curve for exponential decay of ENU with time. Detection of DNA single strand breaks (ssb) by alkaline elution showed that maximal levels were attained within 5 min of treatment with ENU. Fast repair of DNA ssb occurred early after exposure (greater than 50% repair within 10 min). Analysis of DNA ethylation products by h.p.l.c. showed initially rapid removal of O2-ethylcytosine (25% in the first hour), slow removal of 7-ethylguanine, 3-ethyladenine and 3-ethylguanine and no removal at all of O6-ethylguanine, O4-ethylthymine and ethylphosphotriesters. These time-course studies reveal different target gene responses in the fixation of DNA damage into mutations.
Carcinogenesis 1987 Jan
PMID:Induction kinetics of mutations at two genetic loci, DNA damage and repair in CHO cells after different exposure times to N-ethyl-N-nitrosourea. 302 80

Preneoplastic liver lesions were produced in female Wistar rats by oral administration of 2-acetylaminofluorene for 165 days succeeded by a carcinogen-free standard diet up to 420 days. During the treatment numerous altered hepatic foci (AHF) and hyperplastic nodules (HN) were detected histochemically by a focal decrease or lack of adenosine-5-triphosphatase and glucose-6-phosphatase (G-6-Pase) activities. In addition, the immunohistochemically demonstrable amount of L-type pyruvate kinase was clearly reduced. The histochemically demonstrated decrease of G-6-Pase was substantiated by microbiochemical determination of the enzyme activity in microdissected material. Moreover, during the experimental period a continuous decrease in glucokinase and an increase in hexokinase was detected microbiochemically within AHF and HN. These alterations indicate a shift in the carbohydrate metabolism from gluconeogenesis to glucose utilization and pentose-phosphate-pathway for biosynthesis of nucleic acids. Beside other oncofetal markers, HK may be used as indicator of the early stages of liver carcinogenesis.
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PMID:Decrease in glucokinase and glucose-6-phosphatase and increase in hexokinase in putative preneoplastic lesions of rat liver. 304 Jul 65

The age-dependence of the induction of pre-neoplastic enzyme-altered hepatic foci was investigated. Rats were exposed (8 h/day, 7 days/week) to 2000 p.p.m. vinyl chloride (VC) either 'transplacentally' (exposure of pregnant females), or immediately after birth for different time intervals (5, 11, 17, 47, 83 days) or from an age of 7 or 21 days onwards. The animals were then kept without further treatment; livers were evaluated for ATPase-deficient foci at the age of 4 months. 'Transplacental' exposure and exposure from day 1 through 5 caused no increase over controls in ATPase-deficient foci, probably due to the lack of hepatocellular proliferation and the low rate of VC metabolism at this developmental stage. However, foci area was steeply increased when newborn rats were exposed for 11 and 17 days; but this was not further enhanced by a 47- or 83-day exposure. Only a few ATPase-deficient foci occurred when exposure started 21 days after birth. Exposure of adult rats did not result in more ATPase-deficient foci than were seen in untreated controls; control values could not be increased by a preceding partial hepatectomy. The results indicate that the induction of pre-neoplastic hepatocellular lesions in rats by VC is restricted to a well defined period (approximately day 7-21) in the early lifetime of the animals. This period of highest sensitivity is characterized by the beginning of rapid liver growth.
Carcinogenesis 1985 Jan
PMID:The rat liver foci bioassay: I. Age-dependence of induction by vinyl chloride of ATPase-deficient foci. 315 70

In order to study the dose-dependence of the genotoxic effect of vinyl chloride (VC) hepatocellular ATPase-deficient foci were evaluated after subchronic exposure of newborn rats. Wistar rats were exposed from day 1 after birth over 10 weeks to 10, 40, 70, 150, 500 and 2000 p.p.m. VC (8 h/day; 5 days/week). One week after cessation of exposure hepatic ATPase-deficient foci were quantitated. For a subsequent investigation lower dose range groups of female and male Wistar and Sprague-Dawley rats were exposed (8 h/day; 5 days/week) to 2.5, 5, 10, 20, 40 and 80 p.p.m. VC. Exposure started at day 3 of life and lasted for 3 weeks. After cessation of exposure the animals were maintained for 10 weeks without further treatment until ATPase-deficient foci were quantitated. Both sets of experiments revealed a straight linear relationship between the dose of VC and the % foci area induced. Within the dose range investigated, no obvious threshold for the induction of pre-neoplastic foci by VC was observed.
Carcinogenesis 1985 Jan
PMID:The rat liver foci bioassay: II. Investigations on the dose-dependent induction of ATPase-deficient foci by vinyl chloride at very low doses. 315 71

