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PubMed1987

Regulation of amino acid transport in isolated rat hepatocytes during development.

The effect of amino acid depletion or supplementation and the effect of glucagon and insulin on the amino acid transport mediated by system A were investigated by determining the uptake of either 2-amino [1-14C]isobutyric acid (AIB) or N-methyl 2-amino [1-14C]isobutyric acid (MeAIB) in rat hepatocytes, freshly isolated at different stages of pre- and postnatal development. The data obtained show that the Na+-dependent uptake was higher at the earliest developmental stages, and steadily decreased until the adult level. The hormones increased AlB and MeAIB uptake enhancing the Vmax, while the Km was unchanged. This effect was evident in cells from adult and 18-20-day-old fetuses, while no response was present before the 18th day of fetal life and in the perinatal period. Actinomycin D or cycloheximide abolished this hormone-dependent increase. A decrease in AlB and MeAIB transport after incubation in an amino acid-rich medium was demonstrated at all ages tested, but was particularly evident in the prenatal life. The increase in the activity of the system following amino acid starvation was shown to be mostly dependent from de novo protein synthesis in the fetal life; on the contrary in the adult the increase appeared to be more linked to the release from transinhibition of the transport.

Aging↗
PubMed1987

Parallel changes in amino acid transport and protein kinase C localization in LLC-PK1 cells treated with TPA or diradylglycerols.

Protein kinase C is considered to be a major target for tumor promoting phorbol esters such as 12-0-tetradecanoylphorbol-13-acetate (TPA). We have analyzed the correlation between A-system amino acid transport and the distribution of protein kinase C (PKC) between a membrane-rich fraction (100,000 g pellet) and cytosol (supernatant) from homogenized LLC-PK1 cells, a pig kidney epithelial cell line grown in culture. During log growth 1 day after seeding the cells onto culture plates, PKC activity is high in the membrane fraction and low in the cytosol. As the cells become confluent the PKC distribution shifts to a cytosolic pool. Concomitantly, A-system amino acid transport, as measured by methylaminoisobutyric acid [14C]MeAIB uptake, decreases. TPA (0.01-1.0 microM) induces a shift of PKC activity from the cytosol back to the membrane-rich fraction in post-confluent cells with a concomitant 2-3 fold stimulation of MeAIB uptake. The same responses can be achieved by treating cells with certain diradylglycerols, either diacylglycerols such as 1-oleyl-2-acetyl-sn-glycerol (OAG) or alkylacylglycerols such as 1-hexadecenyl-2-oleyl-sn-glycerol. Both responses to TPA are blocked by cytochalasin B, but cycloheximide inhibits the transport response without affecting PKC redistribution. It is suggested that the redistribution may be a necessary but not sufficient concomitant to the transport activation.

Amino Acids↗
PubMed1988

Induction of system A amino acid transport through long-term treatment with ouabain: correlation with increased (Na+/K+)-ATPase activity.

Mouse embryo fibroblast cells (C3H-10T1/2) and the methylcholanthrene-transformed derivative (MCA-10T1/2) were treated with basal modified Eagle's medium (BME) containing 10% fetal bovine serum and varying concentrations of ouabain ranging from 0.05 mM to 0.7 mM for 16 h in culture. After replacing the ouabain-containing medium with Earl's balanced salts solution, System A amino acid transport activity increased from approximately 40 to 500 pmol AIB accumulated.mg protein-1.min-1 in the C3H-10T1/2 cells and from approximately 300 to 700 pmol AIB accumulated.mg protein-1.min-1 in the MCA-10T1/2 cells. The (Na+/K+)-ATPase pump activity also increased from approximately 12 to 46 nmol Rb+ accumulated.mg protein-1.min-1 in the normal cells and from approximately 20 to 42 nmol Rb+ accumulated.mg protein-1.min-1 in the transformed cells. System A and the (Na+/K+)ATPase activity were maximally increased at approximately 0.4-0.6 mM ouabain in the normal cells in contrast to the transformed cells which were maximally stimulated at a concentration of approximately 0.2 mM ouabain. This treatment with ouabain increased the [Na+]i/[K+]i as measured by atomic absorption spectroscopy, and thereby decreased the Na+ and K+ electrochemical gradients. Our data show that the internal ion gradients inverted at a lower concentration of ouabain in the transformed cells compared to the normal cells. The ouabain-induced increase in pump and System A activity shown here was used as a tool to further investigate the coordinated ion transport regulation in the control of cell growth.

