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PubMed1979

13C NMR studies of gluconeogenesis in rat liver cells: utilization of labeled glycerol by cells from euthyroid and hyperthyroid rats.

The gluconeogenic pathway from [2-13C]glycerol and [1,3-13C]glycerol has been followed in suspensions of isolated rat hepatocytes at 25 degrees C by 13C NMR at 90.5 MHz. The flow of label through the major pathway from glycerol to L-glycerol 3-phosphate and into glucose was followed in cells from control and triiodothyronine-treated rats. Treatment increased the rates of glucose formation and glycerol consumption 2-fold and decreased the alphaGP level to 40%. We calculate that approximately 60% of the flux is through the mitochondrial glycerol phosphate dehydrogenase in cells from triiodothyronine-treated rats, compared with approximately 15% in cells from the controls. Equal distribution of label between the trioses of glucose was obtained and, because the C3-C4 spin-spin coupling gives the distribution of labeled carbons in the same molecule, it was possible to measure the amount of triose from unlabeled fructose incorporated into the glucose labeled at carbons 1, 3, 4, and 6. About 10% of the hexoses had flowed through the pentose cycle and back into the hexose pathway in cells from fasted rats. From the distribution of label at glucose carbons not labeled via the major pathway and from the carbon spin-spin splitting patterns observed, we conclude that transketolase is reversible whereas transaldolase is essentially irreversible in the nonoxidative pentose branch.

Animals↗
PubMed1985

13C NMR studies of carbon metabolism in the hyphal fungus Aspergillus nidulans.

Natural-abundance high-resolution 13C NMR spectra (linewidth, 10 Hz) of the hyphal fungus Aspergillus nidulans have been obtained after growth on glycolytic or gluconeogenic carbon sources. Various polyols, some tricarboxylic acid-cycle intermediates and amino acids, and some phospholipids and fatty acyl compounds are present. The polyols found are mannitol, arabitol, erythritol, and glycerol. The nature of the carbon source has a pronounced effect on the pool sizes of the various polyols. All are present when the fungus is grown on sucrose or sucrose/acetate under strongly aerobic conditions. When grown on acetate, both arabitol and glycerol levels are low, whereas on glycerol erythritol is also hardly detectable. The effect of oxygen is most outspoken in glycolytically grown cultures. Limited oxygenation leads to low levels of arabitol and glycerol. Strong oxygenation changes the ratio of erythritol to mannitol, favoring the C4 polyol. An increase in oxygen supply leads to (i) stimulation of the fluxes through the pentose phosphate pathway and glycolysis, (ii) an overflow of reduced metabolites both at the pentose phosphate pathway level (erythritol and arabitol) and at the C3 level of the glycolytic pathway (glycerol), and (iii) the usual accumulation of mannitol. Upon starvation, glycerol, the other three polyols, and the tricarboxylic acid-cycle intermediates and their associated amino acids disappear in this order. As in yeast, gluconeogenic substrates lead to the synthesis of trehalose, which also occurs when mycelium is grown on acetate/sucrose under limiting aeration. A transient formation of trehalose has been observed upon incubation of starved mycelium, cultured on different substrates, with [13C]glucose.

Aerobiosis↗
PubMed1989

Mechanism of inhibition of growth of 3T3-L1 fibroblasts and their differentiation to adipocytes by dehydroepiandrosterone and related steroids: role of glucose-6-phosphate dehydrogenase.

Dehydroepiandrosterone (DHEA) and certain structural analogues block the differentiation of 3T3-L1 mouse embryo fibroblasts to adipocytes. These steroids also are potent uncompetitive inhibitors of mammalian glucose-6-phosphate dehydrogenases (G6PDs). We provide direct evidence that treatment of the 3T3-L1 cells with DHEA and its analogues results in intracellular inhibition of G6PD, which is associated with the block of differentiation: (i) Levels of 6-phosphogluconate and other products of the pentose phosphate pathway are decreased; (ii) the magnitude of these decreases depends on the potency of steroids as inhibitors of G6PD and on concentration and duration of exposure, and it is accompanied by a proportionate block of differentiation; (iii) in cells exposed to 16 alpha-bromoepiandrosterone (a more potent inhibitor of G6PD than DHEA) at concentrations that block differentiation, introduction of exogenous 6-phosphogluconate in liposomes raises the levels of 6-phosphogluconate and other products of the pentose phosphate pathway and partially relieves the steroid block of cell growth and differentiation.

