Gossypol activates pancreatic polyamine catabolism in normal rats and induces acute pancreatitis in transgenic rats over-expressing spermidine/spermine N1-acetyltransferase

BACKGROUND: The male antifertility agent gossypol has been reported to induce spermidine/spermine N1-acetyltransferase (SSAT) in canine prostate cells. As SSAT is the rate-controlling enzyme in the catabolism of the polyamines and is involved in the development of acute pancreatitis in a recent transgenic rat model, we exposed normal and transgenic rats over-expressing SSAT to gossypol to evaluate its effect on pancreatic polyamine metabolism and organ integrity. METHODS: Pancreatic SSAT activity, polyamine pools, pancreatic histology and plasma 2-amylase activity were determined after different doses of gossypol. RESULTS: Gossypol increased pancreatic putrescine and decreased spermidine and spermine pools in normal rats accompanied by tissue oedema and significantly elevated plasma amylase activity. In transgenic rats, the drug strikingly induced SSAT, profoundly depleted the higher polyamines and caused distinct pancreatitis. The combination of gossypol at doses harmless to transgenic pancreas with an inhibitor of polyamine oxidase caused massive synergistic induction of SSAT, profound depletion of the polyamine pools and acute pancreatitis. CONCLUSIONS: The results indicate that gossypol induces pancreatitis through an activation of polyamine catabolism.     

Activation of polyamine catabolism in transgenic rats induces acute pancreatitis

Polyamines are required for optimal growth and function of cells. Regulation of their cellular homeostasis is therefore tightly controlled. The key regulatory enzyme for polyamine catabolism is the spermidine/spermine N(1)-acetyltransferase (SSAT). Depletion of cellular polyamines has been associated with inhibition of growth and programmed cell death. To investigate the physiological function SSAT, we generated a transgenic rat line overexpressing the SSAT gene under the control of the inducible mouse metallothionein I promoter. Administration of zinc resulted in a marked induction of pancreatic SSAT, overaccumulation of putrescine, and appearance of N(1)-acetylspermidine with extensive depletion of spermidine and spermine in transgenic animals. The activation of pancreatic polyamine catabolism resulted in acute pancreatitis. In nontransgenic animals, an equal dose of zinc did not affect pancreatic polyamine pools, nor did it induce pancreatitis. Acetylated polyamines, products of the SSAT-catalyzed reaction, are metabolized further by the polyamine oxidase (PAO) generating hydrogen peroxide, which might cause or contribute to the pancreatic inflammatory process. Administration of specific PAO inhibitor, MDL72527 [N(1),N(2)-bis(2,3-butadienyl)-1,4-butanediamine], however, did not affect the histological score of the pancreatitis. Induction of SSAT by the polyamine analogue N(1),N(11)-diethylnorspermine reduced pancreatic polyamines levels only moderately and without signs of organ inflammation. In contrast, the combination of N(1), N(11)-diethylnorspermine with MDL72527 dramatically activated SSAT, causing profound depletion of pancreatic polyamines and acute pancreatitis. These results demonstrate that acute induction of SSAT leads to pancreatic inflammation, suggesting that sufficient pools of higher polyamine levels are essential to maintain pancreatic integrity. This inflammatory process is independent of the production of hydrogen peroxide by PAO.     

Acute Pancreatitis Induced by Activated Polyamine Catabolism Is Associated with Coagulopathy: Effects of α-Methylated Polyamine Analogs on Hemostasis

