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Title: Effects of randomized supplementation of methionine or alanine on cysteine and glutathione production during the early phase of treatment of children with edematous malnutrition

item GREEN, CURTIS - University Of The West Indies
item BADALOO, ASHA - University Of The West Indies
item HSU, JEAN - Children'S Nutrition Research Center (CNRC)
item TAYLOR-BRYAN, CAROLYN - University Of The West Indies
item REID, MARVIN - University Of The West Indies
item FORRESTER, TERRENCE - University Of The West Indies
item JAHOOR, FAROOK - Children'S Nutrition Research Center (CNRC)

Submitted to: The American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/30/2014
Publication Date: 5/1/2014
Citation: Green, C.O., Badaloo, A.V., Hsu, J.W., Taylor-Bryan, C., Reid, M., Forrester, T., Jahoor, F. 2014. Effects of randomized supplementation of methionine or alanine on cysteine and glutathione production during the early phase of treatment of children with edematous malnutrition. American Journal of Clinical Nutrition. 99(5):1052-1058.

Interpretive Summary: There are two main types of severe childhood malnutrition, kwashiorkor and marasmus. In kwashiorkor the child is not only severely malnourished, but also has edema (water retention in the tissues), his/her liver does not work very well and he/she cannot fight off infections. Not surprisingly, whereas it is relatively easy to treat children with marasmus, it is very difficult to treat children with kwashiorkor and worldwide about 25% of these children die. Despite extensive research it is still not known why a child develops kwashiorkor instead of marasmus during chronic food deprivation. We have found that children with kwashiorkor have evidence that their cells are being destroyed by compounds called oxidants and that they are not making sufficient quantities of glutathione, the most important anti-oxidant that destroys harmful oxidants in the body. The compound glutathione is made from another compound called cysteine which is part of the protein we eat in our meals. Cysteine is also released from the breakdown of our body proteins and it is made in the body from another compound called methionine. Both cysteine and methionine levels are very low in the blood of children with kwashiorkor suggesting that there is a shortage of both. In this study we wanted to find out whether giving the children extra methionine with their meals will increase the amount of cysteine their bodies make and whether this in turn will increase the amount of gluthathione that they make. When we provided the children with extra methionine they did not make more cysteine or glutathione. However, they released more cysteine from their body proteins. This finding suggests that extra cysteine, not methionine should be added to the diet fed to the children during treatment for kwashiorkor.

Technical Abstract: We have shown that a low glutathione concentration and synthesis rate in erythrocytes are associated with a shortage of protein-derived cysteine in children with edematous severe acute malnutrition (SAM). We tested the hypothesis that methionine supplementation may increase protein-derived cysteine and upregulate cysteine synthesis, thereby improving glutathione synthesis during the early treatment of edematous SAM. The cysteine flux, its de novo synthesis and release from protein breakdown, and erythrocyte glutathione synthesis rate were measured in 12 children with edematous SAM in the fed state by using stable isotope tracers at 3 clinical phases as follows: 3 +/- 1 d (+/-SE) [clinical phase 1 (CP1)], 8 +/- 1 d [clinical phase 2 (CP2)], and 14 +/- 2 d (clinical phase 3) after admission. Subjects were randomly assigned to receive equimolar supplements (0.5 mmol / kg(-1) / d(-1)) of methionine or alanine (control) immediately after CP1. In the methionine compared with the alanine group, cysteine flux derived from protein breakdown was faster at CP2 than CP1 (P < 0.05), and the change in plasma cysteine concentration from CP1 to CP2 was greater (P < 0.05). However, there was no evidence of a difference in cysteine de novo synthesis and its total flux or erythrocyte glutathione synthesis rate and concentration between groups. Methionine supplementation increased cysteine flux from body protein but had no significant effect on glutathione synthesis rates. Although cysteine is made from methionine, increased dietary cysteine may be necessary to partially fulfill its demand in edematous SAM because glutathione synthesis rates and concentrations were less than previous values shown at full recovery.