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© 2004 The American Society for Nutritional Sciences J. Nutr. 134:2540-2545, October 2004

Human Nutrition and Metabolism

Phenylalanine Kinetics Differ between Formula-Fed and Human Milk–Fed Preterm Infants1

Pauline B. Darling2,*,{dagger}, Michael Dunn**,{ddagger}, G. Sarwar Gilani{dagger}{dagger}, Ronald O. Ball{dagger},{ddagger}{ddagger} and Paul B. Pencharz*,{dagger},**

* Research Institute, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; {dagger} Department of Nutritional Sciences, University of Toronto, Toronto, Ontario M5S 1A1, Canada; ** Department of Paediatrics, University of Toronto, Toronto, Ontario M5S 1A1, Canada; {ddagger} Perinatal Unit, Women’s College Hospital, Toronto, Ontario M5S 1B2, Canada; {dagger}{dagger} Bureau of Nutritional Sciences, Health Protection Branch, Ottawa, Ontario K1A 0L2, Canada; and {ddagger}{ddagger} Department of Agricultural, Food, and Nutritional Sciences, University of Alberta, Edmonton, Alberta T6G 2P5, Canada

2To whom correspondence should be addressed. E-mail: darlingp{at}smh.toronto.on.ca.


   ABSTRACT
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 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 
Infants fed casein-dominant formulas have higher plasma phenylalanine and tyrosine concentrations than those fed mother’s milk. Conversely, elevated plasma threonine concentrations are observed in infants fed whey-dominant formulas. We recently showed that formula-fed preterm infants have a lower capacity to degrade threonine than do preterm infants fed mother’s milk. We hypothesized that these same infants (n = 18) would differ in their catabolism of phenylalanine in response to phenylalanine loads provided by formulas with increasing casein content of formulas (whey:casein 60:40, 40:60, and 20:80) compared with preterm infants fed mother’s milk. Plasma phenylalanine concentrations significantly rose (49, 46, 79 µmol · L–1 for whey:casein 60:40, 40:60, and 20:80, respectively, pooled SD 8, P < 0.05); and plasma phenylalanine concentrations in infants fed mother’s milk were low (40 ± 4 µmol · L–1). Using [1-13C]phenylalanine tracer and 13CO2 production in breath we found that although there was a significant positive relation between phenylalanine oxidation and phenylalanine intake in formula-fed infants (r2 = 0.43, P = 0.03), these infants were not able to increase their oxidation of phenylalanine enough to prevent a significant rise in plasma phenylalanine when fed the 20:80 formula. Compared to infants fed mother’s milk, formula-fed infants had significantly lower phenylalanine oxidation (39.1 vs. 30.7% of phenylalanine intake, respectively, P < 0.05). We conclude that one of the mechanisms for the differences in plasma amino acid concentration between formula-fed and mother’s milk–fed preterm infants may be in vivo down-regulated catabolism of 2 important essential amino acids (phenylalanine in addition to threonine) in formula-fed preterm infants.

KEY WORDS: • phenylalanine kinetics • tyrosine • preterm infants • infant formula • breast milk

Cow’s milk–based formulas are used to feed both term and preterm infants (1–3). Since human milk contains a whey-dominant protein source the question has been raised as to whether a better human milk substitute would be produced if whey:casein ratios were altered (4). Cow’s milk has a whey to casein ratio of 20:82 and human milk has a ratio of 60:40 (5–7). The initial approach was to produce infant formulas based on a whey:casein ratio of 60:40, approximating that in human milk, but this resulted in infants with high plasma threonine levels (6). Earlier we published a study in which we showed that formula-fed preterm infants did not increase threonine degradation in response to increased threonine intake (8). Conversely infants fed their mother’s own milk increased their oxidation of threonine and thereby could handle the relatively high load of threonine present in human milk protein (8). Since casein-dominant formulas are known to cause elevations in plasma phenylalanine and tyrosine levels (6,9,10) we decided to also investigate the ability of preterm neonates to handle an increased load of phenylalanine and tyrosine and compare the results with infants fed their mother’s own milk. To serve as a basis for comparison we studied preterm infants fed formulas that were made to be identical except for their whey:casein ratio; the ratios used were 60:40, 40:60, and 20:80 (8). Earlier work showed that the whey to casein ratio does not affect protein accretion (11). However, altering the whey to casein ratios does affect plasma amino acids (12–16). The purpose of this study was to determine phenylalanine kinetics (flux, oxidation, and plasma concentration) in preterm infants fed formulas with various whey:casein ratios and in preterm infants fed their mother’s breast milk.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 LITERATURE CITED
 
    Subjects. Eighteen low-birth-weight infants were recruited from the transitional care nursery at Women’s College Hospital. Selection criteria included gestational age ≤34 wk (17), appropriate weight for gestational age (18), and body weight between 1600 and 2200 g at the time of the study. Infants tolerated full enteral feeds of 460–502 kJ · kg–1 · d–1 (110–120 kcal · kg–1 · d–1), were without acute or chronic disease or congenital abnormalities, and were not receiving antibiotic therapy. The clinical characteristics of these infants are shown in Table 1; their threonine metabolism was previously reported (8). The study was approved by the Research Ethics Boards of The Hospital for Sick Children and by that of Women‘s College Hospital. Informed written consent was obtained from 1 or both parents.