Amino Acids↗
PubMed1989

Epidermal growth factor: modulator of murine embryonic palate mesenchymal cell proliferation, polyamine biosynthesis, and polyamine transport.

Polyamines (putrescine, spermidine, and spermine) are normal cellular constituents able to modulate cellular proliferation and differentiation in a number of tissues and cell types. This investigation explores the response of murine embryonic palate mesenchymal (MEPM) cells to epidermal growth factor (EGF) in terms of biosynthesis of putrescine and its transport across the plasma membrane and tests the hypothesis that polyamine transport can serve as an alternative mechanism (other than biosynthesis) for elevating intracellular polyamines during stimulation of MEPM cellular proliferation. MEPM cells treated with EGF were stimulated to proliferate and showed a dose- and time-dependent stimulation of ornithine decarboxylase (ODC) which was maximal at 4-6 hours. EGF also stimulated the initial rate of putrescine transport in a dose- and time-dependent manner. This stimulation was found to be maximal 3 hours after treatment and specific for the putrescine transport system. The kinetic parameters of putrescine transport shifted from 2.52 microM (Km) and 23.6 nmol/mg protein/15 minutes (Vmax) in nonstimulated cells to 4.48 microM (Km) and 39.8 nmol/mg protein/15 minutes (Vmax) in EGF-treated cells. This kinetic shift did not require de novo protein or RNA synthesis, as cycloheximide (10 micrograms/ml) and actinomycin D (50 micrograms/ml) had little effect on the ability of EGF to stimulate the initial rate of putrescine uptake. The rate of transport, however, was found to be inversely related to cell density. The addition of exogenous putrescine concomitantly with EGF blocked the induction of ODC, while in the presence of difluoromethylornithine (DFMO) (irreversible inhibitor of ODC) the initial rate of putrescine transport remained elevated throughout the time course studied. This stimulation of putrescine uptake caused by polyamine deprivation was reversed by exogenous putrescine and Ca++ while alpha-aminoisobutyric acid (AIB) further stimulated the rate of uptake. EGF's ability to stimulate cellular DNA synthesis was inhibited by DFMO. If DFMO-treated cells were stimulated with EGF in the presence of exogenous putrescine, this stimulatory effect was preserved. These studies indicate that the rate of polyamine transportation is highly responsive to a signal which initiates biosynthesis of polyamines. Further, this transportation system provides a compensatory mechanism allowing the cell to increase intracellular levels of polyamines when environmental conditions inhibit biosynthesis or when polyamines are abundant.

Animals↗
PubMed1984

An insulin receptor defect in murine muscular dystrophy.

A study has been made of the I125 insulin binding and postbinding effects on excised soleus muscles from the 129 ReJ strain of dystrophic mice. Results are compared with those in sex- and weight-matched controls. The data suggest that, in the range of physiological hormone concentrations, the affinity of insulin receptors on dystrophic muscles is less than normal and that the insulin-dependent uptake of both 2-deoxyglucose (2-DG) and aminoisobutyric acid (AIB) is impaired. These findings are taken to indicate that many of the biochemical and electrophysiological abnormalities observed in murine dystrophy could arise from some genetic defect in the receptor proteins controlling uptake of raw materials.

Amino Acids↗
PubMedDate not supplied

Biosynthetic uniform 13C,15N-labelling of zervamicin IIB. Complete 13C and 15N NMR assignment.

