Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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Immature female rats (23-30 days old) were implanted subcutaneously with diethylstilbestrol (DES) in silastic capsules. After 48 h their ovaries were removed and the granulosa cells isolated (Foreman et al. (1984) Life Sci. 35, 1273-1279). The cells were incubated in Hepes balanced saline buffer with substrates with or without follicle-stimulating hormone (FSH). At the end of incubation perchloric acid extracts were made for 31P NMR spectroscopy. The resonances of fructose 1-phosphate, fructose 6-phosphate, glucose 1-phosphate, and ribose 5-phosphate were identified in the granulosa cell extracts. The relative intensities of fructose 6-phosphate to ribose 5-phosphate decreased after incubation with FSH in vitro. This suggests that FSH increases the activity of the pentose pathway within 1 h. Thus, FSH can acutely activate those metabolic pathways which provide nicotinamide-adenine dinucleotide phosphate (NADPH) to be used in steroid synthesis and cholesterol mobilization.
Mol Cell Endocrinol 1990 Oct 22
PMID:31P nuclear magnetic resonance (NMR) identification of sugar phosphates in isolated rat ovarian follicular granulosa cells and the effects of follicle-stimulating hormone. 212 82

Neonatal and adult rat islets, cultured for 7-9 days in the presence of 10.5 mM D-glucose, were incubated for 120 min with either D-glucose (2.8 and 16.7 mM) or L-leucine (1.0 and 20.0 mM). The total and anaerobic rates of glycolysis, as judged respectively through the generation of 3H2O from D-[5-3H]glucose and 14C-labelled lactate from D-[3,4-14C]glucose or D-[6-14C]glucose were higher in neonatal than adult islets, but increased to a lesser relative extent in neonatal than adult islets in response to a rise in hexose concentration. The flow through the pentose phosphate pathway, as judged from the difference between D-[1-14C]glucose and D-[6-14C]glucose oxidation was higher in neonatal than adult islets. The flow through the reaction catalyzed by pyruvate dehydrogenase, as judged from the oxidation of D-[3,4-14C]glucose, was lower in neonatal than adult islets incubated in the presence of 16.7 mM (but not 2.8 mM) D-glucose. The oxidation of acetyl residues relative to their generation rate, as judged from the ratio of D-[6-14C]glucose to D-[3,4-14C]glucose oxidation, was not affected by the hexose concentration whether in neonatal or adult islets, but was about twice higher in the latter than former islets. The rate of D-[6-14C]glucose oxidation was also higher in adult than neonatal islets, especially at the high concentration of D-glucose. In both neonatal and adult islets, a rise in hexose concentration stimulated preferentially the oxidation of D[3,4-14C]glucose or D-[6-14C]glucose relative to the utilization of D-[5-3H]glucose.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1990 Oct 01
PMID:D-glucose and L-leucine metabolism in neonatal and adult cultured rat pancreatic islets. 229 40

Prolactin deficiency, induced by bromocryptine treatment, brought about reciprocal changes in the ability of adipocytes and acini isolated from lactating rats to synthesize lipids. The capacity to synthesize fatty acids and phospholipids decreased in the mammary gland and increased in adipocytes by bromocryptine treatment. In the mammary gland, the maximum potential activity of the pentose shunt as well as the specific activities of the pathway dehydrogenases were significantly reduced by bromocryptine treatment. Simultaneously, adipose tissue increased its lipogenic capacity but neither the maximum potential of the shunt nor the specific activities of the pentose phosphate shunt dehydrogenases were significantly changed with respect to the control lactating rats. Thus, a differential regulatory mechanism(s) of the pentose phosphate shunt activity appears to operate in these two tissues. Adipocytes from lactating rats showed a poor responsiveness to insulin in terms of lipid synthesis from glucose. In contrast, in adipocytes from bromocryptine treated rats insulin was able to increase lipid synthesis (105%). Sheep prolactin administration 'in vivo' partially reversed the effects of bromocryptine. These data suggest that prolactin mediates adipocytes resistance to insulin during lactation. Phospholipid synthesis, as occurred in fatty acid synthesis, is increased in adipose tissue and decreased in mammary gland by bromocryptine treatment. However, alpha 1-adrenergic stimulation increases phosphatidylinositol turnover to about the same percentages in both mammary gland acini and adipocytes from lactating rats independently of bromocryptine treatment.
Mol Cell Biochem 1990 Mar 27
PMID:Integration of lipid metabolism in the mammary gland and adipose tissue by prolactin during lactation. 234 43

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


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