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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↗
PubMed1982

[Polyamine levels in blood and plasma of patients with malignant melanoma].

The polyamines putrescine, cadaverine, spermidine, spermine, and the amine histamine in whole blood and plasma of 42 patients with malignant melanoma were analysed after cold acid extraction and ion-exchange chromatography by fluorescence detection. Depending on the degree of tumor spreading the patients were grouped into 5 subpopulations; results were statistically compared with the values obtained from a normal population. The mean values of polyamine concentrations in the patient groups were generally not distinguishable from the mean values of the controls. Solely the mean of the spermidine values of postoperative patients with or without medical therapy and the spermine mean value for postoperative patients in tumor stage I and III were elevated. Cadaverine was never detected. The individual frequency of elevated polyamine levels in the plasma of single patients and variable, depending on patient subpopulation and polyamine under consideration. Spermidine was most frequently elevated (44%) in patients of tumor stage I under immunetherapy. We conclude that due to the low frequency of polyamine elevations to be found in plasma of melanoma patients by our method no diagnostic or prognostic significance and only limited importance for monitoring patients under therapy can be claimed for.

Adult↗
PubMed1994

Ornithine decarboxylase activity and concentrations of polyamines in embryos of diabetic rats.

Previous studies have demonstrated high concentrations of polyamines in neoplastic tissue and embryos and these compounds are therefore believed to play a role in cellular growth and embryonic development. Maternal diabetes causes embryonic dysmorphogenesis and alterations in embryonic polyamine concentrations may contribute to this process. In the present study we have measured the contents of DNA, putrescine, spermidine and spermine in embryos on days 10 and 11 of gestation in normal and diabetic rats. We also estimated the activity of ornithine decarboxylase (ODC) in embryos on days 9-11. We found that maternal diabetes causes delayed growth as reflected by decreased content of DNA on day 11 in the embryos of the diabetic group. Both the polyamine content and ODC activity were altered in the embryos of diabetic rats. Thus, the polyamines were increased on day 10 and decreased on day 11, and the ODC activity was decreased in a down-regulated manner in day-10 embryos of the diabetic rats. These findings suggest that polyamine metabolism is involved in the dysmorphogenesis of diabetic pregnancy.

Animals↗
PubMed1991

Hepatic polyamine metabolism in children with Reye's syndrome.

Acute mitochondrial insult has been suggested as a primary reason for the clinical, histopathological and biochemical abnormalities seen in Reye's syndrome. However, the etiology of mitochondrial dysfunction has not been identified. Polyamines have been known to alter the mitochondrial structure and function. Influenza infection may cause an increase in ornithine decarboxylase activity and thereby channel ornithine for polyamine biosynthesis, leading to mitochondrial dysfunction in Reye's syndrome. To test this hypothesis, the hepatic concentrations of polyamines, polyamine-metabolizing enzymes and urea cycle enzyme activities in Reye's syndrome patients were determined and compared with patients who died from illnesses other than Reye's syndrome. The hepatic concentration of putrescine, spermidine and spermine were increased in Reye's syndrome patients. The activity of ornithine decarboxylase was elevated but, due to the small number of samples, these values did not reach statistical significance. Ornithine carbamoyltransferase activity was decreased in the liver of Reye's syndrome patients. Our results suggest that increased synthesis of polyamines from ornithine may initiate mitochondrial injury in Reye's syndrome.

Child↗
PubMed1998

Thrombin stimulates vascular smooth muscle cell polyamine synthesis by inducing cationic amino acid transporter and ornithine decarboxylase gene expression.

Thrombin, a serine protease, is a potent mitogen for vascular smooth muscle cells (SMCs), but its mechanism of action is not known. Since L-ornithine is metabolized to growth-stimulatory polyamines, we examined whether thrombin regulates the transcellular transport and metabolism of L-ornithine by vascular SMCs. Treatment of SMCs with thrombin initially (0 to 2 hours) decreased L-ornithine uptake, whereas longer exposures (6 to 24 hours) progressively increased transport. Kinetic studies indicated that thrombin-induced inhibition was associated with a decrease in affinity for L-ornithine, whereas stimulation was mediated by an increase in transport capacity. Thrombin induced the expression of both cationic amino acid transporter (CAT)-1 and CAT-2 mRNA. Furthermore, thrombin stimulated L-ornithine metabolism by inducing ornithine decarboxylase (ODC) mRNA expression and activity. The stimulatory effect of thrombin on both L-ornithine transport and ODC activity was reversed by hirudin, a thrombin inhibitor, and was mimicked by a 14-amino acid thrombin receptor-activating peptide. Thrombin also markedly increased the capacity of SMCs to generate putrescine, a polyamine, from extracellular L-ornithine. The thrombin-mediated increase in putrescine production was reversed by N(G)-methyl-L-arginine, a competitive inhibitor of cationic amino acid transport, or by alpha-difluoromethylornithine (DFMO), an ODC inhibitor. DFMO also inhibited thrombin-induced SMC proliferation. These results demonstrate that thrombin stimulates polyamine synthesis by inducing CAT and ODC gene expression and that thrombin-stimulated SMC proliferation is dependent on polyamine formation. The ability of thrombin to upregulate L-ornithine transport and direct its metabolism to growth-stimulatory polyamines may contribute to postangioplasty restenosis and atherosclerotic lesion formation.