Zervamicin IIB is a member of the alpha-aminoisobutyric acid containing peptaibol antibiotics. A new procedure for the biosynthetic preparation of the uniformly 13C- and 15N-enriched peptaibol is described This compound was isolated from the biomass of the fungus-producer Emericellopsis salmosynnemata strain 336 IMI 58330 obtained upon cultivation in the totally 13C, 15N-labelled complete medium. To prepare such a medium the autolysed biomass and the exopolysaccharides of the obligate methylotrophic bacterium Methylobacillus flagellatus KT were used. This microorganism was grown in totally 13C, 15N-labelled minimal medium containing 13C-methanol and 15N-ammonium chloride as the only carbon and nitrogen sources. Preliminary NMR spectroscopic analysis indicated a high extent of isotope incorporation (> 90%) and led to the complete 13C- and 15N-NMR assignment including the stereospecific assignment of Aib residues methyl groups. The observed pattern of the structurally important secondary chemical shifts of 1H(alpha), 13C=O and 13C(alpha) agrees well with the previously determined structure of zervamicin IIB in methanol solution.

Amino Acid Sequence↗
PubMedDate not supplied

Trichogin: a paradigm for lipopeptaibols.

Lipopeptaibols are members of a novel family of naturally occurring, short peptides with antimicrobial activity, characterized by a lipophilic acyl chain at the N-terminus, a high content of turn/helix inducing alpha-aminoisobutyric acid and a 1,2-amino alcohol at the C-terminus. Using solution methods, the prototypical lipopeptaibol trichogin GA IV and a large series of appropriately designed analogues were synthesized, which allow: (i) determination of the minimal lipid chain and peptide main-chain lengths for the onset of membrane activity, and (ii) exploitation of a number of physico-chemical techniques aimed at assessing the trichogin preferred conformation under a variety of conditions and at investigating its mechanism of interaction with the phospholipid membranes.

Amino Acid Sequence↗
PubMed1998

Effect of dimethoate and chlorfenvinphos on plasma membrane integrity of Synechocystis sp. PCC 6803.

The organophosphorus (OP) insecticides dimethoate and chlorfenvinphos, at all selected concentrations (0-500 micromol liter-1), reduced the rate of accumulation of uranine and enhanced fluorescence quenching of 9-amino-6-chloro-2-methoxyacridine (ACMA). There was a significant nonlinear negative correlation between insecticide concentrations and uranine accumulation. The reduction in amount of uranine trapped inside the cells was greater in cultures treated with chlorfenvinphos, whereas quenching of ACMA fluorescence was found to be greater with dimethoate treatment. A marked difference between the effects of dimethoate and chlorfenvinphos on permeability changes in the plasma membrane of Synechocystis was also noted. The release of cellular organic carbon was observed at each concentration of chlorfenvinphos, whereas with dimethoate such an effect was noted at >/=200 micromol liter-1. The rate of uptake of substrates like 2-deoxyglucose and 2-aminoisobutyric acid (AIBA) was significantly (negatively) correlated with concentrations of both the insecticides. Chlorfenvinphos was more effective than dimethoate in reducing the active uptake of nonmetabolizable sugar and amino acid analogues.

Cell Membrane↗
PubMed1976

Energetics of low affinity amino acid transport into brain slices.

It appears possible to dissect and study some of the potential energy sources for amino acid transport in brain slices despite the apparent complexity of the tissue in comparison to that of isolated bacterial vesicles23. The uptake capability of the tissue may be inadvertently damaged in some experimental protocols so that very special controls must be used to ensure that the treatment did not somehow inactivate the very mechanism that thereafter will be tested. We have presented some evidence that brain slice amino acid transport may not be obligatorily linked to glycolysis, ATP levels, Na+, K+-ATPase activity, K+ levels or direction of flux, or to Na+ flux. However, the energy source linkage for different amino acids appears to be rather specific, so that further generalizations are difficult to sustain. For instance, the incubation media and conditions we describe here were experimentally adjusted to maximize uptake of D-glu or alpha-AIB in the absence of glucose, or in lowered K+ or Na+. Therefore, these procedures, the results of which directly challenge some common assumptions regarding the energy basis for active transport in brain slices, probably will not be universally extensible to all other actively transported amino acids.

