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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↗
PubMedDate not supplied

Animal disease models generated by genetic engineering of polyamine metabolism.

The polyamines putrescine, spermidine and spermine are natural components of all living cells. Although their exact cellular functions are still largely unknown, a constant supply of these compounds is required for mammalian cell proliferation to occur. Studies with animals displaying genetically altered polyamine metabolism have shown that polyamines are intimately involved in the development of diverse tumors, putrescine apparently has specific role in skin physiology and neuroprotection and the higher polyamines spermidine and spermine are required for the maintenance of pancreatic integrity and liver regeneration. In the absence of ongoing polyamine biosynthesis, murine embryogenesis does not proceed beyond the blastocyst stage. The last years have also witnessed the appearance of the first reports linking genetically altered polyamine metabolism to human diseases.

Animals↗
PubMed1993

Inhibition of calcium hydroxyapatite formation by polyamines.

The lithogenic potential of bile depends not only on supersaturation of solutes but also on the presence of pro- and anti-nucleating factors. For example, glycine-conjugated dihydroxy bile salt dimers are potent inhibitors of calcium hydroxyapatite precipitation that function by "poisoning" the nascent crystal. Although most inhibitors of apatite formation are anions, theoretically polycations should also be effective, and because significant concentrations of polyamines are present in bile, we have investigated the ability of these molecules to inhibit apatite formation. In vitro, each polyamine (2-10 mmol/l) was able to inhibit apatite formation, and the inhibiting power was correlated with ionic charge. Thus putrescine (2+) was the weakest inhibitor and spermine (4+) was the strongest. Mixtures of polyamines were less effective than were the individual polyamines, except at higher concentrations. Although polyamines were effective over short periods of time (270 min), over longer times (3 days) spermine was unable to prevent apatite formation. Using infrared spectroscopy, we found no evidence for interaction between phosphate ions and spermine in solution. Taken together, these results suggest that polyamines are modest inhibitors of apatite formation that likely function by retarding the dissolution of the intermediate amorphous calcium phosphate phase.

Bile↗
PubMed1990

The polyamines of Xanthium strumarium and their response to photoperiod.

Flowering plants of Xanthium strumarium L., grown in 8 h photoperiods, were analysed for polyamines. Putrescine, spermidine and spermine were found throughout the plant in three forms: (a) as free polyamines; (b) conjugates soluble in 5% trichloracetic acid (TCA); and (c) bound to the TCA-insoluble precipitate. On a fresh weight basis, total polyamines are most abundant in young leaves and buds, especially flower buds. Spermidine predominates in the free polyamine fractions, while spermine is dominant in the conjugated fraction. Transfer of vegetative plants from 16 h photoperiods to 1, 2, 3, or 4 inductive cycles (8 h light + 16 h uninterrupted dark) caused rapid and marked changes in the polyamine titer of the leaves and ultimately, floral initiation. The titer of free putrescine per mg protein declined progressively with induction in all leaf sizes, while the titers of free spermidine and spermine rose during days 2 and 3 in small and expanding leaves. Conjugated putrescine, spermidine and spermine rose sharply after only 1 inductive cycle, especially in small and expanding leaves, and maintained the higher level for at least several cycles. In plants given 4 inductive cycles, buds harvested after 4 additional days had sharply elevated levels of conjugated polyamines, especially spermine, on a protein basis.

Light↗
PubMed2003

Small interfering RNA suppression of polyamine analog-induced spermidine/spermine n1-acetyltransferase.

