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Selenium metabolism in pigs

Selenium metabolism, the glutathione peroxidase system and their interaction with some B vitamins in pigs

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Selenium (Se) is an essential trace element for animal nutrition. Organic forms of selenium are recognized as more bioavailable than inorganic forms (Daniels, 1996) for most species including pigs (Mahan and Peters, 2004; Fortier and Matte, 2006). In a recent study (Fortier and Matte, 2006), we have shown that the improved selenium status of sows via supplementation with organic selenium (0.3 ppm Se as Sel-Plex® selenium yeast) has drastic consequences for embryos. In early gestation, selenium transfer from the dam increased up to 60% and embryonic development improved by approximately 10% compared with either no treatment or treatment with an inorganic source (0.3 ppm Se as selenite).


Apparent disconnect between performance criteria and Se-dependent GSH-Px

Although those results (Fortier and Matte, 2006) are clear and coherent (selenium transfer to embryo and embryo development), they were observed despite a lack of long-term effect on (or even with a decrease in) Se-dependent glutathione peroxidase (GSH-Px, Figure 1) in sow’s blood although one might expect treatment response in GSH-Px activity, since it is known to be a key metabolite involved in selenium metabolism. However, these findings are not unique to the present experiment. Indeed, in sows, Mahan and Peters (2004) showed that serum GSH-Px over four parities was numerically lower by approximately 6% with Sel-Plex® supplementation compared with selenitefed sows at 30 days of gestation, a finding similar to our own of 8.5% (Fortier and Matte, 2006).

In poultry, the source of selenium (organic vs inorganic) had no significant effect on blood GSH-Px (Payne and Southern, 2005; Petrovic et al., 2006); and similar results have been reported in humans (Burk et al., 2006). In goats, Chung et al. (2007) has recently shown no effect of organic selenium on systemic GSH-Px, although the GSH-Px activity did increase in gastrocnemius muscle.

Classically, this effect is attributed to the fact that the phosphate form of selenium, which is essential for some steps of the gene transcription for Se-GSH-Px synthesis, would be more readily available from selenite than from selenomethionine (Yasumoto et al., 1979; Flohé et al., 1997). In our previous experiment (Fortier and Matte, 2006), however, when we looked at the short-term profile of GSH-Px during the the peri-ovulation period (Figure 2) it appeared that its activity increased suddenly in Sel-Plex®- fed sows on day 0, corresponding to the time of ovulation. This peri-ovulation profile was originally planned to follow the changes of Se-GSH-Px during the preovulatory phase of the estrus cycle in sows.

We hypothesized that there might be a transient lack of metabolically available antioxidants that could induce a suboptimal quality of ovulation and, eventually, of (or some) embryos. Although both sources of selenium apparently covered the peri-estrus lack of antioxidants after day 0 (Figure 2), the positive effects on embryo development were seen only with Sel-Plex®-fed sows.


Figure 1. Blood Se-GSH-Px activity as affected by level and/or source of dietary selenium and to stage of post-pubertal period (behavioural estrus).



Figure 2. Blood Se-GSH-Px activity as affected by level and/or source of dietary selenium and to the peri-estral period (the day 0 = physiologic estrus, i.e., time of LH peak).


The question then arises: “What is the explanation for this unique apparent regulation of Se-GSH-Px by organic selenium?”


Regulation of the GSH-Px system

The glutathione (GSH) system, comprising oxidized and reduced GSH and the two enzymes GSH peroxidase and GSH reductase, is closely related to the metabolism of two amino acids, cysteine (Cys) and methionine (Met) (Figure 3) via the key intermediary metabolite, homocysteine. Homocysteine is a sulfur-containing amino acid derived from the hydrolysis of S-adenosylhomocysteine (AdoHcy) generated from AdoMet, the major cellular methyl donor.



Figure 3. Regulation of homocysteine metabolic disposal by peroxides (H2O2) and other reactive oxygen species. From Mosharov et al. (2000). Up-regulation: towards cysteine and glutathione peroxidase system (transulfuration). Down-regulation towards methionine (transmethylation).


