Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of lonidamine (LND), 1-(2,4-dichlorobenzyl)-1H-indazol-3 carboxylic acid, on the utilization of carbon from 14C-labeled glucose by cell cultures of the permanent strain LI derived from a human glioblastoma multiforme (astrocytoma) has been investigated. The results may be summarized as follows. Aerobic glycolysis is the main energy-yielding process as shown by the fact that the greatest part of glucose carbon atoms is incorporated into lactate. Nevertheless, the amount of glucose converted accounts for only 63% of the lactate produced, indicating the presence of an elevated endogenous aerobic glycolysis. The amount of glucose carbon atoms incorporated into CO2, lipids, nucleic acid, and supporting structures is low. LND decreased the incorporation of 14C activity in all the above mentioned isolated compounds because of its ability to inhibit glucose phosphorylation. Consequently, there is a lower concentration of glucose-6-phosphate which, in turn, affects the rate of formation of several metabolites in glycolytic and pentose phosphate pathways. Experiments with [1-14C]-2-deoxy-D-glucose further substantiate the idea of glucose phosphorylation as a main target of LND and strongly suggest the presence of a mitochondrially bound hexokinase. The higher inhibition of glucose phosphorylation in exponentially growing cells indicates a further shift of the enzyme toward mitochondria-bound form and confirms the importance of the energy status of the cell in eliciting the response to LND. The reduced capacity of LND-treated cells to synthetize ATP and glucose-6-phosphate reflects the decreased synthesis of proteins and nucleic acids, which affects cell growth and duplication.
Exp Mol Pathol 1987 Oct
PMID:Effect of lonidamine on the utilization of 14C-labeled glucose by human astrocytoma cells. 282 Jul 86

Renal tubular lesions induced in male rats by two different carcinogens, N-nitrosomorpholine (NNM) and N-ethyl-N-hydroxyethylnitrosamine (EHEN), using a limited exposure "stop" protocol were investigated histochemically to demonstrate phenotypic cellular changes. The parameters measured included basophilia, glycogen content and the activity of the enzymes glucose-6-phosphatase (G6PASE), glycogen synthetase (SYN), glycogen phosphorylase (PHO), glucose-6-phosphate dehydrogenase (G6PDH), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), succinate dehydrogenase (SDH), alkaline phosphatase (ALP), acid phosphatase (ACP) and gamma-glutamyl transpeptidase (gamma-GT). The lesions observed were predominantly of either basophilic or oncocytic types. In each case, tubular lesions (altered tubules) appeared to give rise to epithelial tumors (epitheliomas) with the same cellular phenotype. Basophilic tubules and epitheliomas proved to be strongly positive for GAPDH and G6PDH while demonstrating a reduction or loss of G6PASE, ALP, ACP, gamma-GT, and SDH compared with controls and the surrounding proximal or distal tubules. In addition, large basophilic epitheliomas demonstrated an increase in both SYN and PHO activities. In contrast, most oncocytic tubules and oncocytomas characterized by abundant densely granular cytoplasm showed a reduction in the activity of G6PDH, but were intensely positive for SDH. However, a few oncocytic lesions demonstrated a decrease in both SDH and G6PDH activity. Rarely, decreased SDH and elevated G6PDH activities were observed in altered tubules resembling oncocytic tubules. It remains to be clarified whether these tubules represent a variation of the oncocytic lesions or, perhaps, another type of tubular lesion. The results indicate that basophilic and oncocytic epithelial tumors differ in their cytochemical pattern and histogenesis. In line with earlier suggestions, the basophilic tumors apparently originate from the proximal renal tubules, while the oncocytomas develop from the distal parts of the nephron. The basophilic tumors are characterized by an increased pentose phosphate pathway and glycolysis, with a corresponding reduction in mitochondrial respiration. However, the majority of the oncocytomas show an increased activity of the mitochondrial enzyme SDH, and a marked decrease in the activity of the key enzyme of the pentose phosphate pathway.
Virchows Arch B Cell Pathol Incl Mol Pathol 1986
PMID:Correlative histochemical studies on preneoplastic and neoplastic lesions in the kidney of rats treated with nitrosamines. 287 45