N1,N11-diethylnorspermine (DENSPM) is a polyamine analog that down-regulates polyamine biosynthesis and potently upregulates the polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase (SSAT). In certain cells, such as SKMEL-28 human melanoma cells, induction of SSAT is associated with rapid apoptosis. In this study, we used small interfering RNA (siRNA) to examine the role of SSAT induction in mediating polyamine pool depletion and apoptosis. siRNA duplexes were designed to target three independent sites in the SSAT mRNA coding region (siSSAT). When transfected under nontoxic conditions, two of the duplexes selectively reduced basal SSAT mRNA in HEK-293 cells by >80% and prevented DENSPM-induced SSAT mRNA by 95% in SK-MEL-28 cells. Treatment of SK-MEL-28 cells with 10 muM DENSPM in the presence of 83 nM siSSAT selectively prevented the 1400-fold induction of SSAT activity by approximately 90% and, in turn, prevented analog depletion of spermine (Spm) pools by approximately 35%. siSSAT also prevented DENSPM-induced cytochrome c release and caspase-3 cleavage at 36 h and apoptosis at 48 h as measured by annexin V staining. Overall, the data directly link analog induction of SSAT to Spm pool depletion and to caspase-dependent apoptosis in DENSPM-treated SK-MEL-28 cells. This represents the first use of siRNA technology directed toward a polyamine gene and the first unequivocal demonstration that SSAT induction initiates events leading to polyamine analog-induced apoptosis.

Acetyltransferases↗
PubMed1996

Polyamine content of Pneumocystis carinii and response to the ornithine decarboxylase inhibitor DL-alpha-difluoromethylornithine.

Difluoromethylornithine (DFMO; eflornithine hydrochloride [Ornidyl]), a suicide inhibitor of the key polyamine biosynthesis enzyme ornithine decarboxylase (ODC), is effective in treating Pneumocystis carinii pneumonia, a common opportunistic infection associated with AIDS. Despite DFMO's specificity for ODC, the reason for its selective toxicity against P. carinii is unknown since both host and parasite are dependent on the same enzyme for polyamine biosynthesis. A new high-performance liquid chromatography method was used with P. carinii cells isolated from infected rat lungs to measure polyamine content, to confirm the presence of ODC, and to examine the effect of DFMO on polyamine concentrations. Putrescine, spermidine, and spermine were found to be present at 2.00 +/- 0.54, 1.26 +/- 0.51, and 1.59 +/- 0.91 nmol (mg of protein)-1, respectively, neither unusually high nor low values. ODC's specific activity was 79 +/- 11 pmol (mg of protein)-1 h-1, again not a remarkable value. However, the rates of both DFMO-induced polyamine depletion and subsequent repletion upon DFMO removal were unusually high. A 3-h exposure to 1 mM DFMO in vitro caused the depletion of putrescine, spermidine, and spermine to levels 12, 29, and 16%, respectively, of that of control cells. After DFMO removal and incubation for 1 h in serum-free media, polyamine levels returned to 78, 88, and 64%, respectively, of that of the control cells not exposed to DFMO. Since such depletions and repletions usually occur over periods of days rather than hours, these rapid changes may provide a clue to the selective action of DFMO against P. carinii and may guide the development of new compounds and an optimal drug administration schedule for DFMO.

Animals↗
PubMed1988

Adjustment of polyamine contents in Escherichia coli.

Adjustment of polyamine contents in Escherichia coli was studied with strains of Escherichia coli producing normal (DR112) and excessive amounts of ornithine decarboxylase [DR112(pODC)] or S-adenosylmethionine decarboxylase [DR112(pSAMDC)]. Although DR112(pODC) produced approximately 70 times more ornithine decarboxylase than DR112 did, the amounts of polyamines in the cells of both strains did not change significantly. The amounts of polyamines in DR112(pODC) were adjusted by excretion of excessive amounts of putrescine to the medium. When ornithine was deficient in cells, polyamine contents in DR112(pODC) were much higher than those in DR112, although polyamine contents were low in both strains. This indicates that large amounts of ornithine decarboxylase increased the utilization of ornithine for putrescine synthesis. During ornithine deficiency, strain DR112 produced 3.4 times more ornithine decarboxylase. Strain DR112(pSAMDC) produced seven times more S-adenosylmethionine decarboxylase than DR112 did. In DR112(pSAMDC) an increase (40%) in spermidine content, a decrease (35%) in putrescine content, and no significant excretion of putrescine and spermidine were observed. The amount of ornithine decarboxylase in DR112(pSAMDC) was approximately 30% less than that in DR112. In addition, S-adenosylmethionine decarboxylase activity was strongly inhibited by spermidine. A possible regulatory mechanism to maintain polyamine contents in Escherichia coli is discussed based on the results.