Background/Aims: Polyamines are ubiquitous organic cations essential for cellular proliferation and tissue integrity. We have previously shown that pancreatic polyamine depletion in rats overexpressing the catabolic enzyme, spermidine/spermine N¹-acetyltransferase (SSAT), results in the development of severe acute pancreatitis, and that therapeutic administration of metabolically stable α-methylated polyamine analogs protects the animals from pancreatitis-associated mortality. Our aim was to elucidate the therapeutic mechanism(s) of α-methylspermidine (MeSpd). Methods: The effect of MeSpd on hemostasis and the extent of organ failure were studied in SSAT transgenic rats with either induced pancreatitis or lipopolysaccharide (LPS)-induced coagulopathy. The effect of polyamines on fibrinolysis and coagulation was also studied in vitro. Results: Pancreatitis caused a rapid development of intravascular coagulopathy, as assessed by prolonged coagulation times, decreased plasma fibrinogen level and antithrombin activity, enhanced fibrinolysis, reduced platelet count and presence of schistocytes. Therapeutic administration of MeSpd restored these parameters to almost control levels within 24 h. In vitro, polyamines dose-dependently inhibited fibrinolysis and intrinsic coagulation pathway. In LPS-induced coagulopathy, SSAT transgenic rats were more sensitive to the drug than their syngeneic littermates, and MeSpd-ameliorated LPS-induced coagulation disorders. Conclusion: Pancreatitis-associated mortality in SSAT rats is due to coagulopathy that is alleviated by treatment with MeSpd.     

Polyamine Levels in the Pancreas and the Blood Change according to the Severity of Pancreatitis

Background/Aims: Polyamines are essential to survival, growth, and proliferation of mammalian cells. Previous studies have suggested that the pancreatic polyamine levels may change in acute pancreatitis. In this study, the changes of polyamine levels in the pancreas have been studied with respect to the severity of pancreatitis. We investigated whether there is a relationship in polyamine levels between pancreas and blood, and whether pancreatic and blood polyamine levels change according to the severity of pancreatitis. Methods: In rats, sublethal pancreatitis was induced by intraductal infusion of 2% taurodeoxycholate, while lethal pancreatitis was induced with 6% taurodeoxycholate. Results: Infusion of 6% taurodeoxycholate as compared with 2% resulted in more severe pancreatitis, as revealed by mortality, histology, and serum amylase activity. Pancreatic spermidine/spermine N¹-acetyltransferase was induced early after pancreatitis and was associated with increased putrescine and decreased spermidine levels. The extent of pancreatic necrosis significantly correlated with the polyamine catabolism indicators pancreatic putrescine/spermidine ratio (r = 0.29, p < 0.01) and pancreatic putrescine/spermine ratio (r = 0.32, p < 0.01). The two pancreatic polyamine ratios correlated well also with the red blood cell polyamine ratios (r = 0.75 and r = 0.72, respectively, both p < 0.01). Furthermore, the extent of pancreatic necrosis correlated with red blood cell putrescine/spermidine (r = 0.32, p < 0.01) and putrescine/spermine (r = 0.37, p < 0.01) ratios. Conclusions: Acute experimental pancreatitis is associated with an early pancreatic spermidine/spermine N¹-acetyltransferase induction and consequent changes in polyamine levels in pancreas and red blood cells, depending on the severity of pancreatitis. Because changes in red blood cell spermidine, spermine, and putrescine levels evolve already early during the time course of pancreatitis, and correlate with the extent of pancreatic necrosis, their clinical value as early markers of the severity of acute pancreatitis needs to be further evaluated. Copyright © 2008 S. Karger AG, Basel and IAP     

Prolactin and polyamine catabolism: specific effect on polyamine oxidase activity in rat thymus

Much evidence suggests that prolactin has an immunoregulatory function and that its effects on cells of the immune system depend on the level and specific forms of the receptors present on the target cells. The effect of administration of prolactin on polyamine catabolism was investigated in thymus of male intact rats by measuring the activities of spermidine/spermine N(1)-acetyltransferase and polyamine oxidase, because of the relationships between polyamines (especially putrescine) and the immune system. The administration of prolactin to rats resulted in the rapid induction of spermidine/spermine N(1)-acetyltransferase activity in the thymus (1.6-times the level of control rats, within 4 h), and in a marked decrease in polyamine oxidase activity at 24 h. The changes in enzyme activities were accompanied by an increase in putrescine concentration and a decrease in spermidine and spermine concentrations. In the spleen, prolactin increased SAT activity only 24 h after administration and was ineffective on PAO activity.     