Elevated levels of homocysteine are correlated with several pathologies, and are recognized as an initiating factor for arteriosclerosis of coronary, cerebral and peripheral vessels (Boushey et al., 1995; Refsum et al., 1998). They also have harmful effects on embryo development (Pietrzik and Bronstrup, 1997; DiSimone et al., 2004) and cell proliferation (Chen et al., 2000). In view of the adverse effects of homocysteine on tissue integrity and its pro-oxidizing properties, organisms must rid themselves of this metabolite as quickly and as efficiently as possible. Therefore, it is metabolized via either transmethylation or transsulfuration reactions (Figure 3).

In transmethylation, the conversion of homocysteine to methionine is catalyzed by the enzyme methionine synthase, a vitamin B12-dependent zinc protein (Figure 3). This reaction requires the release of a methyl group from CH3-H4folate to H4folate, the two main circulating forms of folic acid (vitamin B9) in pigs (Natsuhori et al., 1996). Transmethylation can also proceed through another zinc-containing enzyme, betaine homocysteine methyltransferase. Betaine is an intermediate step in the catabolism of choline. In this last case, transmethylation capacity is limited because the tissue distribution of the enzyme is restricted to specific organs (Delgado-Reyes et al., 2001).

In transsulfuration, the disposal of homocysteine is catalyzed by the B6-dependent cystathionine β-synthase, which leads to cystathionine and subsequently to cysteine and GSH biosyntheses (Figure 3). Thus, the transsulfuration reaction provides a direct link between homocysteine and GSH, the major redox buffer in mammalian cells. The two major homocysteine-utilizing enzymes, methionine synthase and cystathionine β-synthase, show reciprocal sensitivity to oxidative conditions (Mosharov et al., 2000). In fact, reactive oxygen species (ROS) and peroxides (H2O2) upregulate the transsulfuration pathway (homocysteine towards cysteine and eventually the GSH-Px system) and downregulate the transmethylation (homocysteine towards methionine) (Figure 3). Therefore, the presence (or the production) of oxidative metabolites will stimulate the pathway (transsulfuration) that will eventually result in their neutralization.

Thus, returning to the example of gilts during the peri-estral period, it appears that the prooxidative conditions brought about by ovulation upregulated the GSH system. This upregulation only occurred with organic selenium supplementation. The fact that there is no upregulation with the control treatment is probably due to the lack of metabolically available selenium; but what about the absence of estrus-related regulation with inorganic selenium?


Selenoamino acids, mineral forms of selenium and the regulation of the GSH-Px system

To better understand this last point, we must look again at the remethylation and transsulfuration pathways but, this time, with the selenoamino acids, selenomethionine and selenocysteine (Figure 4). In fact, animal metabolism does not distinguish between methionine and cysteine (sulfur forms) and their selenium analogs (cited by Daniels, 1996). This time, selenocysteine also becomes a key factor along with seleno-homocysteine. Selenocysteine can be transformed to seleno-glutathione, but the size of that metabolic pool compared with sulfur-glutathione is likely to be negligible (small arrows, Figure 4).

The importance of selenocysteine comes from its role in gene expression and activity of the Se-dependent enzyme, GSH-Px (Flohé et al., 1997; Johansson et al., 2005). This role is due to a metabolite of selenocysteine called seleno-cysteinyl (a molecular form of the cysteine moiety) that allows the full gene transcription of Se-GSH-Px (Johansson et al., 2005). In this process, one could think that the selenocysteine is cleaved and directly incorporated but that is not the case; the metabolism involved is much more complicated. In fact, selenocysteine is mineralized to selenide and then, to selenium phosphate before being resynthesized in seleno-cysteinyl, which is metabolically active for Se-GSH-Px (Yasumoto et al., 1979; Suzuki and Ogra, 2002; Johansson et al., 2005) (Figure 4). Not only does this complicated metabolic process explain a delayed response of Se-GSH-Px to organic selenium supplementation, but it also provides information on how inorganic selenium is processed (Figure 5).