Adenosylmethionine Decarboxylase↗
PubMed1989

Polyamines and regulation of ornithine biosynthesis in Escherichia coli.

The growth rate of several polyamine-deficient mutants of Escherichia coli was very low in minimal medium and increased markedly upon the addition of putrescine, spermidine, arginine, citrulline, or argininosuccinic acid. The endogenous content of polyamines was not significantly altered by the supplementation of polyamine-starved cultures with arginine or its precursors. In contrast, these compounds as well as putrescine or spermidine caused a 40-fold reduction in intracellular ornithine levels when added to polyamine-depleted bacteria. In vivo experiments with radioactive glutamic acid as a precursor and in vitro assays of the related enzymes showed that the decrease in ornithine levels was due to the inhibition of its biosynthesis rather than to an increase in its conversion to citrulline or delta 1-pyrroline-5-carboxylic acid and proline. High endogenous concentrations of ornithine were toxic for the E. coli strains tested. The described results indicate that the stimulatory effect of putrescine and spermidine on the growth of certain polyamine-starved bacteria may be partially due to the control of ornithine biosynthesis by polyamines.

Amino Acids↗
PubMed1987

Polyamines in intestinal and pancreatic adaptation.

The intestinal mucosa is a rapidly proliferative tissue, with a highly dynamic cell population. Its total cellular mass is well controlled and can adapt, with hypo- or hyperplasia, to a wide variety of stimuli. Luminal nutrients, hormonal factors, and pancreatic and biliary secretions have all been implicated in the regulation of intestinal mucosal adaptation. Similarly, the same factors appear essential for the maintenance of exocrine pancreatic structure and function. The polyamines (putrescine, spermidine, and spermine) and the key enzyme controlling their synthesis (ornithine decarboxylase, ODC) are important for many cell growth processes, and may play important roles in intestinal and pancreatic adaptation. During intestinal adaptation in response to jejunectomy, lactation and pancreatico-biliary diversion (PBD), intestinal contents of ODC and polyamines are increased, paralleling increases in mucosal proliferative indices and DNA synthesis. With administration of the specific inhibitor of ODC (difluoromethylornithine, DFMO) the increases in ODC and polyamines are suppressed, and intestinal adaptation is abrogated. In pancreatic hyperplasia induced by caerulein, pancreatic polyamines are increased. With DFMO administration, caerulein-induced increases in pancreatic DNA synthesis were inhibited and pancreatic hypertrophy was partially suppressed. PBD-induced pancreatic hypertrophy, however, was not affected by DFMO. Thus, the role of polyamines in the adaptation of the pancreas, with a relatively quiescent proliferative status, is as yet undefined. It seems clear, however, that the induction of ODC and the resultant increase in polyamine biosynthesis are critical for the normal growth and especially for adaptive hyperplasia of the intestinal mucosa.

Adaptation, Physiological↗
PubMed1993

Mucosal polyamine metabolism in the columnar lined oesophagus.

Mucosal ornithine decarboxylase activity and polyamine content has been proposed as a possible marker for malignant potential in gastrointestinal mucosa. Polyamine content and histological findings were examined in 107 pairs of endoscopic biopsy specimens taken from gastric fundus, fundic and specialised Barrett's oesophagus and Barrett's adenocarcinoma. The content of putrescine (median nmol/mg protein, range) the primary product of ornithine decarboxylase showed a progressive increase from gastric fundus (0.41, 0.15-1.5); fundic (0.45, 0.01-4.08); specialised Barrett's oesophagus (0.54, 0.01-2.0); dysplastic columnar lined oesophagus (0.56, 0.31-3.1) to adenocarcinoma (1.23, 0.29-8.98). Adenocarcinoma putrescine content was significantly greater than gastric fundus (p < 0.018) and fundic (p < 0.03). Mucosal spermine, spermidine, and total polyamine values were greater in gastric fundus than fundic, specialised Barrett's oesophagus, and dysplastic columnar lined oesophagus (all p < 0.001) suggesting failure to further metabolise putrescine to its higher polyamines in the metaplastic epithelium. Although metaplastic columnar lined oesophagus shows significant differences in polyamine metabolic activity from the stomach the important distinction between specialised and dysplastic columnar lined oesophagus cannot be made by measuring the polyamine content.