Changes in hepatic polyamine catabolism in elderly rats

Abstract: Aims/Background: Given the important role of polyamines (putrescine, spermidine, spermine) in the modulation of macromolecular syntheses, gene expression and proteolysis, alterations in their metabolic pathways could be relevant during senescence. Since the few existing data address mainly polyamine biosynthesis, we studied the oxidative catabolism of polyamines in the liver of rats 3–36 months of age. Methods: Polyamine oxidase activity was fluorimetrically measured using N¹-acetyl-spermine as substrate. Spermidine/spermine N¹-acetyltransferase and diamine oxidase were measured by radiochemical methods using labeled acetyl-coenzyme A and putrescine, respectively, as substrate. Polyamines were separated by HPLC and fluorimetrically quantified after post-column derivatization with o-phthaldialdehyde. Results: Spermidine/spermine N¹-acetyltransferase activity increased in 36-month-old rats and polyamine oxidase activity in 24- and 36-month-old rats. A decline in spermine and increases in spermidine and putrescine in elderly rats suggested an activation of the interconversion pathway of higher into lower polyamines. The activity of diamine oxidase, which degrades putrescine, was enhanced starting from 12 months of age. Conclusion: In the liver of aged rats, an increase in the catabolic enzymes leads to a reconversion of the higher polyamines to putrescine. This increased catabolism may represent an important age-related change and may contribute to impairment of the expression of growth-related genes in senescence.     

The alpha9beta1 integrin enhances cell migration by polyamine-mediated modulation of an inward-rectifier potassium channel

The alpha9beta1 integrin accelerates cell migration through binding of spermidine/spermine acetyltransferase (SSAT) to the alpha9 cytoplasmic domain. We now show that SSAT enhances alpha9-mediated migration specifically through catabolism of spermidine and/or spermine. Because spermine and spermidine are effective blockers of K(+) ion efflux through inward-rectifier K(+) (Kir) channels, we examined the involvement of Kir channels in this pathway. The Kir channel inhibitor, barium, or knockdown of a single subunit, Kir4.2, specifically inhibited alpha9-dependent cell migration. alpha9beta1 and Kir4.2 colocalized in focal adhesions at the leading edge of migrating cells and inhibition or knockdown of Kir4.2 caused reduced persistence and an increased number of lamellipodial extensions in cells migrating on an alpha9beta1 ligand. These results identify a pathway through which the alpha9 integrin subunit stimulates cell migration by localized polyamine catabolism and modulation of Kir channel function.     

多胺代谢与大鼠心肌缺血再灌注损伤关系的实验研究

目的 观察缺血再灌注不同时期大鼠心肌多胺代谢变化规律,探讨多胺代谢与心肌缺血再灌注损伤的关系.方法 采用结扎冠状动脉方法复制大鼠在体心肌缺血再灌注损伤模型,应用逆转录聚合酶链反应(RT-PCR)、Western免疫印迹(Western blot)方法分别测定正常、缺血再灌注2 h、6 h、12 h和24 h时心肌鸟氨酸脱羧酶(ODC)和精胺/精脒乙酰转移酶(SSAT)mRNA的转录和蛋白表达水平,并用高效液相色谱仪测定多胺含量变化.结果 心肌缺血再灌注后ODC和SSAT mRNA的转录和蛋白表达均上调,至再灌注24 h时,与假手术组比,ODC mRNA和SSAT mRNA转录分别增加了3.1倍和3.8倍(P＜0.01),ODC和SSAT的蛋白表达分别增加了3.1倍和2.9倍(P＜0.01).精胺、精脒和多胺总代谢池含量减少,至再灌注24 h时,分别比假手术组少了33.6%、35.3%和32.9%,而腐胺多了58.9%(P＜0.01).结论 心肌缺血再灌注损伤可导致多胺代谢失衡,二者密切相关.     