Adipose Tissue↗
PubMed1998

Importance of glucose-6-phosphate dehydrogenase activity for cell growth.

The intracellular redox potential, which is determined by the level of oxidants and reductants, has been shown to play an important role in the regulation of cell growth. The principal intracellular reductant is NADPH, which is mainly produced by the pentose phosphate pathway through the actions of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway, and by 6-phosphogluconate dehydrogenase. Previous research has suggested that an increase in G6PD activity is important for cell growth. In this article, we suggest that G6PD activity plays a critical role in cell growth by providing NADPH for redox regulation. The results show the following: 1) inhibition of G6PD activity abrogated growth factor stimulation of [3H]thymidine incorporation in all cell lines tested; 2) overexpression of G6PD stimulated cell growth, as measured by an increase in [3H]thymidine incorporations as compared with cells transfected with vector alone; 3) inhibition of G6PD caused cells to be more susceptible to the growth inhibitory effects of H2O2; 4) inhibition of G6PD led to a 30-40% decrease in the NADPH/NADP ratio; and 5) inhibition of G6PD inhibited cell anchorage and significantly decreased the growth-related stimulation of tyrosine phosphorylation.

3T3 Cells↗
PubMed2000

Identification, cloning, and properties of cytosolic D-ribulose-5-phosphate 3-epimerase from higher plants.

Plant cells contain a complete oxidative pentose phosphate pathway in the chloroplasts, but an incomplete pathway was proposed to be present in the cytosol, with cytosolic (cyt) isoforms of ribulose-5-phosphate 3-epimerase (RPEase) and other non-oxidative branch enzymes being undetectable. Here we present for the first time the identification, cloning, and properties of a cyt-RPEase in rice (Oryza sativa) and presence of its homologues in other plant species. Recombinant cyt-RPEase is a homodimer of 24.3-kDa subunits such as in the case of the animal and yeast enzymes, whereas the chloroplast (chl) RPEase is a hexamer. Cytosolic and chloroplastic RPEases cannot be separated by anion exchange chromatography. Since plant cyt-RPEase is more closely related in its primary structure to homologous enzymes in animal and yeast cells than to the chloroplast RPEase, the plant nuclear genes coding for cytosolic and chloroplast RPEases were most likely derived from eubacteria and cyanobacteria, respectively. Accumulation of cyt-RPEase-mRNA and protein is high in root cells, lacking chl-RPEase, and lower in green tissue. These and other observations support the view that green and non-green plant cells possess a complete oxidative pentose phosphate pathway in the cytosol.

Amino Acid Sequence↗
PubMed2001

Gleevec (STI571) influences metabolic enzyme activities and glucose carbon flow toward nucleic acid and fatty acid synthesis in myeloid tumor cells.

Chronic myeloid leukemia cells contain a constitutively active Bcr-Abl tyrosine kinase, the target protein of Gleevec (STI571) phenylaminopyrimidine class protein kinase inhibitor. Here we provide evidence for metabolic phenotypic changes in cultured K562 human myeloid blast cells after treatment with increasing doses of STI571 using [1,2-13C2]glucose as the single tracer and biological mass spectrometry. In response to 0.68 and 6.8 microm STI571, proliferation of Bcr-Abl-positive K562 cells showed a 57% and 74% decrease, respectively, whereas glucose label incorporation into RNA decreased by 13.4% and 30.1%, respectively, through direct glucose oxidation, as indicated by the decrease in the m1/Sigma(m)n ratio in RNA. Based on the in vitro proliferation data, the IC50 of STI571 in K562 cultures is 0.56 microm. The decrease in 13C label incorporation into RNA ribose was accompanied by a significant fall in hexokinase and glucose-6-phosphate 1-dehydrogenase activities. The activity of transketolase, the enzyme responsible for nonoxidative ribose synthesis in the pentose cycle, was less affected, and there was a relative increase in glucose carbon incorporation into RNA through nonoxidative synthesis as indicated by the increase in the m2/Sigma(m)n ratio in RNA. The restricted use of glucose carbons for de novo nucleic acid and fatty acid synthesis by altering metabolic enzyme activities and pathway carbon flux of the pentose cycle constitutes the underlying mechanism by which STI571 inhibits leukemia cell glucose substrate utilization and growth. The administration of specific hexokinase/glucose-6-phosphate 1-dehydrogenase inhibitor anti-metabolite substrates or competitive enzyme inhibitor compounds, alone or in combination, should be explored for the treatment of STI571-resistant advanced leukemias as well as that of Bcr-Abl-negative human malignancies.