Female F-344 rats were fed a diet containing up to 1.2% di(2-ethylhexyl)phthalate (DEHP) for 2 years, which previously resulted in hepatocarcinogenesis under bioassay conditions. Peroxisome proliferation, decreased glutathione peroxidase activity, and lipofuscin accumulation were all associated with prolonged feeding of 1.2% DEHP and induction of hepatic neoplasia. These results establish a potential role for persistent peroxisome proliferation and oxidative injury in the hepatocarcinogenicity of dietary DEHP. Increased hepatocellular proliferation and hepatomegaly were not detected. DEHP feeding did not increase the volume density of basophilic or ATPase-deficient foci of altered hepatocytes, suggesting that these lesions are not suitable indicators of DEHP carcinogenesis.
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PMID:Association of persistent peroxisome proliferation and oxidative injury with hepatocarcinogenicity in female F-344 rats fed di(2-ethylhexyl)phthalate for 2 years. 369 May 5

C3H10T1/2 cells have been found to be relatively insensitive to transformation by N-ethyl-N-nitrosourea (ENU) and some other strongly carcinogenic, direct-acting, monofunctional alkylating agents. Because these agents are strong inducers of gene mutations we have considered the possibility that they transform 10T1/2 cells through a gene mutation. Such an event could have been missed in the standard assay, in which relatively low numbers of cells are treated. We found that the yield of ENU-induced transformed foci could be increased drastically by increasing the seeding density (up to 10(4) viable cells/cm2). The transformation frequency (foci/survivor) after ENU treatment was lower but much less dependent on cell density than after 3-methylcholanthrene. To investigate the mechanism of transformation by ENU in more detail, we used a modified transformation protocol which involved treatment of the cells at high density, followed by a period of exponential growth and reseeding at high density for focus selection. We found that ENU-induced transformation frequency is independent of the length of the growth period, thus independent of the total number of posttreatment cell divisions. This means that the focus-forming ability is completely fixed within maximally four generations. The transformation frequency does, however, depend on the number of divisions between the final reseeding and confluence. This suggests that the phenotypic expression of at least a part of the ENU-induced transformants is influenced by their clone size at confluence. Finally, we observed that the dose dependency of transformation was qualitatively and quantitatively similar to that of mutation at the Na-K-ATPase locus. Together, these experiments indicate that transformation of C3H10T1/2 cells by ENU is the result of a single, low frequency event, probably a gene mutation.
Carcinogenesis 1986 Aug
PMID:Transformation of C3H10T1/2 cells by N-ethyl-N-nitrosourea occurs as a single, low frequency, mutation-like event. 373 93

Nitrosamine-induced hepatocarcinogenesis has been used to investigate the regulation and expression of different drug-metabolizing enzymes in preneoplastic and neoplastic lesions in the female Wistar rat. The enzymes investigated were two phenobarbital-inducible cytochrome P-450 (cyt. P-450) isoenzymes (PB1 and PB2, mol. wt. 52 000 and 53 500, respectively), two 3-methylcholanthrene-inducible forms (MC1 and MC2, mol. wt. 54 500 and 57 000, respectively), NADPH-cytochrome P-450 reductase, the cytosolic glutathione transferases (GSTs) B and C and the microsomal epoxide hydrolase with broad substrate specificity (mEHb). Carcinogen-induced lesions were identified by use of the known markers of hepatocarcinogenesis adenosinetriphosphatase and gamma-glutamyl transpeptidase. While the GSTs and mEHb were increased in all preneoplastic and neoplastic lesions, the levels of the individual cyt. P-450 isoenzymes were characteristically different from each other. In many of the early ATPase deficient islets PB1 was elevated, whereas the content of the other cyt. P-450 forms and NADPH-cytochrome P-450 reductase was either unchanged or slightly lowered. At later stages of hepatocarcinogenesis PB1 returned to the levels of the surrounding tissue, while the other cyt. P-450 isoenzymes were decreased, the most prominent reduction being found in MC1. In neoplastic nodules all the cyt. P-450s and NADPH-cyt. P-450 reductase were diminished, some of them dramatically. These findings indicate that in spite of a common response of groups of P-450s to inducing agents, individual P-450 isoenzymes are also regulated separately. Moreover, the constant elevation of mEHb and GSTs in all lesions investigated in this study demonstrates that these enzymes, which are largely involved in deactivation, are regulated in a different fashion from the predominantly carcinogen-activating monooxygenases. The observed differences in enzyme pattern may provide a useful method for subdividing and categorizing preneoplastic and neoplastic lesions.
Carcinogenesis 1985 Apr
PMID:Regulation and expression of four cytochrome P-450 isoenzymes, NADPH-cytochrome P-450 reductase, the glutathione transferases B and C and microsomal epoxide hydrolase in preneoplastic and neoplastic lesions in rat liver. 392 Dec 70

