Putrescine treatment reverses α-tocopherol-induced desynchronization of polyamine and retinoid metabolism during rat liver regeneration
© The Author(s) 2016
Received: 7 July 2016
Accepted: 12 October 2016
Published: 26 October 2016
The pre-treatment with α-tocopherol inhibits progression of rat liver proliferation induced by partial hepatectomy (PH), by decreasing and/or desynchronizing cyclin D1 expression and activation into the nucleus, activation and nuclear translocation of STAT-1 and -3 proteins and altering retinoid metabolism. Interactions between retinoic acid and polyamines have been reported in the PH-induced rat liver regeneration. Therefore, we evaluated the effect of low dosage of α-tocopherol on PH-induced changes in polyamine metabolism.
This study evaluated the participation of polyamine synthesis and metabolism during α-tocopherol-induced inhibition of rat liver regeneration. In PH-rats (Wistar) treated with α-tocopherol and putrescine, parameters indicative of cell proliferation, lipid peroxidation, ornithine decarboxylase expression (ODC), and polyamine levels, were determined.
Pre-treatment with α-tocopherol to PH-animals exerted an antioxidant effect, shifting earlier the increased ODC activity and expression, temporally affecting polyamine synthesis and ornithine metabolism. Whereas administration of putrescine induced minor changes in PH-rats, the concomitant treatment actually counteracted most of adverse actions exerted by α-tocopherol on the remnant liver, restituting its proliferative potential, without changing its antioxidant effect. Putrescine administration to these rats was also associated with lower ODC expression and activity in the proliferating liver, but the temporally shifting in the amount of liver polyamines induced by α-tocopherol, was also “synchronized” by the putrescine administration. The latter is supported by the fact that a close relationship was observed between fluctuations of polyamines and retinoids.
Putrescine counteracted most adverse actions exerted by α-tocopherol on rat liver regeneration, restoring liver proliferative potential and restituting the decreased retinoid levels induced by α-tocopherol. Therefore interactions between polyamines and retinol, mediated by the oxidant status, should be taken into consideration in the development of new therapeutic strategies for pathologies occurring with liver cell proliferation.
KeywordsCell proliferation Ornithine decarboxylase Putrescine Lipid peroxidation Citrulline
The α-tocopherol is the predominant form of vitamin E in the human plasma, and the most effective antioxidant tocopherol (α > β > γ > δ) ; however, γ-tocopherol, but not α-tocopherol, has anti-inflammatory properties . As to the effects of α-tocopherol in the diseased liver, efforts have been made to evaluate the impact of vitamin E (VE) on hepatocellular carcinoma (for review, see Hernández-Muñoz et al., Ref. ). Several vitamins such as retinoic acid, ascorbic acid, vitamin D and E are known to prevent the development and progression of breast cancer ; indeed, retinoic acid and α-tocopherol act synergistically in inhibiting human breast cancer cell proliferation, upregulating antioxidant enzymes and proteins involved in apoptosis . Moreover, VE plays a protective effect against cigarette smoke extract-induced cytotoxicity in mouse embryonic lung cells, apparently involving the mitochondrial pathway of cytochrome c-mediated caspase activation . In the same context, abdominal obesity is a risk factor associated with enhanced oxidative stress; it has proved that this condition has relationships with dietary vitamin E and A intake and genetic variants of thioredoxin and catechol-O-methyltransferase . In this regard, we have demonstrated that the oxidant status can control the progression of partial hepatectomy (PH)-induced rat liver regeneration [8, 9], and treatment with the α-tocopherol promotes an early termination of priming cell events, culminating in a partial inhibition of rat liver regeneration .
The proliferating liver after PH is highly sensible to small dosing of α-tocopherol, which alters the pattern of signal transducer and activator of transcription (STAT) protein activation, and blunts retinoic acid formation by decreasing alcohol dehydrogenase (ADH) activity [11, 12], probing that reactive oxygen species (ROS) participate in changing the cell redox state during liver cell proliferation . Retinoic acid is synthesized in the liver and can interact with retinoid receptors which control expression of a large number of genes involved in hepatic processes . We have demonstrated that interactions between α-tocopherol and retinoid compounds (retinol, retinal, and retinoic acid) are important for impacting rat liver regeneration after PH. In this context, an anti-tumor effect of VE might be attributed to a kind of disruption of signal transduction , as we have already explored [10, 15]. In this regard, it has been highlighted the role of STAT3 signaling in liver injury, steatosis, inflammation, regeneration, fibrosis, and hepato-carcinogenesis, proposing that cytokines and small molecules that activate STAT3 in hepatocytes may readily have therapeutic benefits to treat liver diseases, including cancer .