Adenocarcinoma↗
PubMed1983

Polyamines in colorectal cancer--a clinical and experimental approach.

The urinary polyamines putrescine, spermidine and spermine were measured prior to operation in 10 patients with colorectal cancer and 10 control subjects. Carcinoembryonic antigen assays were also performed in an attempt to correlate these values with polyamine excretion. The total polyamine rates in patients with colorectal cancer were 3.2 +/- 1.5 (SD) mg/24 h and 2.6 +/- 1.2 (SD) mg/24 h in the controls. The difference between the group with colorectal cancer and the controls was not statistically significant. Urinary polyamines were also measured in an experimental animal model for colorectal cancer in which tumour cell mass could be assessed. Only marginal differences occurred in polyamine rates between animals with extensive tumours and controls. These findings suggest that urinary polyamine measurement is unlikely to be a useful procedure to assess tumour cell mass in patients with colorectal cancer.

1,2-Dimethylhydrazine↗
PubMed1990

Ornithine and S-adenosylmethionine decarboxylase activities and polyamine contents in developing muscle tissues and primary cultures of normal and polymyopathic hamsters.

Polyamine (putrescine, spermidine, and spermine) contents and ornithine (ODC) and S-adenosylmethionine (SAMDC) decarboxylase activities have been assessed in an age-dependent manner, in normal and polymyopathic (dystrophic) hamster skeletal muscle, heart, and tongue extract and in primary tongue myoblast and skin fibroblast cultures. At 2 weeks of age, polyamine contents were significantly elevated in all of the dystrophic hamster tissues studied when compared with their age-matched controls. The degree of this elevation decreased with the age of the animals, generally, to a level where no significant difference in polyamine contents could be noted between normal and dystrophic hamster tissues. ODC and SAMDC activities in whole tissue extracts were consistently highest in 2-week-old muscle extracts and also declined with age. However, no significant changes in ODC or SAMDC activities were evident in any of the dystrophic muscle tissues studied when compared with their age-matched controls. Polyamine contents in dystrophic hamster myoblast and fibroblast primary cultures were also during proliferation (1 and 2 days after the initial seeding) compared with cultures prepared from normal hamsters. ODC and SAMDC activities in primary myoblast and fibroblast cultures clearly reflected the rate of cell proliferation, with highest activities found in subconfluent cell cultures. However, in general, no significant dystrophic-related abnormality in ODC or SAMDC activity was evident in proliferating myoblast or fibroblast cultures. These results suggest that the elevated polyamine contents of dystrophic hamster tissues and primary cultures may be due to a deficiency in polyamine catabolism or transport.

Adenosylmethionine Decarboxylase↗
PubMed2002

Polyamines regulate beta-catenin tyrosine phosphorylation via Ca(2+) during intestinal epithelial cell migration.

Polyamines are essential for early mucosal restitution that occurs by epithelial cell migration to reseal superficial wounds after injury. Normal intestinal epithelial cells are tightly bound in sheets, but they need to be rapidly disassembled during restitution. beta-Catenin is involved in cell-cell adhesion, and its tyrosine phosphorylation causes disassembly of adhesion junctions, enhancing the spreading of cells. The current study determined whether polyamines are required for the stimulation of epithelial cell migration by altering beta-catenin tyrosine phosphorylation. Migration of intestinal epithelial cells (IEC-6 line) after wounding was associated with an increase in beta-catenin tyrosine phosphorylation, which decreased the binding activity of beta-catenin to alpha-catenin. Polyamine depletion by alpha-difluoromethylornithine reduced cytoplasmic free Ca(2+) concentration ([Ca(2+)](cyt)), prevented induction of beta-catenin phosphorylation, and decreased cell migration. Elevation of [Ca(2+)](cyt) induced by the Ca(2+) ionophore ionomycin restored beta-catenin phosphorylation and promoted migration in polyamine-deficient cells. Decreased beta-catenin phosphorylation through the tyrosine kinase inhibitor herbimycin-A or genistein blocked cell migration, which was accompanied by reorganization of cytoskeletal proteins. These results indicate that beta-catenin tyrosine phosphorylation plays a critical role in polyamine-dependent cell migration and that polyamines induce beta-catenin tyrosine phosphorylation at least partially through [Ca(2+)](cyt).