Amino Acid Transport Systems, Basic↗
PubMed1989

Polyamines and epidermal growth factor in monocrotaline-induced pulmonary hypertension.

Multiple lines of evidence suggest that the polyamines, a family of low-molecular-weight organic cations with documented regulatory note in cell growth and differentiation, are involved with hyperplastic and hypertrophic responses of lung cells underlying hypertensive pulmonary vascular disease. Little is known, however, of the factor(s) initiating polyamine synthesis in pulmonary hypertension. This study tested the key aspects of the hypothesis that augmented polyamine synthesis, and attendent vascular structural alterations in monocrotaline (MCT)-treated rats can be ascribed to elaboration of an epidermal growth factor (EGF)-like mitogen. In lungs of rats treated 4 days previously with 60 mg/kg, EGF-like immunoreactivity was detected diffusely throughout perivascular regions. Intravenous administration of human recombinant EGF (125 pg/h) to rats for 1 wk was associated with medial thickening in pulmonary arteries between 100 and 200 microns in diameter, significant increases in lung polyamine contents, and a moderate elevation in mean pulmonary arterial pressure. These observations indicate that EGF can be detected in the lungs of MCT-treated rats and that exogenous EGF mimics some of the action of MCT on the rat lung. It is thus reasonable to speculate that an EGF-like mitogen may participate in the response to MCT in part through a polyamine-dependent mechanism.

Animals↗
PubMedDate not supplied

Pattern and concentration of free and acetylated polyamines in urine of cirrhotic patients.

The pattern and concentration of urinary, free, monoacetylated and total polyamines were determined in 31 cirrhotic patients, divided into three classes according to Child's classification, and in 28 healthy subjects. Cirrhotic patients had increased levels of free, monoacetylated and total polyamines. They also showed a significant increase in N1-acetylspermidine to N8-acetylspermidine molar ratio. Urinary polyamine excretion was not related to the severity of liver disease nor to the values of laboratory liver function tests. Furthermore, polyamine excretion was not significantly different in cirrhotics with or without diabetes or IGT, while plasma insulin and glucagon levels were increased in all cirrhotic patients. The results suggest that enhanced polyamine biosynthesis and catabolism, particularly N1-acetylation, occur in cirrhotic patients, probably due to hepatic regeneration and/or increased levels of insulin and glucagon.

Acetylation↗
PubMed1984

Nutritional parameters affecting erythrocyte polyamine levels in cancer patients.

Changes in erythrocyte polyamine levels during intravenous hyperalimentation in cancer and noncancer patients were determined, and the influence of host nutritional status on polyamine metabolism was analyzed. RBC putrescine (P less than .001), spermidine (P less than .01), and spermine (P less than .005) levels, and the putrescine-spermidine ratio (P less than .001) increased in the cancer group while no significant increases were noted in the noncancer group. The degree of malnutrition, based on body weight loss and plasma albumin, transferrin, prealbumin, and retinol-binding protein levels, was significantly greater in the cancer group than in the noncancer group, giving rise to the possibility that repletion of nutritional deficits in host tissues could have contributed to the rise in RBC polyamines. When cancer patients of similar nutritional status were matched with the noncancer group, increases in RBC putrescine level and putrescine-spermidine ratio were noted in the selected cancer patients. These results suggest that correction of nutritional deficits did not contribute significantly to the RBC polyamine pool and that increases in RBC polyamines during intravenous hyperalimentation were related to the presence of tumor.

Adult↗
PubMed1992

Polyamine concentration in rat milk and food, human milk, and infant formulas.