Antineoplastic Agents↗
PubMed2002

Mutation in the glucose-6-phosphate dehydrogenase gene leads to inactivation of Ku DNA end binding during oxidative stress.

Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the oxidative pentose phosphate cycle, regulates the NADPH/NADP(+) ratio in eukaryotic cells. G6PD deficiency is one of the most common mutations in humans and is known to cause health problems for hundreds of millions worldwide. Although it is known that decreased G6PD functionality can result in increased susceptibility to oxidative stress, the molecular targets of this stress are not known. Using a Chinese hamster ovary G6PD-null mutant, we previously demonstrated that exposure to a thiol-specific oxidant, hydroxyethyldisulfide, caused enhanced radiation sensitivity and an inability to repair DNA double strand breaks. We now demonstrate a molecular mechanism for these observations: the direct inhibition of DNA end binding activity of the Ku heterodimer, a DNA repair protein, by oxidation of its cysteine residues. Inhibition of Ku DNA end binding was found to be reversible by treatment of the nuclear extract with dithiothreitol, suggesting that the homeostatic regulation of reduced cysteine residues in Ku is a critical function of G6PD and the oxidative pentose cycle. In summary, we have discovered a new layer of DNA damage repair, that of the functional maintenance of repair proteins themselves. In view of the rapidly escalating number of roles ascribed to Ku, these results may have widespread ramifications.

Animals↗
PubMed2004

Diphenyleneiodonium inhibits the cell redox metabolism and induces oxidative stress.

Diphenyleneiodonium (DPI) and the structurally related compound diphenyliodonium (DIP) are widely used as inhibitors of flavoenzymes, particularly NADPH oxidase. Here we report further evidence that DPI and DIP are not specific flavin binders. A 3-h incubation of N11 glial cells with DPI significantly inhibited in a dose-dependent way both the pentose phosphate pathway and the tricarboxylic acid cycle. In parallel, we observed a dose-dependent increase of reactive oxygen species generation and lipoperoxidation and increased leakage of lactate dehydrogenase activity in the extracellular medium. The glutathione/glutathione disulfide ratio decreased, whereas the efflux of glutathione out of the cells increased. This suggests that DPI causes an augmented oxidative stress and exerts a cytotoxic effect in N11 cells. Indeed, the cells were protected from these events when loaded with glutathione. Similar results were observed using DIP instead of DPI and also in other cell types. We suggest that the DPI-elicited inhibition of the pentose phosphate pathway and tricarboxylic acid cycle may be mediated by the blockade of several NAD(P)-dependent enzymes, such as glucose 6-phosphate dehydrogenase, glyceraldehyde 3-phosphate dehydrogenase, and lactate dehydrogenase. In light of these results, we think that some effects of DPI or DIP in in vitro and in vivo experimental models should be interpreted with caution.

Animals↗
PubMed2005

Positive regulation of sugar catabolic pathways in the cyanobacterium Synechocystis sp. PCC 6803 by the group 2 sigma factor sigE.

The sigE gene of Synechocystis sp. PCC 6803 encodes a group 2 sigma factor for RNA polymerase and has been proposed to function in transcriptional regulation of nitrogen metabolism. By using microarray and Northern analyses, we demonstrated that the abundance of transcripts derived from genes important for glycolysis, the oxidative pentose phosphate pathway, and glycogen catabolism is reduced in a sigE mutant of Synechocystis maintained under the normal growth condition. Furthermore, the activities of the two key enzymes of the oxidative pentose phosphate pathway, glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase, encoded by the zwf and gnd genes were also reduced in the sigE mutant. The dark enhancements in both enzyme activity and transcript abundance apparent in the wild type were eliminated by the mutation. In addition, the sigE mutant showed a reduced rate of glucose uptake and an increased intracellular level of glycogen. Moreover, it was unable to proliferate under the light-activated heterotrophic growth conditions. These results indicate that SigE functions in the transcriptional activation of sugar catabolic pathways in Synechocystis sp. PCC 6803.

Bacterial Proteins↗
PubMed2006

FoxO1 regulates multiple metabolic pathways in the liver: effects on gluconeogenic, glycolytic, and lipogenic gene expression.

