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Results for “Biogenic Polyamines”

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PubMed1991

[Inhibitory effects of interferon and inhibitors of polyamine biosynthesis on clonal growth of Raji cells derived from Burkitt's lymphoma].

Interferon (IFN)-alpha, -gamma, and two inhibitors of polyamine biosynthesis (alpha-difluoromethyl ornithine; DFMO and methyl glyoxal bis-guanyl hydrazone; MGBG) inhibited the clonal growth of Raji cells. The combination-treatment using two agents, particularly IFN-alpha and DFMO represented synergistic effects. In order to investigate the mechanism of the synergism between IFNs and inhibitors of polyamine biosynthesis, the concentrations of polyamines and the levels of 2'-5' oligo-adenylate synthetase (2-5 AS) activity in the treated Raji cells were determined. Not only the inhibitors of polyamine biosynthesis, but also IFNs decreased the content of spermidine in the cells. Furthermore, the clonogenic growth-inhibition by IFN-alpha was recovered partially by exogenous spermidine. On the other hand, 2-5AS activity in the cells was elevated to 57 times by the treatment with interferon-alpha and further more, the combinations of IFN and the inhibitors of polyamine biosynthesis induced higher activities of 2-5AS as compared with those by each agent. From these results, it was suggested that the synergistic effects of IFNs in combinations with inhibitors of polyamine biosynthesis on the inhibition of clonal growth of Raji cells were closely associated with the decrease of intracellular polyamine level and the increase of 2-5AS activity in the treated cells.

2',5'-Oligoadenylate Synthetase↗
PubMed1990

Urinary polyamine excretion measured by a simple enzymatic method is clinically useful as an expression of hepatic regeneration in liver diseases.

Polyamines have been known to play an important role in hepatic regeneration. In the present study, we measured the amount of urinary polyamine excretion in various liver diseases using a simple enzymatic method. Urinary polyamine excretion was elevated above the normal range in 21 out of 47 cases with fulminant hepatic failure, acute hepatitis, chronic active hepatitis, and liver cirrhosis. No change, however, was observed in 11 patients with chronic inactive hepatitis. In fulminant hepatic failure, two patients with urinary polyamine concentrations above 100 mumoles/g.cr. recovered, while two patients with concentrations of 56.2 and 26.7 mumoles/g.cr., died. In acute hepatitis, urinary polyamine excretion was significantly less in the recovery stage compared with the acute stage. When insulin and glucagon infusion therapy was performed in patients with liver cirrhosis without ascites, urinary polyamine excretion was significantly elevated after three days. These results suggest that measuring the amount of polyamine in urine is clinically useful for monitoring hepatic regeneration.

Biogenic Polyamines↗
PubMedDate not supplied

Inhibition of the differentiation of 3T3-L1 cells by interferon-beta and difluoromethyl ornithine.

Both mouse interferon-beta (MuIFN-beta) and the inhibitor of ornithine decarboxylase (ODC), alpha-difluoromethyl ornithine (DFMO), inhibited the differentiation of mouse 3T3-L1 fibroblasts into adipocytes in a dose-dependent manner. DFMO and MuIFN-beta added together to cultures that were induced to differentiate produced an additive anti-differentiation effect. In contrast to this additive cellular effect, DFMO reduced the antiviral activity of MuIFN-beta in both undifferentiated and differentiated cells; DFMO alone had no detectable effect on replication of encephalomyocarditis virus. Putrescine, the product of ornithine decarboxylation, when added to 3T3-L1 cultures (i) enhanced differentiation, (ii) reversed completely the inhibition of differentiation by DFMO, but (iii) had little effect on the anti-differentiation effect of MuIFN-beta. Polyamine content changed four-fold or less in cultures treated with 0.5 mM DFMO and less than two-fold in cultures treated with 100 IU/ml MuIFN-beta for seven days. Thus, it appears not only that MuIFN-beta and DFMO inhibit differentiation of 3T3-L1 cells by different mechanisms but also that the antiviral action of IFN does not involve the regulation of polyamine metabolism by ornithine decarboxylase.

Animals↗
PubMed1995

Structural requirements of analogues of polyamines for migration and growth of IEC-6 cells.