The polyamine concentration in rat milk and food, human milk, and infant formulas was estimated by HPLC. In rat milk, the concentration of putrescine and spermine was low (generally under 2.5 nmol.mL-1 for putrescine and under 1 nmol.mL-1 for spermine). The spermidine concentration was higher and seemed to increase during lactation. The rat food was richer in polyamines than the rat milk (about 150 times for putrescine and spermine, about 30 times for spermidine). We already proved that ingestion of spermine or spermidine can induce precocious maturation of the rat intestine. The present observations suggest that polyamines contained in rat food could play an important role in postnatal maturation of the rat intestine. The polyamine concentration of human milk was measured from 60 different mothers during a period extending from the 1st wk to the 6th mo of lactation. Great variation was observed. During the 1st mo of lactation, the general pattern was as follows: putrescine concentration generally varied little (from 1 to 3 nmol.mL-1), spermine and spermidine concentrations showed a similar pattern (the highest values appeared at the end of the 1st wk of suckling). After the 4th mo of lactation, putrescine concentration increased slightly, whereas spermine and spermidine concentration stayed almost stable. The concentrations of polyamines in 18 powdered milks for babies were estimated. Spermine and spermidine contents were lower than those in human milk. A protective effect of spermine or spermidine against alimentary allergies is suggested.

Animal Feed↗
PubMed2005

Effects of genistein on the polyamine metabolism and cell growth in DLD-1 human colon cancer cells.

Polyamines and their rate-limiting enzyme, ornithine decarboxylase (ODC), are actively involved in cell growth and differentiation. The phytoestrogen genistein has been demonstrated to possess antitumor properties by influencing proliferation, differentiation, and apoptosis. The aim of this study was to investigate the effects of genistein at concentrations ranging from 0.01 to 100 microM on the polyamine biosynthesis, cell proliferation, and apoptosis in the estrogen receptor-positive DLD-1 human colon cancer cell line. Polyamine levels and ODC activity were evaluated by high performance liquid chromatography and radiometric technique, respectively. The proliferative response was estimated by [3H]-thymidine incorporation and the colorimetric 3-(4,5 di-methylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test. Apoptosis was investigated by DNA fragmentation. Bax and Bcl-2 gene expressions were evaluated by multiplex-polymerase chain reaction. At concentration >or=1 microM, genistein decreased significantly the ODC activity and the polyamine levels. At the same concentration, genistein also increased significantly Bax mRNA expression, but not Bcl-2 mRNA expression. Higher concentrations (>or=10 microM) were needed to obtain a significant inhibition of cell proliferation and DNA fragmentation. The results of this study suggest that genistein can affect growth of DLD-1 cells by both decreasing polyamine biosynthesis and inducing apoptosis. However, further studies are required to assess the true ability of a soy rich diet in modifying colon cancer risk.

Anticarcinogenic Agents↗
PubMed2006

An evaluation of a polyamine-deficient diet for the treatment of inflammatory pain.

Polyamines are thought to be involved in the regulation of numerous metabolic and electrophysiological processes in the nervous system. In this study we evaluated the effect of a synthetic polyamine-deficient diet on pain in a carrageenan (Car)-induced inflammatory rat model. Inflammation was induced with a unilateral subcutaneous injection of Car in a plantar hindpaw in rats fed without (control group) or with (deficiency group) a polyamine-deficient diet. Ipsilateral and contralateral hyperalgesia was evaluated using the Randall-Sellito pressure test. Heart rate changes were also recorded under general anesthesia. Then, the effects of a bupivacaine sciatic nerve block and subcutaneous injection of naloxone or ketamine were evaluated for Car-induced hyperalgesia. Data were analyzed using analysis of variance followed by unpaired Student's t-test (significance P < 0.05). Before Car injection, no significant difference was observed in response to mechanical stimuli between the control and the deficiency groups (n = 114 in pooled data). Car injection induced significant ipsilateral and contralateral hyperalgesia in the control groups, whereas a significant analgesic effect appeared in the deficient groups on both the ipsilateral and contralateral hindpaws. This analgesic effect was confirmed by the electrocardiogram recording that showed a significant increase in heart rate in the control group after Car injection compared with the deficiency group that showed a decrease in heart rate under general anesthesia. Bupivacaine sciatic nerve block had no significant effect on hypoalgesia phenomena induced by polyamine deficiency. Naloxone administration had no effect in the control group but reversed the analgesic effect in the deficiency group. Ketamine administration induced a significant analgesic effect in the control group and partly reversed the analgesic effect in the deficiency group. In conclusion, a synthetic polyamine-deficient diet had a significant general analgesic effect on Car-induced mechanical hyperalgesia. The mechanism of analgesic action remains to be elucidated.

Analgesia↗
PubMed1997

[Methodological approach to regulation of polyamine].