Figure 4. Selenoamino acid metabolism and fate of Se-cysteine (mineralization) towards activation of the Se-dependent GSH-Px system.


In fact, selenite, the most common form of dietary inorganic selenium, is rapidly transformed to selenide and enters this metabolic pathway directly through that ‘selenide door.’ One can understand that it is then rapidly incorporated in the seleno-cysteinyl moiety and activates Se-GSH-Px. Therefore, inorganic selenium will short-circuit the overall previously described process (Figures 4 and 5) that involved the selenoamino acids (selenomethionine, selenohomocysteine and selenocysteine). This short-circuit taken by inorganic selenium will also exclude the regulation of the Se-GSH-Px by redox changes (Figure 5). Therefore, it can be hypothesized that inorganic selenium will produce a rapid, important and persistent response on Se-GSH-Px, whether or not the enzyme is needed.


Figure 5. Fate of dietary inorganic selenium (selenite) in the activation of the Se-dependent GSH-Px system. In this case, the regulation of the Se-dependent GSH-Px system by redox changes is lost (see text).


In contrast, the response to selenoamino acids might be slower but will be regulated by redox changes. Returning to our experiment with gilts and the profiles of Se-GSH-Px (Figures 1 and 2), the selenium status of the control animals was inadequate and Se GSH-Px declined, which is in agreement with an oxidative pressure brought by the peri-estral period. In gilts supplemented with dietary inorganic selenium, Se-GSH-Px increased rapidly and was insensitive to oxidative pressure brought by the peri-estral period, which is in agreement with the situation described in Figure 5. In gilts supplemented with dietary organic selenium, the Se-GSH-Px was lower than in those fed inorganic selenium when there was no oxidative pressure (long-term profiles). However, the Se- GSH-Px system was sensitive and responded rapidly to the oxidative pressure brought by the peri-estral period (short-term profiles). Taking into account the effects on embryo development in Sel-Plex® sows, this regulation of Se-GSH-Px might have been important for the subsequent steps of the ovulation process and eventually for the quality of conceptuses.


Vitamin B6 and fate of selenium for the control of the GSH-Px system


Most of the reactions involved in the fate of organic selenium for the control of the GSH-Px system (Figure 4) are B6-dependent (Yasumoto et al., 1979). Previous reports on rats have demonstrated that the response of Se-GSH-Px to organic selenium could be dependent upon the dietary provision of vitamin B6 (Yasumoto et al., 1979) (Figure 6). In normal redox balance and low B6 status, Se-GSH-Px was lower with organic selenium than with inorganic selenium, but both sources of selenium gave equivalent Se-GSH-Px responses when the diet was supplemented with vitamin B6 (Figure 6).


Figure 6. Effect of dietary vitamin B6 supplements on the hepatic response of Se-GSH-Px to the dietary form of selenium (from Yasumoto et al., 1979).


If the same process applies to pigs, the status of other micronutrients such as vitamin B6 might have to be considered to reliably interpret studies that compare organic and inorganic selenium supplements. Our results with gilts on blood Se-GSH-Px under normal redox balance (long-term profiles) (Fortier and Matte, 2006) suggest that these animals might have experienced suboptimal vitamin B6 status. The dietary concentration of vitamin B6 used was 3 ppm, a level that exceeds the NRC (1998) recommendation of 1 ppm.

In a recent report from Yoon and McMillan (2006), there was no effect of either organic or inorganic selenium on litter size or piglet weight at birth. Pyridoxine supplementation in that study was 2.1 ppm. However, in this case, comparisons with our data (Fortier and Matte, 2006) are difficult, because the treatments were initiated late in gestation (from 60 days) and unfortunately, no data were reported on GSH-Px in sows. Note that in most experiments reporting comparisons between organic and inorganic selenium (mainly from Dr. Mahan’s group at OSU) and showing no significant effects on performance or GSH-Px of sows, the vitamin premixes were devoid of vitamin B6.

