Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.3.9 (glucose-6-phosphatase)
 3,081 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
Cancer Res 1980 Mar
PMID:Phenotypic diversity as an early property of putative preneoplastic hepatocyte populations in liver carcinogenesis. 611 Apr 77

Characteristic alterations of marker enzymes and tumor-associated antigens have been detected in the preneoplastic lesions of experimental hepatocarcinogenesis. An identical pattern of enzyme activity (increased gammaglutamyl transferase, loss of glucose-6-phosphatase, and canalicular adenosine triphosphatase) was demonstrated in a case of nodular "regenerative" hyperplasia of liver. The lack of marker antigens (alphafetoprotein, carcinoembryonic antigen, alpha 1-antitrypsin) in the hyperplastic nodules in this patient may be related to the discontinuation of oral contraceptive steroids four years earlier. The phenotypic changes of enzyme activity suggest that nodular "regenerative" hyperplasia of the liver in man is preneoplastic.
Cancer 1981 Apr 01
PMID:Enzyme pattern and marker antigens in nodular "regenerative" hyperplasia of the liver. 611 60

A marked heterogeneity of enzyme histochemical phenotypes was demonstrated in 48 primary hepatocellular carcinomas induced by feeding 2-acetylaminofluorene to rats. All eight possible combinations of three abnormal traits, gain of gamma-glutamyl transpeptidase activity, loss of adenosine-5'-triphosphatase activity, and loss of glucose-6-phosphatase activity, were represented among the hepatocellular carcinomas. The four combinations in which two or three traits occurred together were seen in 85% of the carcinomas, while those categories with a normal phenotype or containing only single marker changes contained the few remaining neoplasms. As expected, the carcinomas all showed greatly increased and variable [3H]thymidine labeling indices; however, neither the rates of cell replication or the degrees of differentiation of the carcinomas appeared to correlate in any meaningful way with the patterns of phenotypic diversity. The distribution of histochemical phenotypes in the carcinomas differs greatly from that reported for enzyme-altered hyperplastic islands induced by carcinogens, but the significance of the difference is not apparent at the present time.
Cancer Res 1981 Jun
PMID:Enzyme histochemical phenotypes in primary hepatocellular carcinomas. 611 49

An oval cell-enriched population was isolated using two isopyknic centrifugation steps in Percoll gradients from the livers of young adult male rats maintained for 6 to 12 weeks on a choline-deficient diet containing 0.05% DL-ethionine. This cell population equilibrated sharply at densities ranging between 1.07 and 1.08 g/ml, possessed a mean cell diameter in fixed-cell smears of 13.6 micron, and showed viabilities of greater than 95% as judged by trypan blue dye exclusion. Contamination of this population by hepatocytes and Kupffer cells was determined to be less than 1% and between 4 and 14%, respectively. gamma-Glutamyl transpeptidase activity was demonstrated both biochemically and histochemically to be the most constant marker for evaluating the oval cell-enriched population isolated at various times over the 6 to 12 weeks of the choline-deficient/DL-ethionine dietary regimen. In contrast, the percentages of nonhepatocytic cells showing labeling for DNA synthesis and for alpha-fetoprotein were both found to be the highest in the oval cell-enriched population isolated at 6 weeks and lowest in that obtained at 12 weeks of dietary treatment. Furthermore, at 10 to 11 weeks, 19.2% of the nonhepatocytic cells in this population were positive for albumin, while 2.1% were positive for glucose-6-phosphatase activity, indicating some cells to be intermediate in function between the oval cell and the hepatocyte. In comparison, hyperplastic bile ductular epithelial cells in tissue preparations isolated from the livers of rats previously subjected to 13 weeks of chronic feeding of the noncarcinogenic cholestatic agent, 1-naphthyl isothiocyanate, or at 8 to 13 weeks following bile duct ligation were found to be strongly positive for gamma-glutamyl transpeptidase activity, as well as to be positive for alkaline phosphatase activity, but to be essentially negative for glucose-6-phosphatase activity, glycogen content, and albumin production. However, an occasional bile ductular cell in these preparations was found to exhibit a strong cytoplasmic binding of [6,7-3H]estradiol, an indirect measure of alpha-fetoprotein production. Also, a low, but demonstrable amount of DNA synthesis was noted in the bile ductular cells present in these preparations. Furthermore, a viable cell population highly enriched in bile ductular epithelial cells was isolated by isopyknic centrifugation in Percoll following enzymatic dissociation of the hyperplastic tissue preparation from bile duct ligated rats.(ABSTRACT TRUNCATED AT 400 WORDS)
Cancer Res 1984 Aug
PMID:Isolation and partial characterizations of oval and hyperplastic bile ductular cell-enriched populations from the livers of carcinogen and noncarcinogen-treated rats. 620 45

