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Department of Biochemistry and Molecular Biology, Medical Faculty, University of Valencia, Valencia, Spain
2To whom correspondence should be addressed. E-mail: eulalia.alonso{at}uv.es.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • arginine • polyamines • putrescine • spermidine • spermine • mice
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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–6
). Furthermore, it stimulates the secretion of several hormones including insulin, glucagon and growth hormone (7
–10
). Thus, arginine availability may affect the homeostasis of the internal milieu through several biochemical pathways and physiologic mechanisms, some of which are beginning to be studied.
Arginine requirements in most mammalian species are met by dietary intake and endogenous synthesis (2
–5
). It is an amino acid considered "essential" for young animals and "conditionally essential" for adult mammals at times of trauma or disease (11
–15
). The extent to which dietary intake of arginine satisfies the requirements for this amino acid to carry out its metabolic and physiologic functions depends on the mammalian species considered and its physiopathologic condition (2
–5
). Castillo et al. (2
,16
,17
), studied the kinetics of arginine metabolism in healthy adult young men and found that arginine homeostasis is achieved by coupling the net rate of arginine degradation to arginine intake. In fact, we reported previously that whole-body arginine catabolism is decreased in arginine-deprived adult mice (18
). However, such an adaptation of arginine catabolism to dietary arginine supply seems to be inadequate to prevent imbalances in the metabolic availability of the amino acid for certain pathways. Thus, inadequate intakes of dietary arginine, even under physiologic conditions, are typically associated with impaired spermatogenesis, alterations in the urea cycle causing orotic aciduria and transitory hyperammonemia, and dramatic reductions in tissue and circulating levels of arginine and ornithine (2
,5
,12
,17
–21
). Little is known about the quantitative importance of endogenous synthesis and dietary arginine in the maintenance of other arginine pathways such as that of polyamine synthesis.
The polyamines putrescine, spermidine and spermine are widely distributed organic cations involved in macromolecular synthesis and cell proliferation and differentiation in a multitude of mammalian cell systems (22
–25
). The maintenance of tissue polyamine levels is the result of a dynamic balance, strictly regulated, between cellular synthesis and interconversion, and their liberation to and import from extracellular sources (26
–30
). Polyamines are synthesized from arginine through a series of reactions that start with the cleavage of arginine to ornithine by arginase (Fig. 1
). Ornithine is then decarboxylated by ornithine decarboxylase (ODC)3 to yield putrescine, which is converted sequentially into spermidine and spermine by spermidine and spermine synthases, using aminopropyl residues from decarboxylated S-adenosyl-methionine. All of these reactions are irreversible in practice. However, a different set of enzymes can convert spermidine and spermine back into putrescine in mammalian cells. In this pathway, cytosolic spermine/spermidine N1-acetyltransferase (SAT) first acetylates spermine or spermidine to its acetyl derivatives which, oxidized by polyamine oxidase, yield spermidine from spermine and putrescine from spermidine. ODC, SAT and S-adenosylmethionine decarboxylase (SAMDC) are highly regulated, inducible enzymes with a high turnover rate and, depending on the physiologic situation, each may become rate limiting (1
,28
,29
). In addition, the import of cellular polyamines from and their export to the extracellular space contribute, when required, to the regulation of individual polyamine levels in tissues (30
,31
).
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Male Swiss albino mice (age 5–6 wk; 25–30 g weight at the start of the experiment) were provided by Interfauna (Barcelona, Spain). They were housed in metabolic cages (Letica, Barcelona, Spain) and maintained on a 12-h light:dark cycle in a room with constant temperature (23°C) and humidity (45–47%). The research protocol complied with NIH guidelines (32
). For 15 or 30 d, mice consumed tap water ad libitum and were pair-fed to the mean of the group fed the arginine-free diet. Diets were pelleted, synthetic amino acid diets, manufactured and provided by Panlab (Barcelona, Spain). Diet compositions were exactly as described previously (12
) with the protein replaced by a mixture of 18 amino acids including 0, 1.12 or 2.24 g/100 g L-arginine. These diets are designated as Arg0, Arg1 and Arg2 diets, respectively. When omitted, arginine was replaced by the same weight of L-alanine (12
).
Chemicals and reagents.