Actin Cytoskeleton↗
PubMed1984

Role of polyamines in differentiation of 3T3-L1 fibroblasts into adipocytes.

The role of polyamines in the differentiation of 3T3-L1 fibroblasts into adipose cells was studied. This conversion was blocked by the addition of alpha-difluoromethylornithine, an enzyme-activated irreversible inhibitor of ornithine decarboxylase, which prevented a rise in spermidine content in the differentiating cells. The inhibition of differentiation could be overcome completely by the provision of exogenous putrescine, spermidine, or spermine. Partial reversal could be produced by exposure to nonphysiological homologues of the natural polyamines such as 1,3-diaminopropane, 1,5-diaminopentane, and sym-norspermine. Reversal of the inhibition of differentiation by exogenous polyamines required a period of exposure to the amines, indicating that the lack of differentiation is not due simply to an obligatory role for polyamines in the biosynthesis of lipids. These results indicate that spermidine is required for the differentiation, but spermidine alone was not able to replace insulin and 1-methyl-3-isobutylxanthine in stimulating conversion to adipocytes. Therefore spermidine appears to be necessary but not sufficient for differentiation to occur. Finally, the elevation of spermidine content that occurs during the conversion of fibroblasts to adipocytes did not correlate with an increased activity of the polyamine biosynthetic enzymes. This implies that the increase must be regulated by changes in the rate of degradation or excretion of the polyamines.

Adipose Tissue↗
PubMed1996

Effects of secretagogues on insulin biosynthesis and secretion in polyamine-depleted pancreatic beta-cells.

To extend previous observations on the importance of polyamines for glucose-stimulated insulinogenesis (N. Welsh and A Sjöholm. Polyamines and insulin production in isolated mouse pancreatic islets. Biochem. J. 252: 701-707, 1988), the impact of other secretagogues on insulin secretion of islets partially depleted in polyamines by selective inhibitors of L-ornithine decarboxylase and S-adenosyl-L-methionine decarboxylase was monitored. Glucose-sensitive, but not basal, insulin release was partially abolished in polyamine-deficient islets. Qualitatively similar impairments in insulin secretion were recorded when such islets were stimulated with nonglucidic nutrients (alpha-ketoisocaproic acid + L-glutamine), a cationic amino acid (L-arginine), activators of phospholipase C (carbachol) or protein kinase C (12-O-tetradecanoylphorbol 13-acetate), an adenosine 1', 5'-cyclic monophosphate-raising agent (forskolin), or a hypoglycemic sulfonylurea (glibenclamide). Additionally, glucose-responsive (pro)insulin biosynthesis was preferentially impeded in polyamine-deficient islets. It is concluded that polyamines act as permissive or stimulatory factors in insulin production and release. In addition, they seemingly do not act in an inhibitory manner on phospholipase C, protein kinase C, or Ca2+ flux into these islets, in contrast to reports in which insulinoma and other cells were used.

Adenosylmethionine Decarboxylase↗
PubMed1998

Polyamine deficiency alters EGF receptor distribution and signaling effectiveness in IEC-6 cells.

