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

Liver carcinogenesis was induced in rats by aflatoxin B1 (AFB1) enhanced by a choline-deficient diet. In Experiment 1, the ornithine decarboxylase inhibitor, alpha-difluoromethylornithine (DFMO), was administered by gavage to one group only during AFB1 administration; another group received DFMO during AFB1 administration and for 2 months after carcinogen administration. These two groups were compared to two control groups, one given AFB1 and fed the choline-deficient diet and another fed the deficient diet only. In a second experiment, DFMO was administered at a concentration of 2% in the water for 3 weeks and then at 1% for the remainder of the study. Rats from each group in Experiment 1 were killed at 2, 8, and 10 months after AFB1 administration and the development of tumors was followed by histology; autoradiography of [3H]thymidine incorporation into DNA; enzyme histochemistry; and alpha-fetoprotein determination. The group given DFMO during AFB1 administration was not significantly different from the AFB1-treated control group at 2 and 8 months after AFB1 administration. However, at 10 months following AFB1 and DFMO administration, the [3H]thymidine-labeling index and glucose-6-phosphatase staining were significantly increased. This group had three animals bearing hepatocellular carcinomas as compared to none in the controls. The group given DFMO for 2 months after AFB1 administration had a significantly depressed growth rate 2 months later, but this difference was not apparent after 8 months. After 10 months, there was a significantly increased [3H] thymidine-labeling index and increased volume fraction of gamma-glutamyltranspeptidase in the AFB1-DFMO-treated group as compared to the controls. DFMO appeared to inhibit growth under some conditions, but if administration was discontinued after AFB1 exposure, it appeared to enhance tumorigenesis. In Experiment 2, where a larger dose of AFB1 was used and DFMO was administered in the water from start to finish of the experiment, DFMO inhibited tumor induction and depressed the appearance of markers examined during carcinogenesis. These data indicate that the regimen used for DFMO administration can markedly affect tumor induction.
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PMID:Effects of the irreversible ornithine decarboxylase inhibitor, alpha-difluoromethylornithine, aflatoxin B1, and choline deficiency on hepatocarcinogenesis. 241 77

Single doses of diethylnitrosamine, N-hydroxy-2-acetylaminofluorene or N-methyl-N-nitrosourea were administered to rats, before or after obstruction of the common bile duct, and liver sections were stained for alpha-fetoprotein, albumin and glucose-6-phosphatase. In these animals, cells expressing hepatocytic traits were not observed in the resulting expanded population of non-parenchymal epithelial cells. A derivation of non-parenchymal epithelial cells with hepatocytic traits from bile ductular cells is not supported, but not completely ruled out, by these findings. In rats with an obstructed bile duct and administered a single carcinogen dose, serum alpha-fetoprotein was slightly increased, to levels comparable with those occurring after a partial hepatectomy. In these rats, and in partially hepatectomized rats, the cellular source of serum alpha-fetoprotein was not apparent, since no alpha-fetoprotein-positive cells were detected in their liver.
Carcinogenesis 1986 Jul
PMID:Bile ductular cells and the phenotypic heterogeneity of the population of hepatic non-parenchymal epithelial cells induced in rats by chemical carcinogens. 242 28

The effects of oral fructose on hepatocarcinogenesis were investigated with cytomorphological, cytochemical and stereological methods. Carcinogenesis was induced in male Sprague-Dawley rats by application of N-nitrosomorpholine (NNM) for 7 weeks. Afterwards, the animals received fructose in the drinking water (120 g/l) and food ad libitum (group I) or tap water and food ad libitum (group II). The incidence of hepatocellular carcinoma in rats treated with NNM plus fructose was 46% as compared to 24% in animals receiving NNM alone (P less than 0.05). There was no difference in the incidences of other malignancies between the groups (group I: 32.1%, group II: 32.0%). Morphometric evaluation of preneoplastic liver lesions indicated the enhancing effect of the fructose treatment several months before malignant tumors appeared. As early as 6 weeks after treatment the hepatic parenchyma occupied by focal lesions was increased from 6.7% in the animals which had received NNM alone to 8.5% (P less than 0.05) in animals having received NNM plus fructose. This increase was predominantly caused by an increase in glycogen storing foci (P less than 0.0005). In addition, the fructose treatment caused a histochemically detectable increase in the activity of glucose-6-phosphatase and glucose-6-phosphate dehydrogenase in both the hepatocytes of the focal lesions and the surrounding parenchyma. In the NNM plus fructose group the activity of the glucose-6-phosphatase in the foci was frequently approximately equal to the activity in the parenchyma of untreated controls. The striking increase in the activity of this enzyme in the surrounding hepatocytes, however, still sharply demarcated the lesions. The potential mechanisms by which fructose enhances hepatocarcinogenesis are discussed.
Carcinogenesis 1989 Jul
PMID:Enhancement of hepatocarcinogenesis in rats by dietary fructose. 256 39