Acetonitrile (HPLC grade), toluene, acetone, perchloric acid and sodium carbonate were provided by Riedel-de Haën (Seelze, Germany). Dansyl chloride (5-dimethylaminonaphthalene-1-sulfonyl chloride), L-proline, 1,6-diaminohexane (1,6-DAH), putrescine (1,4-butanediamine), spermidine (N1-[3-aminopropyl]-1,4-butanediamine), spermine (N1,N4-bis[3-aminopropyl]-1,4-butanediamine), dansyl derivatives of putrescine, spermidine and spermine and other reagents were provided by Sigma Chemical (St. Louis, MO).
Blood samples and tissue processing.
After 15 or 30 d, mice were weighed and anesthetized in a closed chamber with diethyl ether; blood was withdrawn by heart puncture into lithium-heparinized syringes, and samples of 250 µL were transferred into Eppendorf tubes containing 25 µL of 4 mol/L HClO4 and 5 µL of 1 mmol/L 1,6-DAH (internal standard to follow polyamine recovery). After shaking, the tubes were kept at 4°C for 15 min and then centrifuged at 15,000 x g for 10 min. Supernatants were stored at -28°C until polyamine analysis.
Immediately after blood collection, the following organs and tissues were rapidly removed, weighed and homogenized: small intestine (contents were removed by flushing with cold saline), spleen, liver, kidney, testis, epididymal fat, muscle (quadriceps femoris from the proximal end of the pelvic limb), heart, lung, thymus, brain and eyes. They were homogenized in 0.4 mol/L HClO4 (4 mL/g tissue) at 0–4°C, using an Ultra-Turrax cell disrupter (T25 model of IKA, Labortechnik, Staufen, Germany) at maximal speed. 1,6-DAH (1 mmol/L; 100 µL/g tissue) was added to HClO4 extracts. After 15 min at 0–4°C, homogenates were centrifuged at 1500 x g for 10 min, and the supernatants frozen at -28°C until polyamine analysis.
Polyamine analysis.
Analyses of putrescine, spermidine and spermine were performed by HPLC as described (33
) with some minor modifications. Briefly, 100 µL of supernatants from blood and tissues was mixed with 400 µL dansyl chloride (10 g/L in acetone) and 200 µL of a saturated sodium carbonate solution. The mixture was allowed to react in the dark at 55°C for 90 min with occasional shaking. The excess of dansyl chloride was removed by addition of 100 µL L-proline (100 g/L) and incubation under the same conditions for 30 min. Dansylated polyamines were extracted with 700 µL toluene. The toluene solutions were evaporated completely under vacuum (Speed Vac model SC210A, Savant Instruments, Farmingdale, NY) and kept in the dark at -30°C until their analysis by HPLC. For each experiment, a sample with known amounts of the three polyamine standards was processed in parallel with the experimental samples.
The evaporated toluene residues were redissolved in acetonitrile (50–400 µL), centrifuged (1500 x g, 3 min), and aliquots of 20 µL were injected into a HPLC-system (Waters, Milford, MA) equipped with a reverse-phase column (Nova-Pak C18; 3.9 x 150 mm; 4-µm particle size; Waters) and a precolumn with the same characteristics (Nova-Pak C18; 3.9 x 20 mm, 4 µm; Waters). Fluorescence was recorded using a 420 fluorescence detector (Waters) provided with 338 nm excitation and 425 nm emission filters, respectively, and integrated in a 740 data module (Waters). Mobile phases consisted of acetonitrile/water (60:40; solvent A) and acetonitrile (solvent B). Polyamines were separated using a 50-min linear gradient from 100% solvent A to 100% solvent B at a flow rate of 1.5 mL/min. Dansyl derivatives of putrescine, spermidine, spermine and 1,6-DAH were identified by their retention times and quantified by comparison with standards. Recovery of 1,6-DAH in each sample (normally >90%) was used for calculations.
Statistical analysis.
Results are expressed as means ± SD. Analyses were conducted using the statistical package SPSS 8.0 for Windows (Chicago, IL). Data were evaluated by two-way ANOVA (time, dietary arginine) and the post-hoc Least Significant Difference test. Correlations between polyamine levels and arginine intake were estimated by simple linear regression and expressed by the Pearson’s coefficient (r). Differences were considered significant at P 
0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Putrescine levels.
Dietary arginine affected putrescine levels of the intestine (P < 0.0001), kidney (P < 0.0001), testis (P = 0.008), brain (P = 0.015), liver (P = 0.021) and fat (P = 0.022) (Table 1
). Temporal effects were significant only for kidney (P = 0.023) where putrescine levels in mice fed the Arg2 diet were greater at 30 than at 15 d (P = 0.005). There were no diet x time interactions.