Cell growth and migration are essential processes for the differentiation, maintenance, and repair of the intestinal epithelium. Epidermal growth factor (EGF) is an important factor in the reorganization of the cytoskeleton required for both processes. Because we had previously found significant changes in the cytoskeleton during polyamine deficiency, it was of interest to know whether those changes could prevent EGF from stimulating growth and migration. Polyamine biosynthesis in IEC-6 cells was interrupted by treatment with alpha-difluoromethylornithine (DFMO), a specific inhibitor of ornithine decarboxylase, the primary rate-limiting enzyme of polyamine biosynthesis. DFMO halted cell proliferation and inhibited cell migration, and neither function could be normally stimulated by EGF. Immunocytochemistry of the transferrin receptor (used as a marker for the endocytic pathway) revealed an abnormal distribution of the EGF receptor (EGFR) 10 min after binding EGF. Polyamine deficiency depleted the cells of interior microfilaments, thickened the actin cortex, and prevented the prompt association of EGF-bound EGFR with actin. EGF-stimulated 170-kDa protein tyrosine phosphorylation and the kinase activity of purified membrane EGFR were reduced by 50%. Immunoprecipated EGFR protein concentration, however, was not reduced by polyamine deficiency. All of these changes could be prevented by supplementation with putrescine. Cytoskeletal disruption, reduced EGFR phosphorylation and kinase activity, aberrant intracellular EGFR distribution, and delayed association with actin filaments suggest a partial explanation for the dependence of epithelial cell growth and migration on polyamines.

Animals↗
PubMed2001

Ca2+-RhoA signaling pathway required for polyamine-dependent intestinal epithelial cell migration.

Expression of voltage-gated K(+) (Kv) channel genes is regulated by polyamines in intestinal epithelial cells (IEC-6 line), and Kv channel activity is involved in the regulation of cell migration during early restitution by controlling membrane potential (E(m)) and cytosolic free Ca2+ concentration ([Ca2+](cyt)). This study tests the hypothesis that RhoA of small GTPases is a downstream target of elevated ([Ca2+](cyt)) following activation of K(+) channels by increased polyamines in IEC-6 cells. Depletion of cellular polyamines by alpha-difluoromethylornithine (DFMO) reduced whole cell K+ currents [I(K(v))] through Kv channels and caused membrane depolarization, which was associated with decreases in ([Ca2+](cyt)), RhoA protein, and cell migration. Exogenous polyamine spermidine reversed the effects of DFMO on I(K(v)), E(m), ([Ca2+](cyt)), and RhoA protein and restored cell migration to normal. Elevation of ([Ca2+](cyt)) induced by the Ca2+ ionophore ionomycin increased RhoA protein synthesis and stimulated cell migration, while removal of extracellular Ca2+ decreased RhoA protein synthesis, reduced protein stability, and inhibited cell motility. Decreased RhoA activity due to Clostridium botulinum exoenzyme C(3) transferase inhibited formation of myosin II stress fibers and prevented restoration of cell migration by exogenous spermidine in polyamine-deficient cells. These findings suggest that polyamine-dependent cell migration is partially initiated by the formation of myosin II stress fibers as a result of Ca2+-activated RhoA activity.

Animals↗
PubMed2001

Polyamine transport system mediates agmatine transport in mammalian cells.

Agmatine is a biogenic amine with the capacity to regulate a number of nonreceptor-mediated functions in mammalian cells, including intracellular polyamine content and nitric oxide generation. We observed avid incorporation of agmatine into several mammalian cell lines and herein characterize agmatine transport in mammalian cells. In transformed NIH/3T3 cells, agmatine uptake is energy dependent with a saturable component indicative of carrier-mediated transport. Transport displays an apparent Michaelis-Menten constant of 2.5 microM and a maximal velocity of 280 pmol x min(-1) x mg(-1) protein and requires a membrane potential across the plasma membrane for uptake. Competition with polyamines, but not cationic molecules that utilize the y+ system transporter, suppresses agmatine uptake. Altering polyamine transporter activity results in parallel changes in polyamine and agmatine uptake. Furthermore, agmatine uptake is abrogated in a polyamine transport-deficient human carcinoma cell line. These lines of evidence demonstrate that agmatine utilizes, and is dependent on, the polyamine transporter for cellular uptake. The fact that this transport system is associated with proliferation could be of consequence to the antiproliferative effects of agmatine.

Agmatine↗