Polyamine metabolism in rat myocardial ischemia-reperfusion injury

This study was focused on investigating the involvement of polyamine metabolism in the myocardial ischemia-reperfusion injury (MIRI) in an in vivo rat model. A branch of the descending left coronary artery was occluded for 30 min followed by 2 h, 6 h, 12 h, and 24 h reperfusion. Then the expression of spermidine/spermine N1-acetyltransferase (SSAT) and ornithine decarboxylase (ODC) and the concentrations of polyamines were assessed. It was found that the expression of SSAT and ODC were upregulated after reperfusion and the concentrations of spermidine and spermine were significantly decreased, while putrescine concentration was significantly increased. The results suggest that MIRI may cause disturbance of polyamine metabolism, and it may play a critical role in MIRI.     

Structures of wild-type and mutant human spermidine/spermine N1-acetyltransferase, a potential therapeutic drug target

Spermidine/spermine N1-acetyltransferase (SSAT) is a key enzyme in the control of polyamine levels in human cells, as acetylation of spermidine and spermine triggers export or degradation. Increased intracellular polyamine levels accompany several types of cancers as well as other human diseases, and compounds that affect the expression, activity, or stability of SSAT are being explored as potential therapeutic drugs. We have expressed human SSAT from the cloned cDNA in Escherichia coli and have determined high-resolution structures of wild-type and mutant SSAT, as the free dimer and in binary and ternary complexes with CoA, acetyl-CoA (AcCoA), spermine, and the inhibitor N1,N11bis-(ethyl)-norspermine (BE-3-3-3). These structures show details of binding sites for cofactor, substrates, and inhibitor and provide a framework to understand enzymatic activity, mutations, and the action of potential drugs. Two dimer conformations were observed: a symmetric form with two open surface channels capable of binding substrate or cofactor, and an asymmetric form in which only one of the surface channels appears capable of binding and acetylating polyamines. SSAT was found to self-acetylate lysine-26 in the presence of AcCoA and absence of substrate, a reaction apparently catalzyed by AcCoA bound in the second channel of the asymmetric dimer. These unexpected and intriguing complexities seem likely to have some as yet undefined role in regulating SSAT activity or stability as a part of polyamine homeostasis. Sequence signatures group SSAT with proteins that appear to have thialysine Nepsilon-acetyltransferase activity.     

Depletion of Resistance Vessel Polyamines Attenuates Angiotensin II Induced Blood Pressure Rise in Rats

Vascular structural changes in hypertension are proposed to contribute to raised peripheral resistance. Endogenous polyamines (putrescine, spermidine and spermine) have an essential role in cellular growth and may be required in vascular restructuring. We have previously shown raised polyamines in resistance vessels in response to angiotensin I1 (angII) infusion in the rat and here we examined whether polyamine depletion influences the hypertensive process. Wistar-Kyoto rats were infused with either angII or saline by osmotic minipump, and maintained on either 2% difluoromethylornithine (DFMO; polyamine synthesis inhibitor) or water for 12days. AngII significantly increased tail-cuff blood pressure (bp), resistance vessel spermidine and spermine concentration, and media:lumen ratios. DFMO attenuated both the rse in bp (p<0.05) and vascular spermidine (p<0.05) in the angII infused rats but vascular structure was apparently unaffected on day 12. In conclusion, raised concentration of resistance vessel spermidine may be a necessary component of the ang II pressor effect.     

Polyamine synthesis and transport inhibition in a human anaplastic thyroid carcinoma cell line in vitro and as xenograft tumors.