Preneoplastic liver lesions were produced in female Wistar rats by application of 25 mg/kg N-nitrosomorpholine (NNM), 14 mg/kg diethylnitrosamine (DENA), 0.075 mg/kg aflatoxin B1 (AFB1) or 160 mg/kg safrole. These carcinogens were administered in two equal doses 12 and 24 h after partial hepatectomy. The animals then received sodium phenobarbital (0.1% in tap water) for up to 410 days. Numerous altered hepatic foci (AHF) and hyperplastic nodules (HN) were detected enzyme histochemically by their negative ATPase reaction after application of AFB1, DENA and NNM; some AHF and HN were also caused by the weak carcinogen safrole. Immunohistochemically these lesions were also L-pyruvate kinase (L-PK)-negative with a high coincidence with regard to their number and area. These results confirm the role of L-PK, an enzyme affecting the pentose phosphate pathway, as a negative marker of preneoplastic liver lesions.
Virchows Arch B Cell Pathol Incl Mol Pathol 1987
PMID:Immunohistochemical demonstration of decreased L-pyruvate kinase in enzyme altered rat liver lesions produced by different carcinogens. 289 Dec 20

Doxorubicin is an important anticancer drug that undergoes redox cycling leading to the production of oxygen radicals; however, its clinical use is limited by toxicity. Redox cycling due to doxorubicin was assessed in the perfused rat liver from increases in O2 uptake by the organ, and toxicity was determined from lactate dehydrogenase release and trypan blue uptake. Doxorubicin increased O2 uptake in a concentration-related manner with half-maximal increases at about 100 microM drug. Within 5 min after addition of 300 microM doxorubicin, lactate dehydrogenase was detected in the effluent perfusate. Enzyme release increased steadily and reached values of 600 units/liter after 60 min. Rates of O2 uptake due to redox cycling of doxorubicin (300 microM) increased by 57 mumol/g/hr in oxygen-rich (mean [O2] = 473 microM) periportal regions of the liver lobule, but did not change in pericentral regions where O2 tension was lower [( O2] = 247 microM). Concomitantly, fluorescence of NAD(P)H measured from the liver surface decreased in periportal but not pericentral regions. The zone-specific decrease in NADPH was attributed to redox cycling of doxorubicin. Trypan blue was taken up exclusively by cells in periportal regions of the liver lobule after perfusion with doxorubicin. When the average O2 tension was lowered from 550 to 200 microM, O2 uptake due to redox cycling of doxorubicin in periportal regions was reduced 3-fold and toxicity was abolished, indicating that toxicity due to doxorubicin is oxygen-dependent. Redox cycling of doxorubicin was minimal in regions of the perfused liver where the O2 concentration was below 400 microM. In contrast, isolated microsomes displayed maximal changes in O2 uptake due to redox cycling of doxorubicin at O2 tensions of about 10 microM. Thus, oxygen per se is not rate-limiting for redox cycling of doxorubicin in the intact organ. Since NADPH is also required for redox cycling of doxorubicin, the effect of oxygen on the ability of mitochondria and the pentose cycle to supply reducing equivalents for redox cycling of doxorubicin was examined. NADPH supply from the pentose cycle was reduced by fasting while that from mitochondria was inhibited by cyanide. The increase in O2 uptake due to redox cycling of doxorubicin was around 60 mumol/g/hr in livers from fed or fasted rats. In the presence of potassium cyanide, stimulation of O2 uptake by doxorubicin was reduced by about one-half in livers from fed rats (29 mumol/g/hr) yet was abolished nearly completely in livers from fasted rats (7 mumol/g/hr).(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Pharmacol 1988 Nov
PMID:Oxygen-dependent hepatotoxicity due to doxorubicin: role of reducing equivalent supply in perfused rat liver. 319 59