This brief article is dedicated to the late Professor Morizo Ishidate, and concerned in a methodology developed by the author and collaborators, aiming at the regulation of polyamine, especially, the regulation of spermidine synthase. The content is separated in 3 sections. The first section on the development of analytical methods, contains seven items, e.g. fluorometric determination of polyamines by fluorescamine, analysis of naturally occurring polyamines by GC and GC-MS, etc. The second section on the syntheses of needed compounds, contains three items, e.g. syntheses of decarboxylated S-adenosylmethionine which is a substrate for spermidine synthase and its related compounds, syntheses of 15N-enriched polyamines applicable to the preparation of various polyamines, etc. The last section on the studies of aminopropyl transferases, contains three items, e.g. purification of spermidine synthase from mammalian tissues using ATPA-Sepharose, a novel affinity carrier, newly developed inhibitors for the enzymes, etc.

Animals↗
PubMed2006

Suppression of TNF-alpha production by S-adenosylmethionine in human mononuclear leukocytes is not mediated by polyamines.

Endotoxin-induced cytokine production is an important mechanism in the development of several types of liver damage. Methionine, some of its precursors and metabolites were reported to have protective effects against such injury. The aim of this study was to investigate whether methionine, its precursors or metabolites [phosphatidylcholine, choline, betaine, S-adenosylmethionine (SAM)] have a modulating effect on tumor necrosis factor alpha (TNF-alpha) production by endotoxin-stimulated human mononuclear leukocytes and whether SAM-dependent polyamines (spermidine, spermine) are mediators of SAM-induced inhibition of TNF-alpha synthesis. Methionine and betaine had a moderate stimulatory effect on TNF-alpha production, whereas phosphatidylcholine (ID(50) 5.4 mM), SAM (ID(50) 131 microM), spermidine (ID(50) 4.5 microM) and spermine (ID(50) 3.9 microM) had a predominantly inhibitory effect. Putrescine did not alter TNF-alpha release. Inhibitors of polyamine synthesis that blocked either putrescine (difluoromethylornithine) or spermine (CGP48664A) production did not affect TNF-alpha synthesis. Endotoxin stimulation of leukocytes did not alter the intracellular levels of polyamines. In addition, supplementation with SAM did not change the intracellular concentration of either polyamine measured. We conclude that phosphatidylcholine-induced immunosuppression is not caused by methionine and polyamines are not involved in SAM-induced inhibition of TNF-alpha production. The limitation of TNF-alpha release by spermidine is specific and is not due to its conversion into spermine.

Amidines↗
PubMed1975

Antisera to gonadotrophins and placental function in mice. I. Effect on polyamine content.

The effect of antisera to ovine LH and ovine prolactin was studied on polyamine levels in the mouse placenta. The antisera were administered on Day 11, 12 or 13 of pregnancy and the mice were killed 24 hr later. The polyamines (spermine, spermidine and putrescine) in the placentae were estimated. Polyamine levels were reduced after treatment with anti-LH on any of the 3 days and after treatment with anti-prolactin serum on Days 11 or 12. Only the spermidine content was reduced when anti-prolactin serum was injected on Day 13 of pregnancy. Placental DNA and RNA levels paralleled those observed for polyamine content. The changes in polyamine content and nucleic acid levels indicate that these antisera to LH and prolactin interfere with placental function.

Animals↗
PubMed1999

Polyamine biosynthesis inhibitors alter protein-protein interactions involving estrogen receptor in MCF-7 breast cancer cells.

We investigated the effects of polyamine biosynthesis inhibition on the estrogenic signaling pathway of MCF-7 breast cancer cells using a protein-protein interaction system. Estrogen receptor (ER) linked to glutathione-S-transferase (GST) was used to examine the effects of two polyamine biosynthesis inhibitors, difluoromethylornithine (DFMO) and CGP 48664. ER was specifically associated with a 45 kDa protein in control cells. In cells treated with estradiol, nine proteins were associated with ER. Cells treated with polyamine biosynthesis inhibitors in the absence of estradiol retained the binding of their ER with a 45 kDa protein and the ER also showed low-affinity interactions with a number of cellular proteins; however, these associations were decreased by the presence of estradiol and the inhibitors. When samples from the estradiol+DFMO treatment group were incubated with spermidine prior to GST-ER pull down assay, an increased association of several proteins with ER was detected. The intensity of the ER-associated 45 kDa protein increased by 10-fold in the presence of 1000 microM spermidine. These results indicate a specific role for spermidine in ER association of proteins. Western blot analysis of samples eluted from GST-ER showed the presence of chicken ovalbumin upstream promoter-transcription factor, an orphan nuclear receptor, and the endogenous full-length ER. These results show that multiple proteins associate with ER and that the binding of some of these proteins is highly sensitive to intracellular polyamine concentrations. Overall, our results indicate the importance of the polyamine pathway in the gene regulatory function of estradiol in breast cancer cells.

