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)

The influence of sodium phenobarbital (PB) treatment on the sequence of N-nitrosomorpholine (NNM) induced focal preneoplastic lesions in the rat liver was investigated using a combined morphological and enzyme histochemical approach. Quantitative assessment of the different types of foci of altered hepatocytes visible in H&E sections after carcinogen application, namely the clear and acidophilic cell glycogen storage foci and mixed cell foci comprising glycogen storing cells and also more basophilic hepatocytes showing reduction in glycogen reserves, revealed a shift towards mixed cell character and greater size in PB-treated livers in comparison to those receiving NNM alone. Within the three dose levels of PB investigated (0.75, 0.075 or 0.0075 g/l drinking water) a clear dose dependence in appearance of mixed cell foci was apparent. Assessment of alterations in the activities of marker enzymes observed within preneoplastic foci was carried out by comparison of PAS preparations with sections reacted for glucose-6-phosphate dehydrogenase (G6PDH), gamma-glutamyl transpeptidase, glucose-6-phosphatase and adenosine triphosphatase. G6PDH proved the most consistent enzyme marker for small glycogen storage foci whereas larger foci of that type and mixed cell foci were associated with change in activity of all enzymes studied. The results are discussed in relation to the sequence of events occurring during hepatocarcinogenesis and the influence of PB on altered cellular populations. The applicability of enzyme markers is further considered in view of the question of heterogeneity within populations of preneoplastic foci.
Carcinogenesis 1983
PMID:Enhancement of NNM-induced carcinogenesis in the rat liver by phenobarbital: a combined morphological and enzyme histochemical approach. 613 86

Preneoplastic liver foci were produced in female Wistar rats by the administration of 2-acetylaminofluorene (0.03% w/w) in the diet for 174 days. Increased UDP-glucuronyltransferase (UDP-GT) could be visualized immunohistochemically in the same focal areas which were ATPase-negative and gamma-glutamyltranspeptidase-positive. Immunohistochemical detection was possible using rabbit anti-UDP-GT and peroxidase-labeled swine anti-rabbit immunoglobulins. The results of immunohistochemistry were substantiated by enzyme determination in microdissected material. UDP-GT activity was 5-fold higher in focal areas in comparison with the surrounding liver tissue. Increased UDP-GT activity in conjunction with the altered pattern of other drug-metabolizing enzymes is consistent with increased resistance of preneoplastic cells to the cytotoxicity of carcinogens. Immunohistochemical detection of UDP-GT may provide a new marker for preneoplastic lesions which, in conjunction with other markers, may prove useful in analyzing the various stages of liver carcinogenesis and the remodeling of preneoplastic lesions after cessation of carcinogenic stimuli.
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PMID:Immunohistochemical and biochemical detection of uridine-diphosphate-glucuronyltransferase (UDP-GT) activity in putative preneoplastic liver foci. 613 91

The effect of the technical mixture of polychlorinated biphenyls (PCBs) Clophen A 50 on the appearance of enzyme-altered islands initiated by diethylnitrosamine (DEN) in livers of 6 and 3 weeks old female Sprague-Dawley rats was studied. The loss of adenosine-5'-triphosphatase (ATPase), the emergence of gamma-glutamyltranspeptidase (GGTase), and the glycogen storage were used as histochemical markers. Islands were initiated by gastric intubation of 12 X 8 mg DEN/kg body weight/day in adults, or with 1 X 8 mg DEN/kg body weight in weanlings. Clophen A 50 alone initiated only few islands. A dose-dependent enhancement in number and area of islands by an additional treatment with Clophen A 50 of DEN-pretreated animals (2-100 mg/kg body weight/weekly, for 7 weeks) was observed in both age groups. In adults, doses between 2 and 100 mg/kg body weight increased number and area of ATPase-deficient islands 2 to 12-fold. In weanlings, application of 10-100 mg/kg body weight resulted in an increase of number and area up to 7- and 12-fold, respectively. No promoting effect was found with 2 mg/kg body weight compared to DEN-treated weanlings. The number of islands with coincidence of the three histochemical markers was enhanced dose-dependently in adults, and less marked also in weanlings after the application of the promoter.
Carcinogenesis 1984 Mar
PMID:Dose-dependent promoting effect of polychlorinated biphenyls on enzyme-altered islands in livers of adult and weanling rats. 614 72