Rates of 7-ethoxycoumarin O-deethylation were determined in periportal and pericentral regions of the liver lobule in livers from corn oil- and beta-naphthoflavone-treated rats by monitoring the conversion of nonfluorescent 7-ethoxycoumarin to fluorescent 7-hydroxycoumarin with micro-light guides. Rates of monooxygenation in livers from fed, corn oil-treated rats of 1.4 mumol/g/hr were increased markedly to around 21 mumol/g/hr in both regions of the liver lobule after treatment of rats with beta-naphthoflavone. Fasting or treatment with 6-aminonicotinamide diminished the generation of NADPH by the pentose cycle, whereas KCN decreased NADPH generation via mitochondria. Fasting and 6-aminonicotinamide treatment decreased monooxygenation about 0.5 mumol/g/hr in both regions of the liver lobule in livers from corn oil-treated rats and around 5 mumol/g/hr in livers from beta-naphthoflavone-treated rats. KCN decreased rates about 0.5 mumol/g/hr in both regions of the lobule in livers from fed, corn oil-treated rats and nearly completely in livers from fasted rats. Rates declined from 14 to less than 2 mumol/g/hr in livers from fasted, beta-naphthoflavone-treated rats following 30-40 min of perfusion with cyanide. These data indicate that mitochondrial oxidations are the predominant source of reducing equivalents for monooxygenation in both regions of the liver lobule in livers from beta-naphthoflavone-treated rats. Activation of urea synthesis by infusion of ammonia, a process requiring mitochondrial NADPH, inhibited the metabolism of 7-ethoxycoumarin by 30%. Malate, which is a substrate for the malic enzyme shuttle mechanism involved in the transfer of reducing equivalents from the mitochondria to the cytosol, increased 10-fold during infusion of 7-ethoxycoumarin in livers from beta-naphthoflavone-treated rats but less than 3-fold in livers from control rats. Taken together, these data indicate that high rates of 7-hydroxycoumarin production in livers from beta-naphthoflavone-treated rats are sustained by increased rates of NADPH generation from mitochondrial sources.
Mol Pharmacol 1987 Aug
PMID:Effect of beta-naphthoflavone on mitochondrial supply of reducing equivalents for monooxygenation in periportal and pericentral regions of the liver lobule. 349 33

The changes in the activity of the pentose phosphate cycle and the malic enzyme produced by the activation or inhibition of different NADPH-consuming pathways have been studied. The inhibition of the fatty acid synthesis by kynurenate produced a decrease in the flux through the pentose phosphate cycle and a diminution in the malic enzyme pathway. The incubation of the adipocytes in the presence of ter-butyl-hydroperoxide, a compound which is metabolized via a NADPH-consuming pathway, produced a big increase in the pentose phosphate cycle and the malic enzyme activities. The regulation of these NADPH-producing pathways by the NADPH/NADP ratio is discussed.
Mol Cell Biochem 1987 Mar
PMID:The NADPH consumption regulates the NADPH-producing pathways (pentose phosphate cycle and malic enzyme) in rat adipocytes. 358 32

Rates of NADPH generation by the pentose phosphate pathway were evaluated in perfused livers from ethanol-fed or control rats by measuring the production of 14CO2 from 1-14C-glucose. Under basal perfusion conditions, livers from ethanol-fed rats released lactate and pyruvate into the perfusate at rates that were only 19% of the control values. Under these conditions, calculated rates of NADPH generation by the pentose cycle in livers of the ethanol-fed rats were only 50% of rates obtained with livers of control rats. 7-Ethoxycoumarin (7-EC), a substrate for mixed function oxidation, was infused to increase rates of hepatic NADPH utilization. In livers from control rats, 7-EC was oxidized at a rate of 2.6 mumol/g/hr, but rates of NADPH generation by the pentose cycle were increased by 8.8 mumol/g/hr. In livers from ethanol-fed rats, 7-EC was metabolized at rates of 7.2 mumol/g/hr, but the generation of NADPH by the pentose cycle was increased by only 3.9 mumol/g/hr. The infusion of 7-EC was associated with increases in rates of O2 uptake that exceeded rates of mixed function oxidation in both groups of animals. Ethanol feeding decreased the activity of glucose-6-phosphate dehydrogenase by 40% and decreased the concentrations of glycogen by 66%. Thus, the decrease in pentose cycle flux in perfused livers may be due to diminished activity of the rate-controlling enzyme and/or diminished substrate supply from glycogen. However, cytosolic NADP+/NADPH ratios were identical in livers of both groups. Because NADPH was not depleted during the mixed function oxidation of 7-EC in livers from ethanol-fed rats, it is concluded that other hepatic sources of NADPH compensate for the diminished generation by the pentose cycle.
Mol Pharmacol 1987 Jun
PMID:Diminished pentose cycle flux in perfused livers of ethanol-fed rats. 360 Jun 8