Polyamines are essential cellular components for neoplastic transformation and cell proliferation. Antineoplastic efforts that inhibit polyamine synthesis are insufficient to induce cytotoxicity, due to compensatory induction of polyamine transport. Treatment of an anaplastic human thyroid carcinoma cell line (DRO90-1) with a novel polymeric spermine conjugate (polyspermine; PSpm) caused in vitro cytotoxicity and inhibited the growth of xenograft tumors at low concentrations. Similar in vitro antineoplastic effects were noted with two other human anaplastic thyroid carcinoma cell lines. This coincided with inhibition of polyamine uptake and synthetic enzyme activities, with reduced ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SAM-DC) but increased spermidine/spermine N1-acetyltransferase (SSAT) activities, as measured in DRO90-1 cells. In subsequent studies using these cells, PSpm was effective in reducing the intracellular levels of all polyamines in vitro, resulting in cytotoxicity that was not reversed by administration of extracellular polyamines. Low-dose PSpm inhibited tumor growth in vivo, but high doses of PSpm potentiated xenograft tumor growth. PSpm degradation products produced with in vivo treatment may be produced that function as substrates for polyamine biosynthesis. These studies suggest that polyamine metabolism inhibition is a viable target for antineoplastic therapy of anaplastic thyroid carcinoma, although the in vivo response to PSpm suggests that this agent will have limited clinical utility.     

Pancreatic polyamine concentrations and cholecystokinin plasma levels in rats after feeding raw or heat-inactivated soybean flour

We investigated the trophic effect on the pancreas of male Wistar rats fed up to 20 days with either raw soybean flour (RSF) containing an active trypsin inhibitor or heat-inactivated soybean flour (HSF). The concentrations of the polyamines putrescine, spermidine, and spermine in the pancreas as well as cholecystokinin (CCK) concentrations in arterial and portal vein plasma were measured. Plasma CCK concentrations were measured by a sensitive radioimmunoassay specific for the sulfated region of CCK, whereas polyamine concentrations are determined by reversed phase high-performance liquid chromatography. The levels of CCK in both arterial and portal vein plasma were significantly higher in RSF- compared with HSF-fed rats, the concentration in the portal vein being twice as high compared with the aorta. A significant increase in pancreatic weight and protein content was positively correlated to an increase in putrescine and spermidine in the pancreas of RSF-fed rats compared with HSF-fed controls, whereas the spermine content did not differ between the two groups. The pancreatic DNA content in RSF-fed rats was significantly above control values of day 20 only. These data support the hypothesis that the trophic effect of soybean trypsin inhibitor on the pancreas is mediated by CCK and that polyamines might play an important role in CCK-induced pancreatic growth.     

The role of polyamines in growth factor induced DNA synthesis in cultured rat hepatocytes.

BACKGROUND/AIMS: Hepatocyte growth factor and transforming growth factor-alpha are growth factors with important roles in hepatocyte proliferation. The polyamines, putrescine, spermidine, and spermine are widely distributed in many different cells and play an essential role in cell growth and differentiation. The present study examined the role of polyamine in this growth promoting factor-induced hepatocyte proliferation, in primary cultured rat hepatocytes. METHODOLOGY: Hepatocytes were isolated from rats by the collagenase perfusion method. Ornithine decarboxylase and S-adenosylmethionine decarboxylase activities were measured as the release of 14CO2 from L-[-14C]ornithine and S-adenosyl-L-[carboxyl14C]methionine, respectively. The concentration of polyamine was analyzed by high performance liquid chromatography. RESULTS: When transforming growth factor-alpha and hepatocyte growth factor were added to the hepatocyte culture simultaneously, ornithine decarboxylase activity, S-adenosylmethionine decarboxylase activity, polyamine concentration and DNA synthesis increased additively. The increase in DNA synthesis caused by transforming growth factor-alpha, hepatocyte growth factor, or both was completely inhibited by alpha-difluoromethylornithine and methylglyoxal bis(guanylhydrazone). The inhibition was reversed by exogenous spermidine or spermine, but not by putrescine. CONCLUSIONS: Increased spermidine or spermine levels are essential for hepatocyte proliferation in cultured rat hepatocytes.     