Putative preneoplastic hepatocytes were isolated from male Fischer 344 rats treated with a single dose of diethylnitrosamine, 2-acetylaminofluorene feeding, and partial hepatectomy (Solt-Farber model). The isolation procedure involved, after collagenase dispersion of the liver, separation of the hepatocytes into small- and large-cell fractions by centrifugal elutriation, and subsequent selection of cells deficient in asialoglycoprotein receptor(s) by plating onto asialofetuin (ASF)-coated plates. The number of cell surface binding sites for the asialoglycoprotein receptor was measured with both asialoorosomucoid and ASF as ligands. There was a 50% reduction of binding sites for both ligands in the original cell suspensions obtained from preneoplastic livers. The reduction in receptor binding sites was most pronounced in the large cell fraction (less than or equal to 30% of control value) after separating the original cell suspension by elutriation into small and large cell fractions. Immunohistochemical studies showed a lack of asialoglycoprotein receptor in preneoplastic (i.e., hyperplastic foci) areas. These areas were entirely super-imposable with glucose-6-phosphatase-deficient areas and partially overlapped the gamma-glutamyltranspeptidase-positive areas in serial liver sections. The attachment of preneoplastic hepatocytes to ASF-coated tissue culture dishes was greatly impaired, and the number of gamma-glutamyltranspeptidase-positive cells on the ASF dishes was reduced to less than 7% as compared to 45 to 70% on the collagen-coated plates. Thus, the lack of asialoglycoprotein (asialofetuin) surface receptors and the increased size of the early preneoplastic hepatocytes are characteristics that can be used to separate the preneoplastic cell population from normal liver cells.
Cancer Res 1984 Dec
PMID:Isolation of preneoplastic rat liver cells by centrifugal elutriation and binding to asialofetuin. 620

Adult rat parenchymal hepatocytes in primary culture can be induced to enter into DNA synthesis and mitosis. The optimal conditions for hepatocyte replication are low plating density (less than 10,000 cells/sq cm) and 50% serum from two-thirds partially hepatectomized rats (48 hr after hepatectomy). Approximately 80% of the hepatocytes enter the cell cycle, and most of these cells go through mitosis. The replicating hepatocytes remain positive for glucose-6-phosphatase and negative for gamma-glutamyl transpeptidase, and they accumulate fat, in analogy to regenerating liver. Most of the replicating hepatocytes enter into multiple consecutive rounds of DNA synthesis. Dose-response studies between control animal serum and hepatocyte labeling index indicate that in unoperated animals the serum contains substances stimulatory as well as inhibitory for hepatic growth, with the inhibitory effect prevailing at high concentrations. After partial hepatectomy, the inhibitory activity disappears whereas the hepatopoietin activity reaches almost 90% of maximal biological effectiveness at 25% serum concentration. Addition of hormones to the system shows that the hepatopoietin activity is not identical to epidermal growth factor, platelet-derived growth factor, thyroxine, glucagon, or hydrocortisone. Norepinephrine abolishes the difference between control and hepatectomized serum but does not restore hepatopoietin activity when added to heat-inactivated serum. The results show that this system of replicating hepatocytes can be used to investigate the trophic factors that control growth of normal and neoplastic hepatocytes.
Cancer Res 1982 Nov
PMID:Liver regeneration studies with rat hepatocytes in primary culture. 621 20