Liver tumors of the B6C3F1 mouse frequently contain mutations at specific sites of codon 61 of the Ha-ras proto-oncogene. To address whether these mutations occur early or late during carcinogenesis, we analyzed mutations in the Ha-ras gene in small precancerous liver lesions of the B6C3F1 mouse. For this purpose, 10-microns frozen liver sections were prepared and stained for glucose-6-phosphatase activity. Using punching cannuli, we then took small tissue samples of approximately 5-30 micrograms from enzyme-deficient liver lesions and from normal parts of the liver. These tissue samples were analyzed for mutations in the Ha-ras gene by in vitro amplification of DNA via the polymerase chain reaction combined with selective oligonucleotide hybridization. By this approach we were able to analyze mutations in the Ha-ras gene within lesions with diameters of less than 0.5 mm. Our results demonstrate that approximately 15% of the glucose-6-phosphatase-negative lesions that occurred 24-28 wk after a single injection of diethylnitrosamine contain either C----A transversions at the first base or A----G transitions and A----T transversions at the second base of codon 61 of the Ha-ras gene. The same types of mutations, although with a somewhat higher frequency (33%), were found in liver tumors taken 68 wk after diethylnitrosamine treatment. These findings demonstrate that Ha-ras mutations can be detected even in very small precancerous liver lesions, suggesting that these mutations may be an early, perhaps even the first, critical event during murine hepatocarcinogenesis.
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PMID:Mutations at codon 61 of the Ha-ras proto-oncogene in precancerous liver lesions of the B6C3F1 mouse. 267 1

Long-term dietary administration of the adrenal hormone dehydroepiandrosterone (DHEA) to male Sprague-Dawley rats induced significant alterations in the activities of enzymes involved in liver carbohydrate metabolism. Although glycogen synthase activity was increased and phosphorylase decreased, glycogen stores were reduced. This was presumably related to lysosomal glycogen degradation, since alpha-glucosidase was increased. All rate-limiting enzymes of glucose metabolism which were studied (glucose-6-phosphate dehydrogenase, total hexokinases, pyruvate kinase, fructose-1,6-bisphosphatase) revealed markedly reduced activity, only glucose-6-phosphatase activity was increased. These enzymatic changes point to a far-reaching metabolic shift towards energy loss via decreased glucose consumption and increased glucose output. The enzyme pattern induced by DHEA is in many respects opposite to that induced in preneoplastic and neoplastic liver lesions by chemical hepatocarcinogens.
Carcinogenesis 1988 Nov
PMID:Dehydroepiandrosterone induced alterations in rat liver carbohydrate metabolism. 284 96