Adenosine Triphosphate↗
PubMed1979

Glucocorticoids and the plasma membrane.

Glucocorticoids affect the composition and function of the plasma membrane in a variety of cell types. Cultured rat hepatoma (HTC) cells in tissue culture provide an excellent model system for analysis of such effects. In these cells, dexamethasone rapidly and dramatically inhibits the influx of amino acids sharing the A or alanine-preferring transport system. Inhibition is half-maximal within 2 h, and maximal after 6 h incubation with the hormone. The inhibition is rapidly reversed by insulin, and more slowly by removing the steroid. Microtubules and microfilaments are not apparently involved in this hormonal effect, but continuous protein synthesis is required for the glucocorticoid inhibition of transport. Dexamethasone also decreases the number of microvilli on the surface of HTC cells, increases their adhesiveness to a substratum, and dramatically decreases the production of plasminogen activator, but it does not affect the growth rate or plating efficiency of the cells. Variant cell lines stably resistant to dexamethasone inhibition of plasminogen activator production have been isolated using an agar-fibrin overlay technique to detect protease production by individual colonies of HTC cells. The hormonal resistance to inhibition of protease production is associated witha maintenance of inducibility of other glucocorticoid-regulated functions and therefore is not apparently secondary to abnormal or absent glucocorticoid receptor, but due to a lesion in a later step in hormone action specific for plasminogen activator. Combined genetic and biochemical analysis of such dexamethasone-resistant variants should facilitate study of the hormonal regulation of specific membrane phenotypes and of the role of proteases in this regulation.

Alanine↗
PubMed1998

Radiation-induced blood-brain barrier changes: pathophysiological mechanisms and clinical implications.

The pathophysiology of whole-brain radiation (WBR) toxicity remains incompletely understood. The possibility of a primary change in blood-brain barrier (BBB) associated with microvascular damage was investigated. Rats were exposed to conventional fractionation in radiation (200 +/- cGy/d, 5d/wk; total dose, 4,000 cGy). BBB changes were assessed by means of the quantitative 14C-alpha-aminoisobutyric acid (AIB) technique coupled with standard electron microscopy (EM) and morphometric techniques as well as studies of the transcapillary passage of horseradish peroxidase (HRP). At 15 days after WBR, AIB transport across BBB increased significantly in cerebral cortex. EM disclosed vesicular transport of HRP across the intact endothelium without opening of the tight junctions. Ninety days after WBR, well-defined alterations of the microvasculature were observed. The main feature of cortical microvessels was their collapsed aspect, associated with perivascular edema containing cell debris. Data suggest a possible association between damage of the microvascular/glial unit of tissue injury and development of radiation-induced brain cerebral dysfunction. We hypothesize the following sequence of pathophysiological events: WBR causes an early increase in BBB permeability, which produces perivascular edema and microvascular collapse. The interference with microcirculation affects blood flow and energy supply to the tissue, resulting in structural damage on an ischemic/dysmetabolic basis.

Animals↗
PubMed2002

Experimental intracerebral hemorrhage: effect of lysed erythrocytes on brain edema and blood-brain barrier permeability.

Understanding the mechanism of edema formation following intracerebral hemorrhage (ICH) is important for developing treatment protocols for this condition. This study examines the role of red blood cell (RBC) lysis and hemoglobin in edema formation following ICH. Significant brain edema developed after 24 hours in rats infused with lysed RBCs and this was associated with a 3-fold increase blood brain barrier (BBB) permeability to alpha-aminoisobutyric acid. We have previously shown that intracerebral injection of packed RBCs does not cause edema formation at one day but does at three days. In this study, we found that packed RBCs did not cause significant BBB disruption at one day but produced a 4-fold increase in BBB permeability at three days. These studies show that following ICH the leakage of substances inside the RBC, facilitated by cellular lysis, results in delayed edema. This was confirmed by both experimentally induced lysis and naturally occurring in-vivo lysis.