N-Nitrosomorpholine, administered with drinking water to SD rats at the daily dose of 2.4 mg/kg for 7 weeks, induces persisting changes in the hepatocytes as shown by electron microscopy and cytochemistry. In situ, the hepatocytes exhibit a heterogeneous reaction for glucose-6-phosphatase activity. Cells of large diameter, frequently deficient in this enzyme, contain a well-developed rough and/or smooth endoplasmic reticulum. Adult rat hepatocytes from control and N-nitrosomorpholine-treated rats were isolated by enzymatic perfusion. Isolated cell populations in both experimental models were composed of a few contaminating sinusoidal cells; small, intermediate, and large hepatocytes; and doublets or triplets of undissociated cells. Five distinct hepatic subpopulations were separated by elutraition or counterflow centrifugation and analyzed by morphological, morphometric, and cytophotometric methods. Fraction I is composed of small (16 to 18 micrometers) diploid hepatocytes; Fractions II and III consist of homogeneous populations of tetraploid cells (mean diameters, 20.5 and 22.4 micrometers); Fraction IV is enriched with large octoploid cells whose mean diameters reach 25.2 micrometers; and Fraction V contains large cells and cell aggregates. The counterflow centrifugation shows the higher proportion of hypertrophied and polyploid hepatocytes, obtained after carcinogen treatment, in the elutriated Fractions IV and V. The structural integrity of hepatocytes is not affected by the process of elutriation. Large hepatocytes, up to 30 micrometers in diameter, exhibit an abundant smooth endoplasmic reticulum, frequently disposed at the periphery of the cell where it forms a network of anastomosing tubules. Moreover, some of these cells present well-developed rough endoplasmic cisternae, closely associated in large fields. Under the scanning electron microscope, elutriated hepatocytes from control rats show numerous regularly distributed microvilli covering the entire cell surface, whereas hypertrophic hepatocytes from N-nitrosomorpholine-treated rats offer heterogeneous cell surfaces, characterized by the presence of patches of short, closely packed microvilli.
Cancer Res 1980 Feb
PMID:Separation in distinct subpopulations by elutriation of liver cells following exposure of rats to N-nitrosomorpholine. 624 53

Enzyme deviation patterns were examined in primary rat hepatomas induced by short-term sequential administration of two chemical carcinogens from among 2-fluorenylacetamide (FAA), diethylnitrosamine (DENA), and 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB) or by FAA or 3'-Me-DAB followed by phenobarbital as a promoter. The purpose was to discern how the patterns are influenced by different administration schedules of carcinogens and which of the two carcinogens in the sequence affects the pattern more. Biochemical differentiation of hyperplastic hepatic nodules and hepatomas was determined by simultaneous assays of activities and isozyme composition of glucose-adenosine triphosphate phosphotransferase, pyruvate kinase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, and gamma-glutamyltransferase with consideration of histological classification of nodules and tumors. Poorly differentiated hepatomas were predominantly induced by 3'-Me-DAB followed by FAA or DENA except for hepatomas induced by 3'-Me-DAB followed by phenobarbital, which were mainly well and moderately differentiated; well and moderately differentiated hepatomas were predominantly induced by FAA followed by 3'-Me-DAB or phenobarbital. The degree of enzyme deviation of the hepatomas induced by DENA as the first carcinogen was intermediate between those of hepatomas induced by FAA or 3'-Me-DAB, although the degree tended to increase with increased dose or term of DENA. These results indicate that deviations of some enzymes, such as pyruvate kinase and fructose-1,6-bisphosphatase, as well as histological differentiation of the primary hepatomas are more strongly influenced by the first carcinogen than by the second under our administration schedules and that the degree of enzyme deviation shown by hepatomas produced by a particular carcinogen treatment regimen principally related to the potential of that regimen to induce the more anaplastic tumors.
Cancer Res 1981 Oct
PMID:Enzyme deviation patterns in primary rat hepatomas induced by sequential administration of two chemically different carcinogens. 626 36