The stability and response of histochemical phenotypes of altered hepatic foci (AHF) were studied both in the presence and following the withdrawal of 0.05% phenobarbital (PB) treatment in rats previously given a single dose of diethylnitrosamine (DEN) 20-24 h following partial hepatectomy (PH). AHF were scored by their expression of three biochemical markers: gamma-glutamyl transpeptidase (GGT), adenosine triphosphatase and glucose-6-phosphatase (G6P). AHF demonstrated significant heterogeneity with respect to the marker alterations. The use of three markers in the present study confirmed the findings of our earlier study, which showed the maximal response of GGT+ AHF to PB administration following PH/DEN initiation and the stability of GGT+/AHF induced by the PH/DEN/PB regimen after the withdrawal of PB. In the regimen employed, the GGT marker alone scored the great majority of the AHF detected by all three markers. The frequency distribution of histochemical phenotypes remained relatively constant in AHF during continuous PB administration and in AHF promoted by PB followed by a 6-month period of feeding a diet containing no PB. These findings suggest that individual AHF remain phenotypically stable throughout the PB promotion phase, i.e., do not progress from one phenotype to another. In every marker class, the mean volume of AHF increased during continuous PB administration. These data illustrate the enhancing effect of PB on the growth of the AHF. The size of AHF continued to increase following the withdrawal of PB in the 3-month PB treatment group, but not in the animals treated for 4 months. A mechanism that may account for the differences in these two treatment groups is discussed.
Carcinogenesis 1985 Sep
PMID:The quantitative analysis and stability of histochemical markers of altered hepatic foci in rat liver following initiation by diethylnitrosamine administration and promotion with phenobarbital. 286 7

In rats treated orally with a single dose of aflatoxin B1 (5 mg/kg body weight) characteristic focal and nodular liver lesions developed which differed in their fine structure, enzyme histochemical pattern and growth behaviour from other types of carcinogen-induced hepatic foci and nodules described earlier. The foci were composed of a distinct cell population which showed specific structural changes of the cytoplasm. Typically, unusually large and abundant basophilic bodies consisting of highly ordered stacks of cisternae of the rough endoplasmic reticulum (ER) were arranged in long, striped bands and stood out against an acidophilic background which was due to hypertrophy of the smooth ER. We propose the descriptive terms 'tigroid cells', and 'tigroid cell foci' for this population of altered hepatocytes. Correlative cytochemical investigations on the tigroid cell foci revealed characteristic changes in carbohydrate metabolism, such as a decrease in the activity of glycogen synthetase and glycogen phosphorylase and an increase in the activity of glucose-6-phosphate dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase. The activity of glucose-6-phosphatase and ATPase was normal (or partially reduced) and that of the gamma-glutamyl-transpeptidase was always lacking. A progressive increase in the number and size of the tigroid cell foci and transitions from tigroid cell foci to neoplastic nodules with similar morphological and cytochemical features were observed during the time period of 104 weeks. The mitotic index within tigroid cell foci and nodules was approximately 100 times higher than that of the surrounding hepatic tissue or the liver parenchyma of untreated control animals. The important question whether the tigroid cell foci represent a specific pre-neoplastic or early neoplastic cell population requires further investigations.
Carcinogenesis 1985 Nov
PMID:Tigroid cell foci and neoplastic nodules in the liver of rats treated with a single dose of aflatoxin B1. 286 15

Following initial treatment of F344 rats with dihydroxy-di-n-propylnitrosamine, exposure to dehydroepiandrosterone (DHEA) administered in the diet at a concentration of 0.6% brought about significant decrease in weight gain, independent of food consumption, and inhibited the development of thyroid tumors and hepatocyte-altered enzyme foci. In addition to inducing a diffuse increase in glucose-6-phosphatase dehydrogenase (G6PD) and gammaglutamyl transpeptidase in the liver. DHEA treatment was associated with development of small numbers of basophilic hepatocellular foci which differed markedly in enzyme phenotype from the clear cell (glycogen storing) lesions predominating in the carcinogen-treated animals maintained on basal diet. The results are consistent with the concept that DHEA-modification of neoplastic development, as reported earlier in a number of different organs and here in the liver and thyroid, may be in some way partly mediated by changed expression of the key enzyme of the pentose phosphate pathway, G6PD, and related metabolic systems. Heterogeneity in the quality of initiated hepatocytes with regard to capacity for inhibition or promotion indicated by the present data point to the existence of more than one pathway to tumour development in the rat liver.
Carcinogenesis 1986 Feb
PMID:Modifying influence of dehydroepiandrosterone on the development of dihydroxy-di-n-propylnitrosamine-initiated lesions in the thyroid, lung and liver of F344 rats. 286 7