Previous research by the authors had suggested that uridine-diphosphate-glucuronyl-transferase (UDP-GT) is a useful preneoplastic marker in chemical carcinogenesis. Recently the authors report that they found typical clear cell foci in a macroscopically normal liver surrounding focal nodular hyperplasia with a 6 cm diameter in a 27-year old woman who had been using oral contraceptives (OCs) containing ethinyl-estradiol and lynestrenol for 9 years. These foci were further characterized by a reduction of canalicular and cytoplasmic ATPase activity, an increased glycogen content, and a positive immunohistochemical reaction for UDP-GT. OC users develop 2 basic types of benign liver tumors: hepatic adenoma and focal nodular hyperplasia. Hepatic adenoma appears to be caused by OCs, whereas the relationship between OC use and focal nodular hyperplasia is less clear. The tumorigenic action of OCs has been ascribed to a promotor action on liver cells; however, there is no evidence that OCs are initiators of liver tumors. The case reported shows 2 manifestations of toxic lesions promoted by OC use: the development of focal nodular hyperplasia and enzyme-altered foci comparable to those seen in experimental liver carcinogenesis. Further studies are needed to get more information about the preneoplastic potential of these foci in humans. Since enzyme-altered foci could not be identified in the liver tissue of healthy women, these foci may be of prognostic significance in longterm OC users.
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PMID:Increased UDP-glucuronyltransferase in putative preneoplastic foci of human liver after long-term use of oral contraceptives. 392 52

Enzyme biochemical and histochemical assays during chemical carcinogenesis in rat liver have revealed that several adult enzyme activities are lost and some fetal enzyme activities are re-expressed in the hyperplastic foci as well as in the developed hepatomas. How these enzyme alterations are acquired and to what extent these changes are specifically related to the growth alterations leading to neoplastic development are decisive questions. Using a carcinogenesis protocol that combines a single dose of diethylnitrosamine and phenobarbital given continuously as the promoting agent and by assaying serial liver sections for glucose-6-phosphatase, adenosine-5'-triphosphatase and 5'-nucleotidase, we have identified the three-enzyme pattern of 1,746 islands and measured their section areas. We found a clear trend that clones with more deviated enzyme pattern grow faster than less deviated ones.
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PMID:Enzyme pattern and growth rate of liver preneoplastic clones during carcinogenesis by diethylnitrosamine. 608 33

This study was undertaken to answer the following question. Is the phenotypic diversity that is characteristic of hepatocellular carcinomas acquired early during carcinogenesis, or is it more likely to be a property added late in the process? This question was posed using a new model for the sequential analysis of hepatocarcinogenesis. This model utilizes a single initiating dose of a carcinogen, such as diethylnitrosamine, followed by the selective stimulation of the rare, initiated hepatocyte to proliferate under conditions in which the proliferation of the majority of uninitiated hepatocytes is inhibited. Under these conditions, discrete early foci of altered hepatocytes and hyperplastic foci and nodules are quite well synchronized for about 10 to 12 cell cycles, after which the synchrony is progressively lost. As phenotypic expressions, cell proliferation, judged by radioautography after the administration of [3H]thymidine and the activities of four enzyme markers, two positive ones, gamma-glutamyltranspeptidase and DT-diaphorase, and two negative ones, glucose-6-phosphatase and adenosine triphosphatase, all judged histochemically, were used. At the earliest time of observation, 7 days, and at subsequent time points thereafter, all histologically recognizable foci and nodules showed variable degrees of staining for each enzyme activity. Prior to selection, gamma-glutamyltranspeptidase activity was much more consistent than was that of the others; however, during and after the selection, the four markers showed almost the same consistency among developing lesions. During the period of selection, between 80 and 90% of hepatocytes in the proliferating nodules were labeled with [3H]thymidine, while only an occasional labeled hepatocyte was seen in the foci prior to selection and in the nodules following selection. In the postselection period, the majority of nodules acquired the histochemical and architectural properties of normal liver, while a minority persisted as typical hyperplastic nodules. This study suggests that phenotypes of carcinogen-altered hepatocytes are variable, but whether the histochemical diversity among the lesions is merely due to environmental variation or is a reflection of a more basic genotypic variability remains a fundamental question.
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PMID:Phenotypic diversity as an early property of putative preneoplastic hepatocyte populations in liver carcinogenesis. 611 Apr 77


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