As well as retinoid metabolism, the polyamines are also required for animal cell proliferation, since activation of polyamine catabolism invariably leads to growth inhibition . The PH-induced rat liver regeneration is closely linked to synthesis and metabolism of polyamines, and its inhibition resulted in decreased hepatic DNA synthesis , which is reversed by supplementing the polyamine putrescine . Cellular polyamine concentrations are highly regulated, since enhanced levels of these molecules can dysregulate polyamine homeostasis leading to toxic cellular effects. In turn, low levels of polyamines can inhibit cell proliferation and affect embryo development . In this context, perioperative oral polyamine administration attenuates liver ischemia-reperfusion injury and promotes liver regeneration .
Moreover, there is evidence pointing out interactions between retinoic acid and polyamines. The transglutaminase activity (or transamidation function) can cross-link polyamines to target proteins, and retinoic acid increases expression/activation of transglutaminase . Depletion of transglutaminase activity by cadaverine enhances toxicity of retinoids , which can be counteracted by polyamines in several tissues .
Based on the aforementioned, we sought that the inhibitory effect of α-tocopherol on rat liver regeneration could be linked to altered ODC expression and polyamine synthesis and metabolism, in a similar fashion that involves disturbed ADH-mediated retinoid metabolism . Therefore, it is likely that putrescine administration can partial or completely rescue the adverse effects of α-tocopherol on rat liver regeneration.
Animals and treatments
Male Wistar rats weighing 240–270 g (3 months old n = 120), were housed with free access to food and water. Animals were randomly divided into two groups: rats receiving a daily intragastric administration of 6 IU/kg of α-tocopherol (approximately 4 mg/kg of VE) diluted in peanut oil (1 mL/rat), and those receiving only the α-tocopherol vehicle . After completing the treatment with α-tocopherol, animals were again divided according to their surgical status. The 70 % PH was performed according to the previously described  and sham-operated animals provided a surgical control. Another set of sham- and PH-rats, treated or not with α-tocopherol, received an intraperitoneally single dose of 40 mg/kg of body (0.3 mmol/kg of b.w.) of putrescine, as previously reported . Afterwards, rats were euthanized under sodium pentobarbital anesthesia and liver samples were obtained. All manipulations were done according to our Institutional Guide for Animal Experimentation and Care (National University of Mexico).
Liver histology and mitotic index
The cytosolic and plasma membrane fractions were obtained by differential centrifugation, as described by Aguilar-Delfín et al. . The ROS levels in sub-cellular fractions were estimated through the method described by Viarengo et al. , using the fluorescence signal generated by ROS reacting with 2′,7′-dichlorodihydrofluorescein di-acetate (H2DCF-DA, Molecular Probes). The thymidine kinase (TK) activity was determined according to Sauer and Willmans . The ODC activity was detected by using [1-14C] ornithine (specific activity, 54 mCi/mmol), according to Diehl et al. . Liver levels for ornithine and citrulline were determined as previously described, in detail .
Quantification of polyamines and retinoid levels by HPLC
Liver levels of polyamines (putrescine, spermidine, and spermine) present in acid-extracts from cytosol were measured as benzoyl derivatives using HPLC (Beckman-Golden system HPLC with UV detector), prepared essentially as described by Thyssen et al. . The equipment used was a Beckman-Golden system HPLC with UV detector, and a C-18 reverse column was employed. For retinoids, total liver homogenate (200 mL) was extracted with 2 mL of methanol/acetone 1:1 v/v), suspended in methanol/dimethyl sulfoxide (1:1 v/v), and analyzed in the HPLC, as described in detail by Molotkov et al. .
Western-blot analyses for cytosolic amount for ODC
Thirty five µg per well of cytosolic protein were separated in a 10 % SDS-PAGE through increasing voltage from 65 to 110 V. After separation, proteins were transferred to nitrocellulose membrane in a Tobwin buffer at 250 mA 2 h in 4 °C, blocking unspecific sites with PBS-Tween 0.3 % buffer (pH = 7.4) containing casein 1 % and gelatin 0.3 %, followed by an overnight incubation with primary antibody (0.02 µg/mL of monoclonal anti-ODC mouse antibody, SIGMA-Aldrich chemical CO.) and 60 min-incubation with a secondary antibody coupled to horseradish peroxidase (0.001 µg/mL, Santacruz, CA). Afterwards, membranes were incubated with the chemiluminescent kit (Millipore Inc.) and exposed to photographic film (Kodak Quimioluminicents Film). Data was analyzed through Sigma Stat Software 5.0.