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Spermidine levels.
Dietary arginine affected the spermidine levels of liver (P < 0.0001), thymus (P = 0.008), muscle (P = 0.01), intestine (P = 0.039) and kidney (P = 0.049), whereas temporal effects were significant for blood (P < 0.0001) and fat (P = 0.004). There were no diet x time interactions (Table 2
).
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Spermine levels.
Dietary arginine affected only spermine levels of liver (P = 0.015) and temporal effects were significant for muscle (P = 0.001), fat (P = 0.002) and thymus (P = 0.029). There were no diet x time interactions (Table 3
).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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–25
) which may be sustained by several mechanisms (27
–31
). One of them might be arginine availability to maintain putrescine synthesis (34
–37
) because a coordinated regulation of arginine transport and its conversion to NO and polyamines has been demonstrated (38
–41
). However, the whole-body response of polyamine levels to arginine availability has not yet been investigated. We addressed this issue by changing the dietary arginine supply. This work also confirmed previous observations on mammalian polyamine levels, i.e., that the putrescine levels were always very much lower than those of spermidine and spermine (27
,42
–44
). The agreement between our polyamine levels in mice and those in rats (27
,42
,44
) supports the idea of Seiler et al. (30
) that the order of magnitude of various polyamine levels was similar for different mammalian species. Also, as expected, we found the highest levels of the three polyamines in rapidly proliferating tissues such as thymus, intestine, spleen and liver (27
,30
,31
).
Arginine deprivation of adult mice decreases tissue and circulating levels of arginine and ornithine (12
,18
), reduces ornithine synthesis and catabolism (18
), and causes abnormal urea cycle function (12
). In vitro, arginine availability affects cellular polyamine levels and uptake (40
,41
,45
,46
) and, in vivo, this work indicates that neither arginine deprivation nor its supplementation dramatically change polyamine levels in adult mice. Variations are organ, time and polyamine specific, and affect mainly putrescine and spermidine. These results support the idea that changes in putrescine are influential in sustaining polyamine status and the whole-body capacity to maintain polyamine homeostasis. They also show for the first time that, contrary to urea cycle function (12
,18
,19
) or NO generation (unpublished data), tissue polyamine levels in adult mice are largely independent of dietary arginine. The importance of polyamines in cell growth and differentiation, gene expression and protein synthesis (22
,23
) likely underlie these results.
Arginine starvation greatly decreases putrescine, spermidine and spermine contents in rat liver (43
). Hepatic spermidine and spermine levels also decreased in our arginine-deprived mice but, in contrast, the putrescine level was maintained or somewhat increased. Liver was not an exception. Putrescine levels in intestine, kidney, fat, testis and brain were also greater in arginine-deprived mice than in the control or arginine-supplemented groups. In addition, although spermidine levels correlated positively with arginine intake in muscle, thymus, eyes, intestine and kidney, those of spermine correlated positively only in liver. A minor effect of arginine intake on mice polyamine levels would be expected from the greater demand for dietary arginine in rats than in mice (20
). However, the increase in putrescine with arginine deprivation, and the organ-specific changes in the three polyamines with arginine intake do not support a direct relationship between arginine (or ornithine) levels and polyamine status. In fact, putrescine level and ODC activity in liver are not necessarily related (43
). Several processes may lead to putrescine accumulation, i.e., increased synthesis from ornithine by ODC; increased conversion of spermidine and spermine back into putrescine; decreased conversion of putrescine into spermidine and spermine; and/or, increased uptake of the putrescine released by other tissues. Further analysis of all these processes and arginine metabolism in each organ are necessary to establish the biochemical basis of putrescine accumulation due to dietary arginine deprivation.
Decreased ornithine concentrations in arginine-deprived mice (12
,18
) would be expected to diminish putrescine production by ODC, an enzyme with a high Km for ornithine that also favors the accumulation of its active form (38
). The observed putrescine increase suggests that if such a mechanism operated, it must have been balanced by other putrescine-accumulating processes. Because many stimuli regulate ODC, SAT and SAMDC (22
,28
,29
,47
), and arginine supply affects ODC activity (44
), we hypothesize that arginine restriction induces a metabolic stress that increases ODC activity (48
,49
). Arginine has antioxidant properties both in vitro and in vivo (50
–52
), but we have no data about the effect of dietary arginine on oxidative stress. Other mechanisms for increased ODC activity when arginine is limiting might be higher superoxide generation by NO synthases (53
) or decreased inactivation of ODC by S-nitrosilation (54
) due to reduced NO production (55
).