The requirements of vitamin B6 for reproducing pigs have not been clearly established and have not been studied for years. In fact, the effect of pyridoxine on litter size is not well documented and most studies were carried out before the 1960s. NRC (1998) and ARC (1981) have not made formal recommendations, only suggestions, for requirements. INRA (1984) did not mention specific pyridoxine requirements for any physiologic stage.

Two studies from the early 1980s suggest that dietary concentrations of 2.0–3.0 ppm would be required to meet tissue needs and to increase reproductive performance (Easter et al., 1983; Russell et al,. 1985). In piglets, a B6 intake of 8 ppm has been recently recommended (Woodworth et al., 2000; Matte et al., 2005). Therefore, it might be valuable to further study the importance of vitamin B6 status on the effects of organic selenium on either (1) Se-GSH-Px synthesis and regulation or (2) reproductive performance in pig species.


Conclusion

The apparent disconnect between Se-GSH-Px activity and performance or selenium status indicates that Se-GSH-Px activity might not be a reliable indicator of selenium metabolism. In fact, with dietary organic selenium, the response of Se-GSH-Px is likely modulated more by oxidative pressure than by selenium status, which is probably a critical element explaining the beneficial effects of Sel-Plex® on embryo development.

The involvement of some B-complex vitamins in selenomethionine and selenocysteine pathways is the same as their involvement in corresponding sulfur pathways, because animal metabolism does not distinguish between sulfur and selenium amino acid analogs. Although folic acid (vitamin B9) and vitamin B12 are involved in some aspects of methionine metabolism, it appears that the role of vitamin B6 is critical for adequate flow of selenium (selenocysteine and selenomethionine) toward the GSH-Px system and to enable the metabolic and performance-related responses to dietary selenium.


References

ARC. 1981. The Nutrient Requirements of Pigs. Agricultural Research Council. Commonwealth Agricultural Bureaux, Slough. England.

Boushey, C.J., S.A.A. Beresford and G.S. Omenn. 1995. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA 274:1049-1057

Burk, R.F., B.K. Norsworthy, K.E. Hill, A.K. Motley and D.W. Byrne. 2006. Effects of chemical form of selenium on plasma biomarkers in a high-dose human supplementation trial. Cancer Epidemiol. Biomarkers & Prevention. 15:804-810.

Chen, C., M.E. Halkos, S.M. Surowiec, B.S. Conklin, P.H. Lin and A.B. Lumsden. 2000. Effects of homocysteine on smooth muscle cell proliferation in both cell culture and artery perfusion culture models. J. Surg. Res. 88:26-33.

Chung, J.Y., J.H. Kim, Y.H. Ko and I.S. Jang. 2007. Effects of dietary supplemented inorganic and organic selenium on antioxidant defense systems in the intestine, serum, liver and muscle of Korean native goats. Asian-Austr. J. Anim. Sci. 20:52-59.

Daniels, L.A. 1996. Selenium metabolism and bioavailability. Biol. Trace Element Res. 54:185-199.

Delgado-Reyes, C.V., M.A. Wallig and T.A. Garrow. 2001. Immunohistochemical detection of betaine-homocysteine S-methyltransferase in human, pig, and rat liver and kidney. Archiv. Biochem. Biophys. 393:184-186.

DiSimone, N., P. Riccardi, N. Maggiano, A. Piacentani, M. D’Asta, A. Capelli and A. Caruso. 2004. Effect of folic acid on homocysteine-induced trophoblast apoptosis. Molecul. Hum. Reprod. 10:665-669.

Easter, R.A., P.A. Anderson, E.J. Michel and J.R. Corley. 1983. Response of gestating gilts and starter, grower and finisher swine to biotin, pyridoxine, folacin and thiamin additions to corn-soybean meal diets. Nutr. Rep. Internat. 28: 945-950.