FoxO transcription factors are important targets of insulin action. To better understand the role of FoxO proteins in the liver, we created transgenic mice expressing constitutively active FoxO1 in the liver using the alpha1-antitrypsin promoter. Fasting glucose levels are increased, and glucose tolerance is impaired in transgenic (TGN) versus wild type (WT) mice. Interestingly, fasting triglyceride and cholesterol levels are reduced despite hyperinsulinemia, and post-prandial changes in triglyceride levels are markedly suppressed in TGN versus WT mice. Activation of pro-lipogenic signaling pathways (atypical protein kinase C and protein kinase B) and the ability to suppress beta-hydroxybutyrate levels are not impaired in TGN. In contrast, de novo lipogenesis measured with (3)H(2)O is suppressed by approximately 70% in the liver of TGN versus WT mice after refeeding. Gene-array studies reveal that the expression of genes involved in gluconeogenesis, glycerol transport, and amino acid catabolism is increased, whereas genes involved in glucose utilization by glycolysis, the pentose phosphate shunt, lipogenesis, and sterol synthesis pathways are suppressed in TGN versus WT. Studies with adenoviral vectors in isolated hepatocytes confirm that FoxO1 stimulates expression of gluconeogenic genes and suppresses expression of genes involved in glycolysis, the shunt pathway, and lipogenesis, including glucokinase and SREBP-1c. Together, these results indicate that FoxO proteins promote hepatic glucose production through multiple mechanisms and contribute to the regulation of other metabolic pathways important in the adaptation to fasting and feeding in the liver, including glycolysis, the pentose phosphate shunt, and lipogenic and sterol synthetic pathways.

Adenoviridae↗
PubMed1991

Nutritional implications of D-xylose in pigs.

Hemicellulose consists primarily of pentose sugars, joined together in a polysaccharide chain with D-xylose as the most abundant component. Ileal digestibility and urinary excretion of D-xylose and associated effects of this pentose sugar on ileal and faecal digestibility of dry matter (DM), organic matter (OM), gross energy (GE) and nitrogen were studied in pigs. Castrated pigs were prepared with a post-valvular T-caecum cannula to measure ileal digestibility. Faecal digestibility was measured in non-cannulated pigs. D-Xylose was given at dietary inclusion levels of 100 and 200 g/kg, and the control sugar, D-glucose, at a rate of 200 g/kg diet. Ileal digestibility of D-xylose as well as that of D-glucose was found to be close to 100%. The presence of D-xylose in the diet decreased ileal digesta pH and increased ileal flow of volatile fatty acids, suggesting the occurrence of microbial degradation of D-xylose in the pig small intestine. In pigs fed on the 100 g D-xylose/kg diet, 44.5% of the D-xylose intake appeared in the urine. This percentage increased significantly to 52.6 when pigs were fed on the 200 g D-xylose/kg diet. Ileal and faecal digestibility of DM, OM, GE and N, as well as N retention, decreased significantly in pigs fed on the 200 g D-xylose/kg diet.

Animal Feed↗
PubMed1992

Histochemical evaluation of energy metabolism in rat glioma.

The key enzymes of oxidative phosphorylation and glycolysis were evaluated histochemically in rat-implanted C6 gliomas using spot densitometry. Hexokinase, the initial enzyme for the glycolysis pathway, was 40% higher within tumour than the contralateral cerebral cortex. A similar increase within tumours for 2-deoxyglucose was observed by autoradiography. Glucose-6-phosphate dehydrogenase (G6PDH), which is the first enzyme in the pentose phosphate pathway, shunting glucose towards nucleic acid synthesis, was more than 300% higher in gliomas compared with the normal cortex. In contrast, enzymes in the energy producing tricarboxylic acid cycle (succinate-, isocitrate-, and malate-dehydrogenase) and in the electron-transport system (cytochrome c oxidase) were significantly reduced in tumour (58% less than the contralateral cortex). Lactate dehydrogenase activity, which converts pyruvate to lactate, was 50% higher within tumour. Significant reductions of enzymatic activities also occurred in non-neoplastic tissue in ipsilateral hemisphere, with larger tumours. Some enzymes showed heterogeneous activity within tumours, especially G6PDH. These results suggest that: (1) energy production is more dependent on lactate production than on oxidative phosphorylation in C6 glioma, and (2) a significant part of the increased glucose utilization in glioma cells is due to increased activity of the pentose phosphate shunt for increased DNA synthesis, and not energy production.