Amidines↗
PubMed1985

Hormonal regulation of ornithine decarboxylase and polyamines in primary cultured rat hepatocytes--differences in hormonal response between adult and fetal hepatocytes.

Polyamines are polycationic substances which are widely distributed in living organisms and have a close relation to rapid growth phenomena. We examined ornithine decarboxylase (ODC), which is the rate limiting enzyme of polyamine biosynthesis, and polyamine induction in primary cultured rat hepatocytes by various hormones which increase during pregnancy, and revealed differences in hormonal responses between adult and fetal rat hepatocytes. Thirteen hormones, including estrone, estradiol, progesterone, testosterone, human chorionic gonadotropin (HCG), cortisol, dexamethasone, insulin, glucagon, epinephrine and epidermal growth factor (EGF), were tested. Among these hormones, only insulin, dexamethasone and EGF induced ODC activity and polyamine biosynthesis, especially that of putrescine, in both adult and fetal hepatocytes. The effects of EGF were the most significant. The combined effect of insulin and dexamethasone was additive, while that of insulin and EGF was synergistic. The rate of ODC induction was higher in adult hepatocytes than in fetal hepatocytes, however, the reaction was earlier in fetal hepatocytes. These observations suggest that ODC and polyamines in the fetal stage of development are regulated by a mechanism different from that in the adult liver.

Animals↗
PubMed1985

Alterations in polyamine levels in amniotic fluid, plasma and urine during normal pregnancy.

Polyamines have a close relationship with rapid cell proliferation. We measured polyamine levels in amniotic fluid, maternal plasma and urine during normal pregnancy. Plasma putrescine, spermidine and spermine gradually increased in the third trimester and reached the highest concentration at the end of pregnancy. There was a significant correlation between the level of these polyamines and the level of plasma estradiol and progesterone. In urine, putrescine and spermine increased with the progress of gestation and reached the highest level during the 8th to 10th months of gestation. In amniotic fluid, putrescine and spermidine concentrations were significantly high in the first trimester and decreased in the other trimesters, whereas spermine showed no significant change. Polyamine concentrations in maternal plasma and urine appear to reflect not only fetal metabolic changes but also the metabolic changes of the pregnant women, and to be influenced by several hormones which increase during pregnancy. Polyamines in amniotic fluid mainly reflect activated fetal metabolism and may be useful as biochemical indicators of fetal growth.

Amniotic Fluid↗
PubMed1999

Polyamines found in the inflamed periodontium inhibit priming and apoptosis in human polymorphonuclear leukocytes.

BACKGROUND: Polymorphonuclear leukocytes (PMNs) are exposed to high concentrations of polyamines in the inflamed periodontium and possess a transport system for taking up these compounds. Previous studies suggest that polyamines are involved in priming of the PMN respiratory burst by tumor necrosis factor-alpha (TNF-alpha) and can stabilize DNA against degradation. The purpose of this study was to determine whether exogenous polyamines can modulate priming by TNF-alpha or delay nuclear changes associated with PMN apoptosis (programmed cell death). METHODS: Isolated human PMNs were incubated with putrescine or spermidine in vitro. Superoxide generation was measured with a cytochrome C reduction assay, and apoptotic changes were assessed by fluorescence microscopy (after cell staining with acridine orange and ethidium bromide). RESULTS: Incubation with 1 mM putrescine for 1 hour inhibited superoxide production by TNF-primed PMNs by 20%, but enhanced the production of superoxide by unprimed cells by 38%. Both effects were dose dependent and statistically significant (P <0.03, repeated measures ANOVA and Dunnett's test). Spermidine had no significant effects on PMN oxidative function. With regard to apoptosis, 1 mM putrescine or spermidine produced a statistically significant reduction in the proportion of apoptotic PMNs within 6 to 9 hours (P <0.05). In cells incubated for 7 hours with 300 microM putrescine or spermidine, the proportion of apoptotic cells was approximately 30% lower than in untreated controls (P <0.05, Dunnett's test). The delay of apoptosis by spermidine was less profound than that produced by TNF-alpha and was not additive to the effects of this cytokine. CONCLUSIONS: Polyamines could potentially impair the priming of PMN oxidative function by TNF-alpha at sites where this cytokine is present. In the absence of TNF-alpha, polyamines could enhance PMN superoxide release and enhance the maintenance of PMN function in the periodontal pocket.

Acridine Orange↗