Age-related changes in polyamine biosynthesis after fasting and refeeding

The effect of aging on ornithine decarboxylase (ODC) activity and polyamine biosynthesis in the proximal small intestine was studied in two groups of male Fisher 344 rats (young [4-month old] and aged [26- to 27-month old]) using a fasting and refeeding model. In control (nonfasted) rats, levels of polyamines (putrescine, spermidine and spermine) and ODC activity were significantly higher in aged compared with young rats. In aged rats, fasting significantly reduced the levels of putrescine by 41%, spermidine by 23%, and spermine by 11%; however, fasting had no effect on polyamine levels in young rats. ODC activity was decreased 75% in young and 50% in aged rats after fasting compared with the respective age-matched controls. Conversely, 2 h after reinstituting a chow diet increased ODC activity by 17-fold in young rats but only 8-fold in aged rats. Putrescine levels were also increased in both age groups after refeeding; however, similar to ODC activity, these increases were much less in aged rats. In addition, spermidine and spermine levels remained significantly depressed in the aged groups even after 24 h of refeeding. These findings suggest that the normal rigid control of gut polyamine biosynthesis and proliferation noted in young rats is markedly altered with aging.     

Role of ornithine decarboxylase and polyamines in camostate (Foy-305)-induced pancreatic growth in rats

This study was designed to investigate changes of ornithine decarboxylase and polyamines during pancreatic adaptation in response to feeding of the synthetic protease inhibitor camostate. alpha-Difluoromethylornithine, an irreversible and specific inhibitor of ornithine decarboxylase, was applied simultaneously to elucidate the essential role of polyamines in pancreatic growth. Cholecystokinin (CCK) plasma levels in camostate-fed rats increased from basal values of 3-4 pmol/l to a maximal level of 27.4 pmol/l after 2h; they then decreased up to 12 h but remained elevated above controls throughout the 30-day experiments. In the camostate group pancreatic ornithine decarboxylase activity was elevated after 2 h, reaching a maximum after 6 h (1,858.5 pmol 14CO2/h/mg DNA, about 200-fold above controls) followed by a significant increase in putrescine after 4 h and spermidine after 24 h while spermine remained unchanged. The trophic parameters increased in the following time sequence: thymidine kinase (12 h), DNA polymerase (12 h), protein (24 h), pancreatic weight (24 h) and DNA (5 days). alpha-Difluoromethylornithine significantly delayed and reduced the camostate-induced increase in ornithine decarboxylase activity and polyamine concentrations as well as the trophic parameters. Application of the CCK receptor antagonist L-364,718 resulted in complete inhibition of the increases in ornithine decarboxylase, polyamines and all trophic parameters. These data indicate an important role for ornithine decarboxylase and polyamines in camostate-induced pancreatic growth and hormonal mediated pancreatic adaptation in rats.     

Polyamine levels of human colorectal adenocarcinomas are correlated with tumor stage and grade

BACKGROUND AND AIMS: Cellular proliferation and differentiation are regulated by polyamines and their rate-limiting enzyme ornithine decarboxylase (ODC), both of which are correlated with tumor growth, but their role in differentiation is less clear. We investigated the correlation of ODC activity and polyamine levels with tumor stage and grade with respect to sample recruitment. PATIENTS AND METHODS: We determined ODC activity ([(14)C]CO(2) release), polyamines (HPLC), and histological staging and grading (TNM classification) of tissue samples from 64 patients with colorectal adenocarcinomas. RESULTS: We found the concentrations of putrescine, spermidine, and N(1)-acetyl-spermidine and the ODC activity in tumor tissue to be twice as high as in adjacent normal mucosa. A critical parameter affecting ODC activity was ischemic time, which significantly reduced ODC activity levels in tumors (threefold) and in the surrounding normal tissue (ninefold) when the ischemic period exceeded 1 h. By contrast, polyamine content was not affected by ischemia. Total polyamine and spermine concentrations were higher in T3 and T4 than in T2 tumors, but putrescine was higher in T4 than in T3 and T2 tumors. There were significantly higher levels of total polyamines and spermine in moderately differentiated (G2) than in poorly differentiated (G3) tumors. CONCLUSION: The lower spermidine/spermine ratio in G2 (0.44) compared with that in G3 (0.64) tumors suggests the involvement of the polyamines in colonic cell differentiation. Polyamine content is thus correlated with the tumor stage.     