Results are expressed as mean ± SD, and statistical significance of the differences was assessed by two-way ANOVA for a normal distribution of data. In the case of significance, a Newman Keuls test was further applied and a p < 0.01 value was considered as significant.
Liver histology and parameters indicative of liver cell proliferation in animals subjected to PH and treated with α-tocopherol and/or putrescine
Oxidant status in liver subcellular fractions in animals subjected to PH and treated with α-tocopherol and/or putrescine
The ODC activity and its expression (ODC protein) in livers from animals subjected to PH and treated with α-tocopherol and/or putrescine
Liver levels of polyamines in animals subjected to PH and treated with α-tocopherol and/or putrescine
Liver levels of ornithine and citrulline in animals subjected to PH and treated with α-tocopherol and/or putrescine
Liver levels of ornithine and citrulline in animals subjected to PH and treated with α-tocopherol and/or putrescine
378 ± 57
529 ± 63
0.71 ± 0.09
PH + vehicle
6 h post-PH
257 ± 26
438 ± 53
0.59 ± 0.06
12 h post-PH
345 ± 41
575 ± 81
0.60 ± 0.07
24 h post-PH
551 ± 77
631 ± 101
0.87 ± 0.12
48 h post-PH
515 ± 67
746 ± 104
0.69 ± 0.10
72 h post-PH
458 ± 51
309 ± 37*
1.48 ± 0.23*
PH + VE
6 h post-PH
513 ± 62**
616 ± 80
0.83 ± 0.10
12 h post-PH
761 ± 107*,**
614 ± 92
1.24 ± 0.18*,**
24 h post-PH
569 ± 91
584 ± 99
0.97 ± 0.16
48 h post-PH
608 ± 85**
507 ± 76
1.20 ± 0.17*,**
72 h post-PH
746 ± 90*,**
415 ± 54
1.80 ± 0.23*,**
PH + Putrescine
6 h post-PH
468 ± 80**
440 ± 52
1.06 ± 0.15**
12 h post-PH
510 ± 77
185 ± 24*,**
2.76 ± 0.39*,**
24 h post-PH
548 ± 71
601 ± 90
0.91 ± 0.13
48 h post-PH
705 ± 78*
805 ± 137
0.88 ± 0.12
72 h post-PH
488 ± 44
303 ± 39*
1.48 ± 0.16*
PH + VE + Putres
6 h post-PH
983 ± 118*,**
898 ± 135**
1.04 ± 0.14**
12 h post-PH
587 ± 82**
257 ± 41*,**
2.28 ± 0.34*,**
24 h post-PH
674 ± 106*
690 ± 97
0.98 ± 0.15
48 h post-PH
755 ± 78*,**
938 ± 131*
0.80 ± 0.10
72 h post-PH
535 ± 55
217 ± 27*
2.47 ± 0.28*,**
The amount of citrulline, another ornithine by-product (urea cycle), was decreased at later times post-PH, diminishing the ornithine/citrulline ratio, indicative for a diminished citrulline synthesis (Table 1). In PH-rats pre-treated with α-tocopherol, ornithine predominated over citrulline, probably by a diminution of urea production, while putrescine alone promoted increased values for the ornithine/citrulline ratio (Table 1). In the group of the combined treatment, variations in citrulline levels gave ornithine/citrulline ratios similar to those found in the PH group treated with putrescine only (Table 1).
Liver amount of retinoids in livers from animals subjected to PH and treated with α-tocopherol and/or putrescine
In the present study, the α-tocopherol-induced inhibition of PH-induced rat liver regeneration was accompanied by altered amount of ODC, its activity, and the temporality of polyamine production. Pre-treatment with α-tocopherol delayed for 24 h the LP peak in the plasma membranes (Fig. 3), and induced a fatty liver and a decreased number of mitotic images in hepatocytes (Figs. 1, 2), decreasing the rate of cell proliferation (Fig. 1). In addition, α-tocopherol promoted a drastic overexpression of ODC at early times post-PH (Fig. 3), correlating with a desynchronized production of spermidine and spermine (Fig. 6), and also an altered ornithine metabolism (Table 1). ROS by-products becomes relevant in the metabolic adjustment of the proliferating liver , and we have shown that LP plays a role during the progression of rat liver proliferation , probably initiating a general cell response . Indeed, liver metabolism of retinoids, influenced by the NAD+ -dependent ADH activity and cell redox state, are important for the progression of rat liver regeneration, through the expression of STAT proteins .