The effect of feeding hypolipidemic peroxisome proliferators on the induction of altered hepatic foci (AHF) in Fischer rats was studied in order to determine whether such agents can induce or promote the development of AHF. In the first study, rats were fed ciprofibrate (10 mg/kg/day) for 1 yr. AHF, neoplastic nodules, and hepatocellular carcinomas were induced. The presence of putative gamma-glutamyltranspeptidase (GGT) activity was numerically the most common marker, although it was absent in larger foci and nodules. A deficiency in canalicular ATPase and glucose-6-phosphatase provided the best markers for the larger foci and nodules. In the second study, rats were subjected to partial hepatectomy, and half of the animals were then intubated with diethylnitrosamine (10 mg/kg). One wk later, rats were fed Wy-14,643 at concentrations of 0, 0.05, and 0.1% in the diet for 6 mo. At 6 mo, the number and volume of foci were increased by the feeding of Wy-14,643 after partial hepatectomy alone and were greatly increased when Wy-14,643 was fed after partial hepatectomy/diethylnitrosamine administration. Canalicular adenosine triphosphatase and glucose-6-phosphatase deficiencies were the most common markers of AHF, and AHF of these phenotypes occupied practically all of the focal volume. The larger AHF did not express GGT, and those foci exhibiting GGT were much less common and occupied very little volume. The absence of the GGT protein itself, as opposed to an inhibition of GGT activity, was verified by immunohistochemical staining using an antibody to GGT. These studies show that hypolipidemic peroxisome proliferators can stimulate an increase in AHF following a single dose of diethylnitrosamine and a mitotic stimulus, and they thus can act as promoters in two-stage liver carcinogenesis. GGT is a poor marker for identifying AHF induced by peroxisome proliferators during the early, premalignant phase of hepatocarcinogenesis.
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PMID:Induction of altered hepatic foci in rats by the administration of hypolipidemic peroxisome proliferators alone or following a single dose of diethylnitrosamine. 287 87

Pectin-induced changes in microflora have been shown to elevate the covalent binding of 2,6-dinitrotoluene (2,6-DNT)-related materials to total rat hepatic macromolecules. Therefore, the effect of diets varying in pectin content on the induction of foci and hepatic tumors induced by 2,6-DNT was studied in male F344 rats. 2,6-DNT (3.0-3.5 and 0.6-0.7 mg/kg/day) was incorporated into NIH-07 (NIH), an open formula cereal-based diet high in pectin content, AIN-76A (AIN), a purified pectin-free diet, or AIN-76A supplemented with 5% pectin (AP). Hepatic foci were scored after histochemical staining for gamma-glutamyl transpeptidase (GGT), canalicular adenosine triphosphatase or glucose-6-phosphatase following administration of test diets for 3, 6 and 12 months. The number of foci per cm3 of liver increased in a dose- and time-department manner following incorporation of 2,6-DNT into test diets with NIH greater than AP greater than AIN. In the NIH diet, 2,6-DNT did not alter the phenotypic distribution of foci. Animals fed control or 2,6-DNT-containing AIN and AP diets had few or no GGT foci throughout the study. Hepatocellular carcinomas and neoplastic nodules were observed only in rats fed NIH containing 2,6-DNT. The concentrations of 2,6-DNT-related material covalently bound to hepatic macromolecules after a single oral dose of radiolabeled 2,6-DNT given after 12 months on the diets increased in control rats and in rats receiving low dose 2,6-DNT in the diet with AIN less than AP less than NIH. These studies show that the carcinogenicity of 2,6-DNT differs depending on whether rats are fed an NIH or AIN (+/- pectin) diet. The results suggest that diet-induced alterations in the covalent binding of 2,6-DNT are not the sole factor in determining the carcinogenic response to 2,6-DNT. Furthermore, unidentified contaminants in cereal-based diets may influence foci and tumor production in rat liver during carcinogen treatment.
Carcinogenesis 1986 Nov
PMID:The effect of diet on 2,6-dinitrotoluene hepatocarcinogenesis. 287 86


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