Animals↗
PubMed2006

Glutathione-related enzymes and the eye.

Glutathione and the related enzymes belong to the defence system protecting the eye against chemical and oxidative stress. This review focuses on GSH and two key enzymes, glutathione reductase and glucose-6-phosphate dehydrogenase in lens, cornea, and retina. Lens contains a high concentration of reduced glutathione, which maintains the thiol groups in the reduced form. These contribute to lens complete transparency as well as to the transparent and refractive properties of the mammalian cornea, which are essential for proper image formation on the retina. In cornea, gluthatione also plays an important role in maintaining normal hydration level, and in protecting cellular membrane integrity. In retina, glutathione is distributed in the different types of retinal cells. Intracellular enzyme, glutathione reductase, involved in reducing the oxidized glutathione has been found at highest activity in human and primate lenses, as compared to other species. Besides the enzymes directly involved in maintaining the normal redox status of the cell, glucose-6-phosphate dehydrogenase which catalyzes the first reaction of the pentose phosphate pathway, plays a key role in protection of the eye against reactive oxygen species. Cornea has a high activity of the pentose phosphate pathway and glucose-6-phosphate dehydrogenase activity. Glycation, the non-enzymic reaction between a free amino group in proteins and a reducing sugar, slowly inactivates gluthathione-related and other enzymes. In addition, glutathione can be also glycated. The presence of glutathione, and of the related enzymes has been also reported in other parts of the eye, such as ciliary body and trabecular meshwork, suggesting that the same enzyme systems are present in all tissues of the eye to generate NADPH and to maintain gluthatione in the reduced form. Changes of glutathione and related enzymes activity in lens, cornea, retina and other eye tissues, occur with ageing, cataract, diabetes, irradiation and administration of some drugs.

Animals↗
PubMedDate not supplied

Functional characterization of the Escherichia coli K-12 yiaMNO transport protein genes.

The yiaMNO genes of Escherichia coli K-12 encode a binding protein-dependent secondary, or tri-partite ATP-independent periplasmic (TRAP), transporter. Since only a few members of this family have been functionally characterized to date, we aimed to identify the substrate for this transporter. Cells that constitutively express the yiaK-S gene cluster metabolized the rare pentose L-xylulose, while deletion of the yiaMNO transporter genes reduced L-xylulose metabolism. The periplasmic substrate-binding protein YiaO was found to bind L-xylulose, and stimulated L-xylulose uptake by spheroplasts. These date indicate that the yiaMNO transporter mediates uptake of this rare pentose.

ATP-Binding Cassette Transporters↗
PubMed2002

Amadori product and age formation during nonenzymatic glycosylation of bovine serum albumin in vitro.

Glucose reacts with the amino groups of protein to form a Schiff base that rearranges to form a ketoamine adduct. These early products eventually undergo irreversible chemical modifications generating advanced glycation end products (AGES). We reacted various sugars and sugar phosphates with bovine serum albumin allowing the formation of Amadori and AGE products. The rates of browning, Amadori and AGE products formed during incubations at 37 and 55 degrees C were compared. The correlation between AGE fluorescence and bitopical (crosslinking) modifications in the protein have been evaluated. Pentoses generated maximum Amadori products. Sugar phosphates were found to be more potent in generating AGEs than free sugars as measured by fluorescence. Though glucose, fructose and glucose-6-P do not generate fluorescence comparable to pentoses, they generate high molecular weight aggregates. In contrast, ribose-5-P, which shows significantly higher AGE and pentosidine fluorescence than the other sugars, did not generate high molecular weight aggregates. We suggest that there may not be a direct correlation between the levels of Amadori products, AGEs and crosslinking.

Amines↗
PubMed1987

Pulmonary cadmium oxide toxicity in the rat.