Animals↗
PubMed1990

Selective opening of the blood-tumour barrier by intracarotid infusion of leukotriene C4.

Intracarotid infusions of leukotriene C4 (LTC4) were used to selectively open the blood-tumour barrier in rats with RG-2 gliomas. Blood-brain and blood-tumour barrier permeability was determined by quantitative autoradiography using 14C aminoisobutyric acid. LTC4 (4 micrograms total dose) infused into the carotid artery ipsilateral to the tumour increased the unidirectional transfer constant for permeability, Ki, two-fold within the tumour while no effect on permeability was seen in the normal brain. No gamma glutamyl transpeptidase (gamma-GTP) activity was seen in tumour capillaries in contrast to high gamma-GTP in normal brain capillaries. These findings suggest that normal brain capillaries may resist the vasogenic effects of LTC4 while LTC4 will increase permeability in tumour capillaries. This could relate to the ability of gamma-GTP to act as an enzymatic barrier and inactivate leukotrienes in normal brain capillaries. Intracarotid LTC4 infusion may be a useful tool to selectively open the blood-tumour barrier for delivery of antineoplastic compounds.

Animals↗
PubMed1994

Blood-brain barrier, cerebral blood flow, and cerebral plasma volume immediately after head injury in the rat.

The purpose of the present study was to determine blood-brain barrier (BBB) permeability, regional cerebral blood flow (rCBF) and regional cerebral plasma volume (rCPV) in the period immediately after head injury, and thereby to evaluate the effects of vascular factors in the pathophysiology of traumatic brain injury. Male Sprague-Dawley rats (350-450 g) anesthetized with 1.0-1.5% halothane were subjected to an impact acceleration closed head injury at the moderate level. BBB permeability (n = 5), rCBF (n = 8) and rCPV (n = 9) were measured by quantitative autoradiographic techniques using 14C-alpha-aminoisobutyric acid (AIB), 14C-iodoantipyrine and 14C-sucrose, respectively. Intravenous administration of each radiotracer was simultaneous with the traumatic impact. At 10 min after injury, BBB permeability, the transfer constant for AIB, was less than 0.1 ml/kg/min for all regions except for those with a relatively leaky BBB. At 30 s after injury, a significant and heterogeneous increase in rCBF was observed at 9 subcortical regions (p < 0.05). RCPV increased significantly in the frontal cortex, parietal cortex, thalamus, and hypothalamus (p < 0.05). In our closed head injury model without severe hypertension, BBB disruption did not occur immediately after trauma. Vascular responses in the period immediately after trauma may result from the derangement of cerebral autoregulation.

Animals↗
PubMed1981

Gyrate atrophy of the choroid and retina. Approaches to therapy.

Gyrate atrophy of the choroid and retina is caused by deficient activity of ornithine ketoacid aminotransferase, a pyridoxal phosphate dependent enzyme. Besides the typical eye findings, abnormalities have been found on muscle biopsy, electro-encephalography, electromyography and electrocardiography, establishing this as a generalized disorder. Ornithine is markedly elevated in plasma and other body fluids. Plasma lysine, glutamate, glutamine and creatine are reduced. The possible contributions of these biochemical disturbances to the pathogenesis of gyrate atrophy are discussed. The disease is one of the few examples of an inherited chorioretinal dystrophy whose underlying biochemical defect is known. It therefore offers a unique opportunity to develop and test rational approaches to therapy. These include lowering of the abnormally high ornithine by dietary restriction of its precursor arginine, facilitation of ornithine excretion by administration of alpha-aminoisobutyric acid, replacement of deficient products such as lysine or creatine, or increasing residual enzyme activity by high levels of cofactor (vitamin B6). The results of several studies employing such approaches to therapy are presented as well as preliminary indications of possible benefit in a few patients.

Adult↗
PubMed1991

Blood flow and blood-to-tissue transport in 9L gliosarcomas: the role of the brain tumor model in drug delivery research.