Healing of gastrointestinal mucosal lesions occurs through two processes: an early one involving cell migration and a later one in which cell division replaces lost cells. Both processes require the presence of polyamines, but the mechanism of action of these compounds is unknown. In the present study, we examined the ability of analogues of spermidine and spermine to support migration and growth of IEC-6 cells that have been grown in alpha-difluoromethylornithine to inhibit polyamines. All analogues of spermidine with the general formula x-3 (referring to the numbers of carbon atoms on either side of the central nitrogen), where x = 2-12, competed with spermidine for entry into the cells. However, in addition to spermidine (x = 4), only compounds for which x = 2, 3, or 6 supported migration and only those for which x = 2 or 7 supported growth. Spermine analogues 3-x-3, for which x = 3, 6, 9, or 12, competed for entry into the cells, but only compounds for which x = 3 or 6 supported migration and only the compound for which x = 3, in addition to spermine (x = 4), supported growth. In addition, analogues 2-3-2, 3-2-3, and 2-(3)2, a branched compound, supported both migration and growth but entered the cell via a mechanism different than that for spermidine and spermine. These data define some of the specific structural requirements for polyamines to produce their physiological effects.

Animals↗
PubMed1989

Heterogeneous survival and cell kinetics responses of human astrocytoma clones to alpha-difluoromethylornithine in vitro.

The effects of alpha-difluoromethylornithine (DFMO) on survival, cell kinetics and polyamine levels were studied on two clones of human astrocytoma in vitro. The survival responses were dose and time dependent; and treatments with DFMO which lasted for 72 h resulted in heterogeneous responses with one clone being up to 6 times more sensitive than the other. Shorter treatments produced more uniform killing in the clones. A continuous exposure of the cells to 5 mM DFMO resulted in a rapid decrease in putrescine values in both clones, followed by decreases in the spermidine levels. These effects were closely followed by 148% to 170% increases in cell population doubling times, and a lowering of saturation densities. No clear correlations could be established among baseline polyamine levels and cell kinetics or survival responses to DFMO treatments.

Astrocytoma↗
PubMed2003

Polyamine metabolism in primary human colon adenocarcinoma cells (SW480) and their lymph node metastatic derivatives (SW620).

The natural polyamines are multifunctional constituents of all eucaryotic cells. The objective of this work was to compare aspects of polyamine metabolism in two related cell lines with the idea to investigate whether metabolic differences can be attributed to functional differences of the cells. The human colon carcinoma-derived cell lines SW480 and SW620 were chosen as models. SW480 cells were isolated from the primary tumour, SW620 cells from a lymph node of the same patient. SW620 cells grow faster, and the key regulatory enzymes of polyamine biosynthesis (ODC and AdoMetDC) are more active in the metastatic cells. Moreover, their ability to accumulate polyamines from the environment is more important than of SW480 cells. Likewise polyamine concentrations were markedly higher in SW620 cells, although they are much smaller than SW480 cells, and have a particularly small cytoplasmic space. Both cell lines show a striking diminution of ODC and AdoMetDC activities and changes in the polyamine patterns at the transition from exponential to non-exponential growth--most probably as a consequence of high cell density. Depletion of putrescine and spermidine due to inactivation of ODC by DFMO causes accumulation of cells in G1, and a proportional decrease of S-phase cells in both cell lines. Based on morphologic and other criteria SW480 and SW620 cells were typified as poorly differentiated. In agreement with their low grade of differentiation they exhibit a low alkaline phosphatase activity. However, the time-dependent decrease of alkaline phosphatase is not typical of differentiation patterns of other adenocarcinoma-derived cell lines or of normal enterocytes. The high capacity of de novo polyamine biosynthesis and of polyamine uptake is presumably a prerequisite for the rapid growth and invasiveness. The fact that these properties were more accentuated in the case of SW620 cells and paralleled enhanced metastatic properties indicate relationships between basic parameters of polyamine metabolism and malignancy.

Adenocarcinoma↗
PubMed1991

The polyamine synthesis inhibitor alpha-difluoromethylornithine is neuroprotective against N-methyl-D-aspartate-induced brain damage in vivo.

We examined the ability of alpha-difluoromethylornithine (DFMO), an inhibitor or ornithine decarboxylase, the rate limiting enzyme for polyamine biosynthesis, to protect the brain of the perinatal rat from N-methyl-D-aspartate (NMDA)-induced brain damage. Treatment of the rat pups with DFMO administered either by i.p. injection (500 mg/kg x 2) or through the milk of the mother (2% solution in mother's drinking water) significantly reduced, by 48 and 62%, respectively, the brain damage produced by intrastriatal NMDA injection. We conclude that activation of polyamine synthesis may mediate part of the neurotoxic action of NMDA.

Animals↗
PubMed1994

Polyamines promote neurite elongation of cultured rat hippocampal neurons.