Female Wistar rats were treated sequentially with 4-dimethylaminoazobenzene (4-DAB) and N-nitrosodiethanolamine ( NDEOL ) for periods of 6 weeks. One group received first 4-DAB (0.06% in the diet) and NDEOL (2000 p.p.m. in the drinking water) thereafter, while the second group was treated in the reversed sequence; control groups received the single agent alone. The extent of foci negative for adenosine-triphosphatase (ATPase) or positive for gamma-glutamyl-transpeptidase (gamma-GT)-activity was quantitated in liver as a means to assess carcinogenic efficacy. A very low response was obtained in rats treated first with 4-DAB and then with NDEOL whereas a strong increase in number and especially in size of foci was observed when 4-DAB was given after NDEOL . The response in this latter group was clearly over-additive. Treatment of rats with either carcinogen alone resulted in similar pattern of increases in the volumetric fraction of liver occupied by ATPase-deficient foci. A differential behaviour, however, was observed with respect to islet size. NDEOL produced large numbers of small foci whereas with 4-DAB only few foci were obtained which grew rapidly in the presence of the carcinogen. These findings are consistent with the hypothesis that 4-DAB, besides acting as an initiator, has very strong promoting activity as was to be expected from the characteristic relationship between carcinogen dose and time of liver tumour induction.
Carcinogenesis 1984 Jun
PMID:Promoting effect of 4-dimethylaminoazobenzene on enzyme altered foci induced in rat liver by N-nitrosodiethanolamine. 614 2

The roles of chloroethylene oxide (CEO) and chloroacetaldehyde (CAA) in carcinogenicity of vinyl chloride (VC) have been studied by comparing biological effects of VC exposure with those of 2,2'-dichlorodiethylether (bis(chloroethyl)ether, BCEE) as a metabolic precursor of CAA. Biological end-points investigated were covalent protein binding, nucleic acid (RNA and DNA) alkylation and the potency of the two chemicals to induce preneoplastic ATPase-deficient foci in rat liver. After exposure of rats to [1-14C]BCEE, BCEE derived radioactivity was bound to liver proteins. Analysis of hydrolysates of liver RNA and DNA gave no indication for the formation of either 7-N-(2-oxoethyl)guanine, 1,N6-ethenoadenine or 3,N4-ethenocytosine residues within the nucleic acids. After application of VC, BCEE or chloroethanol [CE), also a precursor of CAA) to young rats, only animals exposed to VC developed preneoplastic hepatocellular ATPase-deficient foci. From these investigations it is concluded, that CEO (which is not formed during metabolism of BCEE and CE), not CAA, is the ultimate carcinogenic principle in VC carcinogenicity.
Carcinogenesis 1983 Nov
PMID:Evidence of chloroethylene oxide being the reactive metabolite of vinyl chloride towards DNA: comparative studies with 2,2'-dichlorodiethylether. 619 38

One, two, and three applications of DMBA in mineral oil to hamster buccal pouch mucosa did not result in obvious histologic alterations in experimental periods ranging from 4 1/2 hours to 2 weeks after the last DMBA application. However, there were significant increases in the number of Langerhans cells, as disclosed histochemically with ATPase staining. There was also an increase in the length and size of the dendritic processes of the Langerhans cells. Applications of DMBA in oil resulted in a consistently significant increase in Langerhans cells when compared to the buccal pouch mucosa of untreated animals. However, mineral oil applications also resulted in a slight increase in Langerhans cells when compared to the mucosa of untreated controls. The major effects of the DMBA on Langerhans cells occurred after 2 weeks and with increasing numbers of applications. The increase in Langerhans cells is interpreted as an enhanced response by immunologically competent cells which may represent an early immune response to the very early changes in carcinogenesis.
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PMID:Acute effect of DMBA application on Langerhans cells of the hamster buccal pouch mucosa. 620 76

Altered transport of nuclear RNA sequences is an early response to carcinogens. Nuclear envelopes (NE) were isolated and assayed for nucleoside triphosphatase activity (NTPase), on the premise that this enzymatic activity participates in RNA transport. A common feature of the action of five different carcinogens (thioacetamide, 2-acetylaminofluorene, 3'-methyl-4-dimethylaminoazobenzene, dimethylnitrosamine, and aflatoxin B1), at low doses without significant toxicity, was to increase NE NTPase activity and to increase RNA transport, as assessed by the appearance of rapidly labeled RNA in the cytoplasm and by in vitro assay. The increases in NTPase were specific for the NE fraction, and early toxic effects of higher doses initially masked the increases. The induced increases in NE NTPase were long-lived. In contrast, increases in NE NTPase were observed only during the regenerative phase of CCl4 intoxication; the CCl4-induced increase was short-lived and returned promptly to control levels. These changes in NTPase activity were not associated with parallel changes in phosphorylation/dephosphorylation of NE proteins. Increases in NE NTPase and alterations in RNA transport, without attendant nuclear replication, may relate to altered nuclear RNA restriction. This change in a regulatory phenomenon may make these cells more susceptible to further modification, potentially playing a role in the initiation phase of carcinogenesis.
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PMID:Increased nucleoside triphosphatase activity of rat liver nuclear envelope is associated with hepatocarcinogen exposure. 620 70