We used double-label quantitative autoradiography to measure blood flow (with 131I-iodoantipyrine) and blood-to-tissue transport of 14C-alpha aminoisobutyric acid, AIB) in thirteen 9L gliosarcomas transplanted intracerebrally into Fischer-344 rats. Microscopically, the typical pattern of 9L tumor growth was observed: a solid central tumor mass surrounded by extensive perivascular invasion. The averaged mean whole tumor transfer constant, K, of AIB in the 9L tumors was 33 +/- 15 (+/- SD) microliters/g/min. The averaged mean value of blood flow, F, was 72.2 +/- 27.3 ml/100 g/min. In brain around tumor (BAT), K (13 +/- 4 microliters/g/min) was lower than in the solid tumor, but was still 6-9 times that of tumor-free brain. F in BAT (115.9 +/- 64.6 ml/100 g/min) was comparable to values in tumor-free cortex in the same hemisphere. Values of K and F were used to calculate a net extraction fraction (En) for different regions of brain and tumor. The value of En of AIB in normal cortex was 0.003, in BAT En was 0.02, and in whole tumor the value was 0.09. The delivery of water-soluble compounds in 9L brain tumors is limited by the permeability/surface area characteristics of the tumor capillaries. The properties of blood-to-tissue transport and blood flow of 11 different brain tumor models are compared, and discussed with regard to the choice of brain tumor models for drug delivery research. The 9L brain tumor model is comparable to other transplanted rat brain tumor models, although the extent of tumor cell invasion into BAT makes this model distinctive. However, with regard to blood-to-tissue transport the 9L model differs from autochthonous models and transplanted human glioma models. We discuss guidelines for selecting brain tumor models with which to study the problem of drug delivery to brain tumors.

Animals↗
PubMed1995

Amino acid uptake in skeletal muscle of rats bearing the Yoshida AH-130 ascites hepatoma.

Rats bearing the Yoshida AH-130 ascites hepatoma show decreased activity of neutral amino acid transport in skeletal muscle measured in vivo as the tissue accumulation of the analogue alpha-amino [1-14C]isobutyrate (AIB). The decreased accumulation of AIB observed is not merely a consequence of the hypoinsulinaemia present in these animals (as a result of tumour burden) since in vitro experiments carried out using incubations of isolated soleus muscles also showed a decreased uptake of neutral amino acids. In these preparations the addition of insulin results in similar increases in uptake both in the pair-fed controls and the tumour-bearing animals, thus suggesting similar insulin sensitivities. The decrease in amino acid uptake in soleus muscle is associated with a decrease in the activity of system A, while systems L and ASC show no particular changes as a result of the tumour growth. The kinetic characterisation of system A in the Yoshida-bearing rats shows a decrease in Vmax together with a decrease in KM in relation with the pair-fed animals.

Amino Acids↗
PubMed1995

Permeability change and brain tissue damage after intracarotid administration of cisplatin studied by double-tracer autoradiography in rats.

The present study was designed to find the reliable parameter(s) for the detection of early neurotoxicity following intracarotid (IC) administration of cisplatin. IC administration was performed for 60 minutes in female Wistar rats derived into four groups according to the dose given (1 mg, 1.2 mg, and 1.5 mg of cisplatin, and normal saline in control rats). Blood-brain barrier (BBB) permeability and local cerebral blood flow (LCBF) were measured by a double-tracer autoradiography technique using 1-[14C]-alpha-aminoisobutyric acid (14C-AIB) and 4-[18F] fluoroantipyrine (18F-FAP), respectively. Blood chemistry and neuropathology were also examined. BBB permeability was increased only on the ipsilateral side. This increase was dose-dependent, preceded the brain necrosis, and was statistically significant in the hypothalamus (1.2 mg group), auditory cortex and caudoputamen (1.5 mg group). Renal dysfunction was often observed. The changes in the LCBF did not occur until brain necrosis was noticeable. These findings demonstrate that the increase in the BBB permeability provides a sensitive and reliable indication of an early toxicity to brain tissue following IC administration of cisplatin.

Animals↗