Although occupational exposures to cadmium have usually involved inhalation of insoluble cadmium oxide (CdO) particles, experimental studies of pulmonary cadmium toxicity have relied on aerosol exposures to soluble cadmium chloride particles. The present study describes a model of acute lung injury based on single 3-h exposures of rats to 0.5 and 5.3 mg/m3 CdO. Biochemical changes were correlated with pathological observations for 15 d postexposure to CdO. Four days following CdO exposure, histopathological observations included focal areas of epithelial hyperplasia, a mononuclear interstitial infiltrate, and increased numbers of alveolar macrophages. In the high-dose group, these changes were correlated with increases in tissue protein and DNA contents of 217% and 195% of controls, respectively. While lungs from the low-dose exposures had returned to a normal appearance by 15 d postexposure, high-dose-exposed lungs exhibited an increase in noncellular thickening of the interstitium and a continued general hypercellularity at this time. In the high-dose exposure group, activities of the enzymes glutathione peroxidase, glutathione reductase, and the dehydrogenase of glucose 6-phosphate and 6-phosphogluconate were significantly elevated two- to fivefold at 2-4 d postexposure. When a correction was made for changes in lung cell number, significant increases were observed only in activities of the pentose-cycle dehydrogenases at 180-238% of controls. These increases suggested an enhanced ability of CdO-exposed lungs to generate the pentose-cycle products NADPH and ribose 5-phosphate, which would be needed for lipid and nucleic acid biosynthesis expected during the proliferative stages of epithelial repair. This study has demonstrated that the response to CdO exposure includes the induction of enzymatic activities that are related to antioxidant defense and lung repair.

Air Pollutants, Occupational↗
PubMed1979

Intakes and sources of dietary fiber in the British population.

Intakes of dietary fiber and its different components have been measured in a random sample of the population in Cambridgeshire, England and compared with data from the British National Food Survey. Sixty-three men and women ages 20 to 80 were included in the sample. Total dietary fiber intake was 19.9 +/- 5.3 g/day compared with the calculated value of 19.7 g/day from the 1976 National Food Survey. There was a 4-fold range in fiber intake from 8 to 32 g/day; no significant trends with age or between men and women were detected. Vegetables supplied the majority of the fiber (41.3%); cereals 30.5%, and fruit and mixed sources 28.2%. Of the components of dietary fiber noncellulosic polysaccharide, cellulose, and lignin intakes were 13.8, 4.7, and 1.4 g/day, respectively. In the noncellulosic fraction, hexoses contributed 7.4 g, pentoses and uronic acids 3.3 and 3.0 g. Vegetables and unrefined cereals were the main sources of pentose. These intakes are low in comparison with limited international data from developing countries and of a similar order to those known in dietary experiments to produce low stool weights, slow transit time, and concentrated feces. They could readily be increased by simple dietary changes.

Adult↗
PubMed1990

Effect of lead nitrate on liver carbohydrate enzymes and glycogen content in the rat.

Male Wistar rats were given a single i.v. injection of lead nitrate (10 mumol/100 g body wt) and were killed with matched controls 24, 48, 72 h and 20 days after the treatment. Changes of liver carbohydrate metabolism were studied histochemically testing the following parameters: glycogen content, activities of glycogen synthase (SYN), glycogen phosphorylase (PHO), glucose-6-phosphatase (G6PASE), glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconate dehydrogenase (6PGDH), glyceraldehyde-3-phosphate dehydrogenase (GAPDH). In addition, gammaglutamyltransferase (GGT) activity was demonstrated. Between 24 and 48 h after lead nitrate injection there was a nearly complete loss of liver glycogen. Seventy-two hours later the polysaccharide reappeared in single hepatocytes and after 20 days the livers of the lead-treated animals not only had replenished their glycogen stores but contained even more glycogen than the matched controls. SYN and PHO activities were diminished from 24 to 72 h, but returned to control values after 20 days. G6PASE and GGT remained elevated up to 72 h before dropping to normal at 20 days after treatment. The pentose phosphate pathway enzymes G6PDH and 6PGDH showed the most remarkable changes in livers treated with lead nitrate. G6PDH was already elevated at 24 h, but only in Kupffer cells. At 48 and 72 h, when hepatocytes exhibited a highly increased mitotic rate, the levels of G6PDH, 6PGDH and GAPDH were elevated. After 20 days dehydrogenase activities were comparable to those of controls. The results of this study suggest that a single dose of lead nitrate not only stimulates proliferation of hepatocytes but also induces considerable changes in rat liver carbohydrate metabolism, especially between 24 and 72 h after administration. During that period glycogen metabolism undergoes a strong reduction, whereas gluconeogenesis and particularly the pentose phosphate pathway respond with a remarkable increase. This metabolic profile is most likely associated with lead biotransformation as well as with liver cell proliferation. It corresponds only partially to that found in preneoplastic and neoplastic liver lesions observed in chemical carcinogenesis, and is reversible, in contrast to the persistent alterations associated with neoplastic transformation.

Animals↗