Glucose utilization by different metabolic pathways in bovine adrenal medulla has been studied using freshly isolated adrenal chromaffin cells. The rate of net glucose utilization in resting cells was 10.5 mumoles X g-1 X h-1. 50% was transformed into lactate and pyruvate, the lactate to pyruvate ratio ranging from 3 to 7.27% was metabolized through the tricarboxylic acid cycle and 3.1% was oxidized in the pentose phosphate pathway. The ratio of 14CO2 production from [1-14C] glucose and [6-14C] glucose was close to 2 at one hour of incubation. 3.2% of total glucose consumed was used in protein synthesis, and 1% was incorporated into lipids. Oxygen utilization in respiration by isolated adrenal chromaffin cells was 18.2 mumoles X g-1 X h-1, corresponding to 3.1 mumoles glucose X g-1 X h-1 or about 30% of total glucose consumed. The activities of hexokinase, enolase, pyruvate kinase, lactate dehydrogenase, glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase were assayed in extracts of bovine adrenal medulla, being 1.0, 23, 40, 37, 6.0 and 3.0 U/g respectively. Hexokinase activity was identified as belonging mainly to isoenzyme I, with some isoenzyme II. Enolase was predominantly the alpha gamma hybrid. Pyruvate kinase activity corresponded to a mixture of isoenzymes K and M. Lactate dehydrogenase activity corresponded to isoenzymes 1, 2 and 3, with smaller proportions of isoenzymes 4 and 5. Results are discussed mainly with respect to those reported for the brain.
Mol Cell Biochem 1986 Apr
PMID:Enzymes and pathways of glucose utilization in bovine adrenal medulla. 371 7

Contrary to previous reports in the literature, bloodstream forms of the haemoflagellate protozoan Trypanosoma brucei brucei are not deficient in their ability to metabolize hydrogen peroxide, although they either lack or only possess the normal enzymes for H2O2 detoxification, catalase (EC 1.11.1.6) and glutathione peroxidase (EC 1.11.1.9), at extremely low levels. The hydrogen peroxide which is consumed appears to be reduced by NADPH derived from glucose via the pentose phosphate pathway. This process requires the newly discovered cofactor trypanothione.
Mol Biochem Parasitol 1986 Aug
PMID:Hydrogen peroxide metabolism in Trypanosoma brucei. 374 70

Acetate, propionate, ethanol and propanol were the predominant end-products released during incubation of a thiabendazole resistant and a susceptible strain of Trichostrongylus colubriformis. The parasites in all the incubations appeared to be deficient in reducing equivalents if the end-products arose from the classical catabolic pathway through fumarate reductase (EC 1.3.1.6). Possible alternative pathways for accounting for redox balance, including beta-oxidation, the pentose phosphate pathway and amino acid metabolism were investigated. Palmitate was oxidised aerobically. Radiolabelled tricarboxylic acid cycle intermediates, citrate and alpha-ketoglutarate, were decarboxylated to 14CO2 indicating that at least a partial tricarboxylic acid cycle to succinyl-CoA via alpha-ketoglutarate operates both anaerobically and aerobically in T. colubriformis. These data and the pattern of end-products suggest the presence of two pathways to propanol and propionate either through fumarate reduction or alpha-ketoglutarate oxidation. T. colubriformis may apportion carbon flow through these pathways to maintain a stable redox ratio. Similar calculations on previously reported data indicate that both pathways may also operate in Haemonchus contortus. Exposure of resistant T. colubriformis to thiabendazole under anaerobic conditions caused an increased accumulation of end-products, especially propanol, in the incubation medium. The alpha-ketoglutarate pathway may lower the dependence of the parasite on the fumarate reductase route which is sensitive to thiabendazole. The operation of the alpha-ketoglutarate pathway, with propanol as an end-product, may provide a mechanism for regulating redox balance in trichostrongylidae.
Mol Biochem Parasitol 1985 Mar
PMID:The contribution of a partial tricarboxylic acid cycle to volatile end-products in thiabendazole-resistant and susceptible Trichostrongylus colubriformis. 399 Jul 6


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