Flohé, L., E. Wingender and R. Brigelius-Flohé. 1997. Regulation of glutathione peroxidases. In: Oxidative Stress and Signal Transduction (H.J. Forman and H. Cadenas, eds). Chapman and Hall, New York, NY, USA, pp. 415-440.

Fortier, M.-E. and J.J. Matte. 2006. Organic or inorganic selenium for hyperovulatory first-parity sows? Antioxidant status, hormonal response, embryo development and reproductive performance In: Nutritional Approaches to Arresting the Decline in Fertility of Pigs and Poultry. Proceedings from Alltech’s technical seminar series (J.A. Taylor-Pickard and L. Nollet, eds). Wageningen Academic Publishers, Wagenhingen, The Netherlands, pp. 35-52.

INRA. 1984. Alimentation des animaux monogastriques: porcs, lapins, volailles. Institut National de la Recherche Agronomique.

Johansson, L., G. Gafvelin and E.S.J. Arner. 2005. Selenocysteine in proteins - properties and biotechnological use. Biochim. & Biophys. Acta-General Subjects. 1726:1-13.

Mahan, D.C. and J.C. Peters. 2004. Long-term effects of dietary organic and inorganic selenium sources and levels on reproducing sows and their progeny. J. Anim. Sci. 82:1343-1358.

Matte, J.J., A. Giguère and C. Girard. 2005. Some aspects of the pyridoxine (vitamin B6) requirement in weanling piglets. Br. J. Nutr. 93:723-730.

Mosharov, E., M.R. Cranford and R. Banerjee. 2000. The quantitatively important relationship between homocysteine metabolism and glutathione synthesis by the transsulfuration pathway and its regulation by redox changes. Biochem. 39:13005- 13011.

Natsuhori, M., M. Shimoda and E.I. Kokue. 1996. Alteration of plasma folates in gestating sows and newborn piglets. Am. J. Physiol. 270:R99-R104.

NRC. 1998. Nutrient Requirements of Swine (10th Ed.). National Academy Press, Washington, DC.

Payne, R.L. and L.L. Southern. 2005. Comparison of inorganic and organic selenium sources for broilers. Poult. Sci. 84:898-902.

Petrovic, V., K. Boldizarova, S. Faix, M. Mellen, H. Arpasova and L. Leng. 2006. Antioxidant and selenium status of laying hens fed with diets supplemented with selenite or Se-yeast. J. Anim. Feed Sci. 15:435-444.

Pietrzik, K. and A. Bronstrup. 1997. Folate in preventive medicine: a new role in cardiovascular disease, neural tube defects and cancer. Ann. Nutr. Metab. 41:331-343.

Refsum, H., P.M. Ueland, O. Nygard and S.E. Vollset. 1998. Homocysteine and cardiovascular disease, Ann.. Rev. Medecine 49:31-62.

Russell, L.E., R.A. Easter and P.J. Bechtel. 1985. Evaluation of the erythrocyte aspartate aminotransferase activity coefficient as an indicator of the vitamin B-6 status of postpubertal gilts. J. Nutr. 115:1117-1123.

Suzuki, K.T. and Y. Ogra. 2002. Metabolic pathway for selenium in the body: speciation by HPLC-ICP MS with enriched Se. Food Addit. Contam. 19:974-983.

Woodworth, J.C., R.D. Goodband, J.L. Nelssen, M.D. Tokach and R.E. Musser. 2000. Added dietary pyridoxine, but not thiamin, improves weanling pig growth performance. J. Anim. Sci. 78:88-93.

Yasumoto, K., K. Iwami and M. Yoshida. 1979. Vitamin B6 dependence of selenomethionine and selenite utilization for glutathione peroxidase in the rat. J. Nutr. 109:760-766.

Yoon, I. and E. McMillan. 2006. Comparative effects of organic and inorganic selenium on selenium transfer from sows to nursing pigs. J. Anim. Sci. 84:1729-1733.


Author: J. JACQUES MATTE
Dairy and Swine R & D Centre, Agriculture and Agri-Food Canada, Sherbrooke (Lennoxville), Quebec, Canada
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