As to polyamine metabolism, ROS and nitrogen species inactivate methionine adenosyltransferase I/III , reducing hepatic S-adenosylmethionine levels, which can regulate liver regeneration by forming spermidine and spermine [34, 35]. Furthermore, in colon carcinoma cells (HT-29 cells), the altered ornithine (ODC substrate) flux through urea cycle can lead to ammonia accumulation, reducing ODC activity which results in a decreased polyamine synthesis , indicating that the metabolic fate of ornithine is also involved in the polyamine synthesis.
The overexpression of ODC increases putrescine pool , and transgenic rats with conditioned spermidine/spermine N1-acetyltransferase expression, fail to initiate liver regeneration . From here, synchrony in polyamine synthesis appears to be essential to drive an adequate liver cell proliferation; interestingly, administration of putrescine in PH rats pre-treated with α-tocopherol restored the mitotic rate in the regenerating liver. Since putrescine administered to PH animals improves DNA synthesis in the rat regenerating liver under either, pro-oxidant (ethanol treatment; ref. ) or antioxidant conditions (α-tocopherol administration), this would suggest an involvement of cellular oxidative status in the control of polyamine metabolism.
The inhibitory effects of α-tocopherol on PH-induced rat liver regeneration seem to be due to a kind of modulation of cell signaling pathways . The α-tocopherol-induced early ODC overexpression and its corresponding activity (Figs. 4, 5) could partially block subsequently adaptive step required for PH-induced regeneration. Indeed, ODC expression and activity does not always correlate well, suggesting that ODC could be regulated at the post-translational level , including a non-covalent binding to an inhibitory “antizyme”, microsomal oxidation, transglutamination, and phosphorylation [39, 40]. It has been suggested that hepatic putrescine content only can be essential for liver regeneration after PH . However, the opposite has been also reported, suggesting that spermidine and/or spermine, but apparently not putrescine, are required for liver regeneration . A relationship between rat liver regeneration and the concentration ratio of spermidine/spermine ; in the present study, we also noted that ornithine/putrescine and ornithine/citrulline could be also important (Table 1). These ratios indicate that liver ornithine metabolism through ornithine carbamoyltransferase provides an alternative metabolic pathway for ornithine (urea cycle), competing for this substrate .
It is difficult to explain the restituting effects of putrescine in the mitosis index from livers obtained from PH-animals pre-treated with the VE, since the concomitant treatment did not increase TK and ODC activities, nor expression of the ODC protein (Figs. 1, 3, 4). As to the group of rats subjected to PH and receiving putrescine, this polyamine did favor a higher generation of LP by-products in plasma membranes (24 h; Fig. 3). This suggests that putrescine readily modified by itself the progression of PH-induced liver regeneration, mainly through shifting earlier the peak for ODC activity (Figs. 4, 5). Therefore, results suggest that PH-induced cytosolic changes in LP by-products levels, can be driven to produce enough content of putrescine, for its further metabolism. In this regard, nuclear oxidation of spermine could increase the production of highly reactive H2O2, having an increased potential for oxidative DNA damage in cancerous cells [43, 44]. In fact, polyamines also have a role in facilitating cell death, and the ability of polyamines to alter DNA–protein and protein–protein interactions might be disruptive to cellular functions, which indicates that polyamine pathway can be a molecular target for therapeutic intervention in several types cancers .
Interestingly, the balance in antagonistic activities of ODC and SSAT in the stressed hepatoma cells resulted in increased cell polyamine content. The catabolism of polyamines by SSAT generates toxic products that promote carcinogenesis, whereas polyamine synthesis is favorable for proliferation of cells . However, it is not clear why putrescine induced an enhanced ODC expression; possibly an increased putrescine availability by its exogenous administration might modify the ODC turnover, which is known to be rapid.