Role of polyamines in isoproterenol-induced cardiac hypertrophy: effects of alpha-difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase

DFMO is a selective irreversible inhibitor of ornithine decarboxylase (ODC), the initial enzyme in the polyamine biosynthetic pathway. DFMO was utilized to determine the role of polyamines in isoproterenol (ISO)-induced cardiac hypertrophy. Daily subcutaneous administration of 200 mg/kg of DFMO reduced cardiac putrescine levels but did not significantly alter the basal levels of spermidine or spermine, nor was normal cardiac growth affected. ISO-induced cardiac hypertrophy was accompanied by increased putrescine and spermidine levels but spermine was not significantly altered. DFMO reversed the ISO-induced increases in putrescine and inhibited or attenuated both the increases in spermidine content and the cardiac hypertrophy. Although normal ODC activity appears not to be necessary for the maintenance of basal levels of polyamines or for normal cardiac growth, sustained inhibition of ODC interferes with ISO-induced elevations of putrescine, spermidine and heart weight.     

Modulation of the polyamine biosynthetic pathway in transgenic rice confers tolerance to drought stress

We have generated transgenic rice plants expressing the Datura stramonium adc gene and investigated their response to drought stress. We monitored the steady-state mRNA levels of genes involved in polyamine biosynthesis (Datura adc, rice adc, and rice samdc) and polyamine levels. Wild-type plants responded to the onset of drought stress by increasing endogenous putrescine levels, but this was insufficient to trigger the conversion of putrescine into spermidine and spermine (the agents that are believed to protect plants under stress). In contrast, transgenic plants expressing Datura adc produced much higher levels of putrescine under stress, promoting spermidine and spermine synthesis and ultimately protecting the plants from drought. We demonstrate clearly that the manipulation of polyamine biosynthesis in plants can produce drought-tolerant germplasm, and we propose a model consistent with the role of polyamines in the protection of plants against abiotic stress.     

Polyamine levels as biomarkers of injury response in polytrauma victims

Enhanced protein mobilization and synthesis are common responses to severe trauma. The hypothesis that extracellular polyamine levels could be valid biomarkers for these responses has been investigated. The three polyamines, spermidine, spermine and their precursor putrescine are directly involved in cell growth/death kinetics through regulation of protein metabolism. The lack of tissue uptake of extracellular polyamines and their rapid conjugation and excretion make them excellent biomarkers of variations in cellular kinetics. The polyamine levels in plasma and urine of severely traumatized patients were measured during the early "flow" phase of injury and compared with unstressed normals. Significantly elevated urinary levels of free and total putrescine and spermidine indicate the increase in the protein synthesis and breakdown rates, respectively, in polytrauma patients. Urinary spermidine level correlates well with other known parameters of protein catabolism, such as isotopically measured whole body protein breakdown rate in the basal state and 3-methylhistidine excretion and nitrogen loss in the basal condition and during nutritional therapy. Whole-body protein synthesis rate positively correlates with putrescine levels in urine. Based on these observations, urinary levels of the polyamines spermidine and putrescine may be applied as valid biomarkers of protein breakdown and synthesis rates, respectively, both for the existing pathology of severe trauma and for the response to nutritional therapy.