The promoting effect of Clophen A 50, a commercial mixture of polychlorinated biphenyls (PCBs) on preneoplastic islands, initiated by diethylnitrosamine (DEN), was studied in male and female Sprague-Dawley rats. The islands were identified histochemically by loss of adenosine-5'-triphosphatase (ATPase) and/or emergence of gamma-glutamyltranspeptidase (GGTase). Treatment with 12 X 8 mg DEN/kg body wt./day initiated a similar number and total area of islands in males and females. Additional weekly application of Clophen A 50 (50 or 100 mg/kg body wt./week, for 7 weeks) enhanced the number of ATPase-deficient islands 3-fold in males and 9-fold in females. The total area was increased 4-fold in males and 15-fold in females. Number and area of GGTase-positive islands were similarly enhanced. The emergence of a small number of islands after application of Clophen A 50 alone may indicate a weak carcinogenic potency. PCB treatment caused an increase in liver weight, which amounted to approximately 55% in males and 20% in females compared to controls. This increase is partly due to cell hypertrophy, as indicated by determination of cell size. The mitogenic activity of Clophen A 50 was evaluated by measurement of the mitotic index of unaltered hepatocytes at 24, 48 h, and 7 days after application of a single dose (100/mg/kg body wt.) of Clophen A 50. The mitotic index in control animals of both sexes was approximately 0.3%, and was enhanced approximately 8-fold in males, 24 h after PCB treatment. In females only a slight, non-significant increase was observed. The results indicate that the sex-dependent promoting effect of Clophen A 50 is independent from its mitogenic action.
Carcinogenesis 1982
PMID:Sex-dependent promoting effect of polychlorinated biphenyls on enzyme-altered islands induced by diethylnitrosamine in rat liver. 621 18

The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) influences neither the State 3 nor the State 4 respiration in rat liver mitochondria. The respiratory control and ADP/O ratio were also unaffected by TPA. The oligomycin-sensitive ATPase activity in submitochondrial particles remained unaltered upon TPA addition, whereas the NADH oxidase activity was slightly inhibited at a very high concentration of TPA (15% decrease at 17 microM TPA). The activity of the superoxide dismutase located to the mitochondria was insensitive to the tumor promoter, and no change in the rate of H2O2 production was found on TPA treatment in vitro. Thus, the mitochondrion is not a likely candidate for the site of action of the tumor promoter.
Carcinogenesis 1983
PMID:Oxygen uptake, ATPase activity, and superoxide dismutase activity in isolated rat liver mitochondria are not influenced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate. 622 26

Chronic exposure of rodents to high dose levels of drugs, food additives and environmental chemicals frequently results in liver enlargement. Several of these compounds have been found to enhance the incidence of liver tumors in animals briefly exposed previously to hepatocarcinogens. Accordingly, it has been advanced that these agents act as tumor promoters. This contention has remained subject of controversy following reports that these substances may also cause liver tumors in noncarcinogen-treated rodents, particularly in those characterized by a relatively high incidence of "spontaneous" liver tumors. Since many of these chemicals are in common use, a crucial question would seem to be whether such effects are due to facilitation of the expression of pre-existing oncogenic potential, i.e., to tumor promotion, or to the synergistic action of weakly carcinogenic agents. As a result of mechanistic differences tumor promotion and syn-carcinogenesis must exhibit different dose-time-response characteristics, and, accordingly, it should be possible, in principle, to discriminate between these phenomena. However, since tumor manifestation periods in low-dose groups frequently exceed the animals average lifespan, this approach may not always yield conclusive data, unless a sensitive early marker of carcinogenic activity can be employed. There is evidence that enzyme-deficient preneoplastic areas in liver can be used for this purpose. A strong quantitative correlation between carcinogen dose, the extent of ATPase deficient areas, and the subsequent appearance of tumors has now been established for a number of hepatocarcinogens. Experimental data are consistent with the concept that two critical events (hits) are required for induction of ATPase deficiency in hepatocytes. The first hit is carcinogen-dependent, whereas the second hit would seem to be due to time-dependent event(s). Tumor-promoters, such as phenobarbital, were found to accelerate and increase formation of preneoplastic islets. This evidence, together with data indicating that the compound is devoid of carcinogenic potential, suggests that phenobarbital may be operative at relatively early stages of hepatocarcinogenesis by increasing the probability of the occurrence of the time-dependent second hit. Such effects are dose-dependent and appear to be related to the induction of liver enlargement. The changes in hepatocellular ploidy status and atypical nuclear figures observed during phenobarbital treatment and cessation thereof, suggest that this compound might induce abnormal redistributions of genetic material. It is postulated that these cytological changes may result in phenotypical manifestation of recessive oncogenic information.
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PMID:Quantitative aspects of chemical carcinogenesis and tumor promotion in liver. 622 10


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