Another way in which putrescine levels may be sustained during arginine restriction is that SAMDC activity and/or S-adenosylmethionine levels were decreased, thus reducing the conversion of putrescine into spermidine and spermine. Consistent with this, neither spermidine nor spermine accumulated in tissues of arginine-deprived mice. Moreover, because spermidine levels were unchanged or positively correlated with arginine intake, another possible way to sustain putrescine levels in arginine-deprived mice is increased oxidation of spermidine and spermine by N1-acetyltransferases. The interconversion pathway-derived putrescine would be reutilized for spermidine formation, as occurs in mouse brain (56
). In fact, spermidine and spermine levels in brain did not change with arginine intake. In no case did the increase in putrescine of arginine-deprived mice represent >2–8% of the sum of spermidine and spermine, a value compatible with our results.
Endothelial cells depleted of intracellular arginine increase putrescine uptake, even in the presence of ornithine (45
). Arginine-dependent changes in intertissue putrescine fluxes would help to sustain putrescine levels in arginine-deprived mice. Considering this possibility, the main potential source of putrescine would be the intestine. This organ is very active in putrescine synthesis, uptake and release (57
–59
). It is the sole site of de novo ornithine synthesis from glutamate (1
,60
), and its ornithine and arginine levels are not decreased by arginine deprivation (data not shown). Another potential source of ornithine for polyamine synthesis might be proline via proline oxidase and ornithine aminotransferase, as demonstrated for enterocytes (61
,62
). Because many tissues, in addition to the small intestine, contain these activities (1
), the role of proline in sustaining putrescine levels in arginine-deprived mice should be examined. Polyamines synthesized by these tissues could then be used and/or accumulated by other organs as needed (63
).
In contrast to the urea cycle (12
), the effect of arginine intake on polyamine levels changed with time, thus supporting the idea that polyamines adapt to dietary arginine availability with time (43
). It is probable that at 30 d, exogenous arginine determined spermidine levels in muscle, thymus, eyes, intestine and kidney to a large extent. In these tissues, arginine intake correlated positively with spermidine levels and, in muscle, also with the levels of ornithine (data not shown). Muscle contains low ODC and SAMDC activities (27
) but also demonstrates an active uptake and storage of polyamines (64
). Thus, the mechanisms that relate spermidine levels to arginine intake in each organ and their physiologic relevance remain to be analyzed. We hypothesize that the positive correlation between spermidine levels and arginine intake in thymus could be related to the effect of arginine in improving its endocrine activity (8
,65
). Another aspect that merits further investigation is the importance of the changes in polyamines in adipose tissue on fat accumulation and obesity (9
,66
).
Compared with organs, blood polyamine concentration is very low and reflects that transported by erythrocytes (30
) that accumulate the polyamines released by tissues (27
). Increases in blood spermidine and spermine are common in many diseases, principally in tumor growth or tissue regeneration (22
,56
). In agreement with the minor changes observed in tissues, the low and constant blood polyamine concentration we noted would be expected. However, our results do not rule out an effect of arginine intake on tissue and circulating polyamine levels under pathologic conditions (22
,67
).
Finally, it is worth mentioning the minor effect of arginine intake and time on spermine levels. Spermine levels also remained stable in tumors when the changes in putrescine and spermidine were evident (22
). Different functions for each polyamine have been suggested (29
), in agreement with our findings of divergent responses of putrescine, spermidine and spermine levels to dietary arginine supply.
In conclusion, these results show for the first time the relatively minor influence of dietary arginine on polyamine levels in adult mice. A similar situation is to be expected in humans due to their low arginine requirements (3
,5
,68
). However, as in mice, our results do not rule out a greater effect of arginine intake on polyamine levels in trauma recovery, tumor development or other pathologies in which arginine supplementation has been reported to be beneficial (67
,69
).
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: Arg0, arginine free diet: Arg1, diet containing 1.12 g/100 g arginine; Arg2, diet containing 2.24 g/100 g arginine; 1.6-DAH, 1,6-diaminohexane; ODC, ornithine decarboxylase; SAMDC, S-adenosylmethionine decarboxylase; SAT, spermine/spermidine N1-acetyl-transferase.
Manuscript received 29 May 2002. Initial review completed 26 June 2002. Revision accepted 16 September 2002.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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