The aldehyde dehydrogenase 1a2 (RALDH2), which is the rate-limiting enzyme in the production of retinoic acid from retinaldehyde, and highly induced in the regenerating heart, gives evidence that retinoic acid plays a key role . Retinoids can decrease expression of Bcl-2, and the combination of 13-cis retinoic acid and interferon enhanced the effect of paclitaxel chemotherapy, resulting in that this combination can be safely administered in phase I studies . Interactions between polyamines and retinoids can regulate retinoid-induced apoptosis in Jurkat cells ; similarly, retinoic acid activates transglutaminase that conjugates with putrescine, probably leading to a simultaneous inhibition of DNA synthesis in PH-animals [49, 50]. Polyamines are positively charged organic cations that can physiologically interact with macromolecules such as DNA and RNA. Taking advantage of this property, natural and synthetic polyamines could be used as polyamine-substituted agents carried out for non-viral gene delivery vehicles for therapeutic purposes . In fact, modeling of polyamine-protein conjugates shows that this conjugation induces major alterations of serum protein conformations, and that polyamine-protein interaction is spontaneous and chitosan nanoparticles can be used for delivery of antitumor polyamine analogues [52, 53].
Here, the α-tocopherol effects on rat liver regeneration beyond 24 h could highlight the relevance of early changes in the oxidative status of the PH-induced rat proliferating liver, since VE administration might induce a ‘premature’ but ineffective proliferative response. What could be the mechanism(s) underlying the present findings? After PH, there is a transient increase of ROS mainly in plasma membranes and cytoplasm . The latter (cytosolic fraction) could be part of a signaling pathway activating STATs translocation into the nucleus, as well as stimulating cyclin D1 expression [10, 11]. In fact, we have demonstrated that increased serum levels of cytoplasmic enzymes observed during PH-induced rat liver regeneration is differentially regulated by modifications of the oxidant status, indicating that this release is a strictly controlled event .
Therefore, it is possible that α-tocopherol makes earlier the adaptive changes induced by PH and partially blocks liver cell proliferation, which is largely ameliorated by putrescine, restituting in synthesis of retinoids (Fig. 7) and “normalizing” progression of rat liver regeneration, apparently returning the synchrony of polyamines and retinoid metabolisms. Indeed, our results suggest that the main effect of VE was of “desynchronizing” (shifting earlier) rather than to partial block polyamine synthesis and metabolism by the PH-induced rat regenerating liver. In fact, uncontrolled oxidative stress is involved in the hypocontractility of visceral artery to vasoconstrictors and formation of hyperdynamic circulation in cirrhosis with portal hypertension . This stress the role of a selective control of ROS and LP by-products in liver regeneration, probably mediated by variations in STATs expression, as well as those on polyamine and retinoid metabolism.
The pretreatment with α-tocopherol was capable to shift early the increased activities found for TK and ODC, inducing a dramatic overexpression for the ODC protein. These effects seemed to be related to the antioxidant action exerted by α-tocopherol and occurring during inhibition of PH-induced rat liver regeneration. Polyamine synthesis and catabolism were also temporally affected by pre-treatment with α-tocopherol. Although administration of putrescine induced minor changes in the liver of animals subjected to PH, we noted that the concomitant treatment actually counteracted most adverse actions exerted by α-tocopherol on rat liver regeneration, restoring the proliferative potential in the remnant liver and the levels of liver retinoids, apparently restituting this “synchrony” between both metabolism. These results could represent a novel mechanism underlying the inhibitory action of VE on rat liver regeneration, which can be implicated in pathologies occurring with liver cell proliferation, such as cirrhosis and hepatocarcinoma, and contribute to the ongoing design of possible new therapeutic interventions.
proliferating cell nuclear antigen
reactive oxygen species
signal transducer and activator of transcription
All authors conceived and designed the experiments, performing the experiments. Similarly, all authors carried out the experiments, analyzed the data and wrote the manuscript. All authors read and approved the final manuscript.
We acknowledge to Mr. Juan Manuel Barbosa for his valuable aid in designing the Figures. We also greatly thank to the Programa de Posgrado en Ciencias Biológicas of the UNAM, for providing the “academic formation” to Dr. María de Lourdes Sánchez-Sevilla for getting her Ph.D. degree.
The authors declare that they have no competing interests.
Availability of data and materials
There is availability to share data and materials.
All manipulations were done according to our Institutional Guide for Animal Experimentation and Care (National University of Mexico).
The present research was partially supported by a grant from the PAPIIT-DGAPA, UNAM # IN202014, and from Consejo Nacional de Ciencia y Tecnología (CONACyT) # 219710.
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