The effects of spermine, spermidine and putrescine on the survival and morphology of hippocampal neurons obtained from rat embryos were investigated using low cell density culture. The number of surviving neurons gradually decreased in the control cultures, while addition of spermine significantly promoted neuronal survival. The survival-promoting effect of spermine was seen maximally at a concentration of 10(-8) M. On the other hand, spermidine and putrescine showed no significant effect on neuronal survival. The axon length of neurons cultured in the presence of spermine was significantly longer than that in the medium with no added spermine, indicating that spermine promotes process elongation. The concentration-effect curve for spermine was bell-shaped with the maximum effect at a concentration of 10(-8) M. However, the number of processes per soma, the elongation of dendrites and the process branching in axons were not significantly affected by the presence of spermine. Addition of spermidine and putrescine also promoted the axon elongation of cultured neurons, without affecting the branching number. The effects of spermidine and putrescine on neuronal growth were very similar to that of spermine in terms of the effective concentrations and the patterns of morphological changes. Since spermine specifically promoted neuronal survival while three polyamines affected the neuronal morphology in a similar manner, it is possible that the effects of polyamines on neuronal survival and neurite elongation are mediated by different mechanisms.

Animals↗
PubMed1994

Pattern of polyamines and related monoacetyl derivatives in chick embryo retina during development.

Polyamines and related monoacetyl derivatives were studied in chick embryo retina during development (6th-19th day). Putrescine, which is high in the first phase of retinogenesis, is necessary to sustain both tissue proliferation and via N-acetylputrescine, gamma-aminobutyric acid synthesis. A later increase in spermidine and particularly spermine may play a role in the last phase of development when the retina reaches maturation. The presence of N1-acetylspermidine already at the 8th day indicates that in chick embryo retina, putrescine synthesis can depend on two separate pathways. The first involves ornithine decarboxylase activity; the second, spermidine/spermine N1-acetyltransferase and probably polyamine oxidase that converts spermidine to putrescine via N1-acetylspermidine.

Animals↗
PubMed1998

Lack of evidence for direct involvement of NMDA receptors or polyamines in blood-brain barrier injury after cerebral ischemia in rats.

It is hypothesized that after various types of brain injury, blood-brain barrier (BBB) opening and vasogenic edema result from excessive neuronal release of glutamate and stimulation of capillary N-methyl-d-aspartate (NMDA) receptors linked to polyamine (putrescine) synthesis in endothelial cells. We produced cerebral ischemia in rats and measured BBB opening 6 h later as the increase in regional transfer constants (Ki) for blood to brain diffusion of [3H]sucrose. Such BBB opening was not mitigated by drugs which block NMDA receptors (MK801 or AR-R 15896AR) or polyamine synthesis (difluoromethylornithine). These results question generality of the capillary NMDA receptor/polyamine hypothesis.

Animals↗
PubMed1992

Purification and characterization of polyamine oxidase from Ascaris suum.

The interconversion of polyamines in the parasite nematode Ascaris suum by a novel type of polyamine oxidase was demonstrated. The nematode enzyme was clearly distinguishable from monoamine and diamine oxidases as well as from the mammalian polyamine oxidase, as shown by the use of the specific inhibitors pargyline, aminoguanidine and MDL 72527 respectively. All three inhibitors had no effect on the parasite polyamine oxidase, and the enzyme did not accept diamines such as putrescine, cadaverine or histamine as substrates. The parasite polyamine oxidase selectively oxidizes spermine and spermidine but not N-acetylated polyamines, whereas the mammalian tissue-type polyamine oxidase shows preference for the N-acetylated polyamines. These results suggest a regulatory function of the nematode polyamine oxidase in the degradation and interconversion of polyamines in parasite nematodes. The enzyme was purified to homogeneity by gel filtration, preparative isoelectric focusing and subsequent affinity chromatography on spermine- and berenil-Sepharose 4B. With respect to reaction type, the prosthetic group FAD, the molecular mass (66 kDa) and the contents of thiol and carbonyl groups, the polyamine oxidase from A. suum is similar to the isofunctional enzyme of mammalian tissue.

Animals↗
PubMed1995

Ethanol's effect on tissue polyamines and ornithine decarboxylase activity: a concise review.

An extraordinarily diverse literature describes the cellular/tissue systems in which the molecular effects of both acute and chronic alcohol exposure seem to be mediated by changes in polyamine levels and/or ornithine decarboxylase (ODC) activity. The single unifying factor that links most of these studies is that they all, in some way, involve tissues that are undergoing relatively rapid cell division. Non-dividing cells expressing the NMDA receptor are a notable exception in that ethanol and the polyamines seem to act via discrete regions of that receptor. Under most cellular conditions, ODC activity is a reflection of the relative tissue polyamine content, and an increase in ODC activity and polyamine content seems to be one of the early events in the progression of quiescent cells toward cell division. Thus, it is not surprising that ethanol, which has been widely reported to delay cell division, should be found to interact with the ODC/polyamine pathway. Perhaps the most unique aspect of these studies is the fact that, with rare exception, both acute and chronic ethanol exposure have been found to slow growth and to lower tissue polyamine (putrescine) content. Furthermore, in most studies, the ethanol-induced suppression of cell division could be overcome by the administration of exogenous putrescine. These data suggest that the ethanol-induced suppression of cell division resulted from the loss of putrescine. In addition, because the cells were able to respond to the exogenous putrescine, the studies suggest that the signaling pathway remained intact beyond the polyamine synthesis step.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Drinking↗
PubMed2001

Rat colon ornithine and arginine metabolism: coordinated effects after proliferative stimuli.