The alarming hazardous nature of asbestos makes it the foremost among toxic fugitive dusts. The biochemical mechanisms responsible for the diverse biological effects of asbestos, such as fibrosis, asbestos bodies, pleural plaques, respiratory difficulty, cancer, and cytotoxicity, are being studied in this laboratory. As asbestosis progresses in guinea pigs, along with reticulum formation, lysosomal enzymes are released from membrane-bound latent state to active free form, initiating degradative changes. Considerable alterations take place in the pulmonary metabolic machinery. Mitochondria in lung cells were found to be important loci for the toxic effect of asbestos. A profile of mitochondrial activity, in control and asbestotic animals, revealed specific enzymic changes such as increased cytochrome c oxidase during the disease. The functional organization of mitochondria was also altered, since the organelles from asbestotic lungs were swollen as measured by spectrophotometry. Glutamate dehydrogenase activity of mitochondria became exposed in asbestosis. The maleate dehydrogenase shunt which is involved in transport of the redox potential across the membrane was enhanced in cytosol and mitochondria. The involvement of microsomal enzymes in asbestosis was indicated by alterations in glucose-6-phosphatase and tyrosine transaminase and aniline hydroxylase. Changes in the biotransformational capacity of lung, due to asbestos, could be an important aspect in toxicity, especially the carcinogenic effect. Considerable alterations were encountered in the levels of different phospholipids and in mucopolysaccharide constituents. On the basis of the above, the molecular mechanisms in asbestos toxicity are explained as an integrated model. Interactions of dust constituents with those of membranes and the ensuing metabolic adjustments are thus important in the etiology of asbestosis.
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PMID:Biochemical mechanisms in asbestos toxicity. 631 71

The potential promoting and/or complete carcinogenic activity of a methyl group-deficient (MD) diet lacking methionine, choline, vitamin B12, and folate on liver tumor induction in weanling male F344/NCr rats was examined. Each of 50 rats per group received one injection 20 mg diethylnitrosamine [(DENA) CAS: 55-18-5; N-nitrosodiethylamine]/kg body weight at 4 weeks of age, and then each was maintained on a methyl group-adequate (MA) diet for 52 weeks (groups 2 and 5) or on an MD diet for 15 weeks followed by the MA diet for 37 weeks (group 4). Controls received injections of saline and were maintained on the same two respective diet regimens (groups 1 and 3, respectively). Histologic results from sacrifices at 6, 10, 15, 22, 39, and 52 weeks revealed early development of foci of eosinophilic gamma-glutamyltransferase (GGT)-positive hepatocytes by week 6 in DENA-MD diet-treated rats, with subsequent development of a diffuse hyperplasia of hepatocytes, oval cell proliferation, cholangiofibrosis, nodular cirrhosis, and neoplastic nodule (NN) formation and, at 52 weeks, hepatocellular carcinomas (HCC) in 13 of 15 rats. Similar but significantly fewer lesions were observed at slightly later sacrifice times in the livers of saline-MD diet-treated rats, with development of NN in 5 of 12 rats and an HCC in 1 of 12 rats at 52 weeks. DENA-treated rats on MA diets developed relatively few GGT-positive foci, and none developed any neoplastic lesions. Except for basophilic foci, areas and foci of cellular alteration containing glycogen-rich hepatocytes frequently exhibited diminished uptake of injected iron and decreased glucose-6-phosphatase and ATPase contents focally or throughout. This study indicates that a relatively brief exposure of both untreated and DENA-treated weanling rats to a severely MD diet produces classical preneoplastic and neoplastic lesions in their livers.
J Natl Cancer Inst 1984 Dec
PMID:Profound postinitiation enhancement by short-term severe methionine, choline, vitamin B12, and folate deficiency of hepatocarcinogenesis in F344 rats given a single low-dose diethylnitrosamine injection. 659 43


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