Ornithine decarboxylase (ODC) catalyzes the first step in the polyamine biosynthetic pathway, a highly regulated pathway in which activity increases during rapid growth. Other enzymes also metabolize ornithine, and in hepatomas, rate of growth correlates with decreased activity of these other enzymes, which thus channels more ornithine to polyamine biosynthesis. Ornithine is produced from arginase cleavage of arginine, which also serves as the precursor for nitric oxide production. To study whether short-term coordination of ornithine and arginine metabolism exists in rat colon, ODC, ornithine aminotransferase (OAT), arginase, ornithine, arginine, and polyamine levels were measured after two stimuli (refeeding and/or deoxycholate exposure) known to synergistically induce ODC activity. Increased ODC activity was accompanied by increased putrescine levels, whereas OAT and arginase activity were reduced by either treatment, accompanied by an increase in both arginine and ornithine levels. These results indicate a rapid reciprocal change in ODC, OAT, and arginase activity in response to refeeding or deoxycholate. The accompanying increases in ornithine and arginine concentration are likely to contribute to increased flux through the polyamine and nitric oxide biosynthetic pathways in vivo.

Animals↗
PubMed1990

Acute and chronic effects of cyclosporine A on pancreatic polyamine metabolism and pancreatic adaptation.

The present study was designed to investigate the effects of acute and chronic application of the immunosuppressive agent cyclosporine A (CsA) on pancreatic polyamine metabolism as well as pancreatic growth of rats in vivo. Seven to ten animals per group were treated with either the synthetic trypsin inhibitor camostate (FOY-305, 200 mg/kg b.wt. p.o. twice a day), CsA (10 mg/kg b.wt. p.o. once a day), camostate plus CsA, or oil as control, and animals were killed after 8 h, 1, 5 and 14 days. Feeding of camostate resulted in a significant increase of the measured parameters in the following time-course: cholecystokinin (CCK), 8 h; ornithine decarboxylase (ODC), 8 h: putrescine, 8 h; S-adenosylmethionine decarboxylase (SAM-DC), 1 day; pancreatic weight, 1 day; protein content, 5 days; spermidine, 5 days; RNA, 5 days; and DNA, 14 days. Simultaneous treatment with CsA resulted in a significant inhibition of camostate-induced increases in ODC, SAM-DC as well as putrescine and spermidine and furthermore caused a nearly complete inhibition of the increase of all trophic parameters, while CCK plasma levels were not altered. Counterregulatory mechanisms to maintain the intracellular polyamine pool as known after application of specific inhibitors of enzymes of the polyamine metabolism (i.e. DFMO) were not observed. Therefore we conclude that CsA does not directly interact with the polyamine metabolism, but rather with the second messenger system or any other intracellular mechanism, that is activated after stimulation with CCK before the polyamine metabolism is induced.

Acetyltransferases↗
PubMed1994

Kanamycin depletes cochlear polyamines in the developing rat.

Developing mammals are more sensitive to aminoglycoside antibiotics and other ototoxic agents than adults, with maximum sensitivity occurring during the period of anatomic and functional maturation of the cochlea. For the aminoglycoside antibiotics, the hypersensitive period in rats occurs during the second and third postnatal weeks. Toxicity is initially expressed as outer hair cell (OHC) damage in the high-frequency, basal region of the cochlea. Distortion-product otoacoustic emissions (DPOAEs), physiologic measures of OHC function, are particularly sensitive to aminoglycoside exposure during the period of rapid cochlear physiologic development. Toxicity is characterized by increased DPOAE thresholds and decreased amplitudes. The mechanism of developmental sensitivity to aminoglycosides is unknown. A potential biochemical target of aminoglycosides is the ornithine decarboxylase (ODC)-polyamine pathway. ODC activity is elevated in the developing rat cochlea, aminoglycosides inhibit cochlear ODC in developing rats, and alpha-difluoromethylornithine (a specific ODC inhibitor) impairs development of cochlear function. In the present study we demonstrate an incomplete polyamine response to aminoglycoside damage, characterized by inhibition of the polyamines spermidine and spermine and accumulation of putrescine in the organ of Corti. Aminoglycoside inhibition of polyamine synthesis may mediate developmental ototoxic hypersensitivity by interfering with developmental and repair processes.

Analysis of Variance↗