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  		TABLE 1 Characteristics of preterm infants fed formulas with various whey:casein ratios of their mother’s (preterm) milk1

 
    Diet and experimental design. The parents had previously decided whether to feed their infant with mother’s milk (preterm milk) or formula. Twelve infants were randomly assigned to 1 of 3 experimental formulas. The formulas were manufactured for the study by Wyeth-Ayerst Laboratories. They contained equal amounts of protein (15 g · L–1) and energy (2803 kJ · L–1, or 670 kcal · L–1) and were similar except for their protein source, which differed with respect to their whey to casein protein ratio (8). The nitrogen and amino acid composition of these formulas as well as that of preterm milk was previously published (8). The phenylalanine contents of the 3 formulas were 3.72, 3.92, and 4.12 mmol · L–1 for whey to casein ratios of 60:40, 40:60, and 20:80, respectively. The phenylalanine content of preterm milk was 3.79 ± 1.32 mmol · L–1 (range: 2.73–4.00 mmol · L–1). The comparable concentrations for tyrosine were 3.27, 3.27, and 3.39 mmol · L–1 for the formulas and 4.28 ± 1.86 mmol · L–1 (range: 2.87–4.75 mmol · L–1) for the preterm milk. Six infants were exclusively fed their mothers‘ milk, mainly as expressed milk, and mothers were permitted to attempt to breast-feed, if they so desired. Full details of the human milk feeding protocol, including the analyzed amino acid composition, were previously published (8).

Infants were studied over 7 d with no interference with routine care. Body weight was measured daily and body length was measured with a length board at entry to the study. Following 3 d of adaptation to the study formulas, a metabolic balance study was started at 1200 h on d 3 and ended at 1200 h on d 7. The 4-d balance study included two 24-h tracer infusion periods that were separated by a 48-h washout period, as previously described (8). Each tracer study included a 6-h baseline period and an actual tracer infusion period of 18 h. This was to ensure a stable measurement of baseline enrichments in plasma (urine) and breath. The first tracer administered was always L-[1-13C]phenylalanine and the second tracer was L-[1-13C]threonine. This order of isotope administration was chosen based on pilot work, which showed that the half-life of the clearance of [13C]phenylalanine from the isotopic steady state was 3 h compared to a half-life of 6 h for [13C]threonine.

    Tracer studies. L-[1-13C]Phenylalanine (99% 1-13C) was obtained from Merck Sharpe & Dome and from Cambridge Isotope Laboratories. The oral administration of amino acid tracer doses simulated the primed, constant isotope infusion technique (19,20). Because we used urine as a means of determining the phenylalanine enrichment of arterialized blood (19,20) and we had become aware that the renal tubular reabsorption of D-phenylalanine is much less efficient than of L-phenylalanine (21), we analyzed the urine samples using a chirasil column and a conventional GC-MS column to quantify L-[1-13C]phenylalanine (22). The L-[1-13C]phenylalanine tracer was administered in primed (15 µmol · kg–1), repeated equal doses immediately prior to each 3-h feeding, starting at 1800 h and ending the following day at 0900 h, for a total of 6 doses at a rate of 15 µmol · kg–1 · h–1.

Breath samples were collected prior to and then during the last 2 h of the 18-h tracer infusion using methods previously described (8). Urine was collected by condom urine collector every 3 h throughout the 4-d balance, starting on d 3 at 1200 h and ending on d 7 at 1200 h. Two 3-h baseline samples of urine were collected prior to starting the tracer infusion and five 3-h samples of urine were collected during the tracer infusion and stored at –20°C until analysis for [1-13C]phenylalanine and [1-13C]tyrosine enrichment. Aliquots from each intact 3-h urine sample, representing 10% of volume, collected during the 4-d balance were pooled for analysis for nitrogen concentration and stored at –20°C. The infants continued to wear a diaper over the urine collector and were clothed in their usual apparel. Stool was collected during the first 24 h by inserting a plastic liner into the diaper (8). A blood sample of 1 mL was collected at the end of the [13C]threonine tracer infusion (study day 7), as previously described (8).

    Analytical procedures. Amino acids in 250 µL of urine were derivatized to their N-heptafluorobutyryl O-isobutyl esters according to the method of Ford et al. (22). Separation of the derivatized amino acids was performed on a gas chromatograph (Hewlett-Packard Model No. 5840A), fitted with a 0.2-µm film thickness x 0.32 mm x 25 mm Heliflex chirasil-val capillary column (Alltech Asssociates) that was coupled directly to a quadropole mass spectrometer (Hewlett-Packard Model No. 5985) under conditions of negative chemical ionization and selected ion monitoring. Selected ion chromatographs were obtained by monitoring mass to charge ratio of 397 and 398 for [1-13C]phenylalanine 431 and 432 for [1-13C]tyrosine corresponding to the unenriched (m) and enriched (m + 1), respectively. Areas under the peaks were integrated by a Hewlett-Packard 1000E series computer.

The isotopic enrichment of 13C in breath CO2 was measured on a dual-inlet isotope ratio mass spectrometer (VG Micromass 602D), as previously described (8). Amino acid concentrations (not including tryptophan, methionine, and cysteine or cystine) in samples of the 3 formulas, human milk, and stool were determined by liquid chromatography of precolumn phenylisothiocyanate derivatives. Sample preparation and protein hydrolysis were performed as described by Sarwar et al. (23). Plasma amino acid concentrations were determined by ion-exchange chromatography with postcolumn ninhydrin reaction and visible colorimetric detection, using the Beckman system 7300 high-performance amino acid analyzer (Beckman Instruments).

The total nitrogen content of the formulas, human milk samples, and urine samples was determined using a micro-Kjeldahl nonautomated procedure (24). The total nitrogen content of the stool samples was determined in duplicate by the micro-Kjeldahl procedure using a Kjeltec 1030 Auto Analyzer (Tecator).

    Data analysis. Isotopic steady state in the metabolic pool was indicated by the attainment of plateau in urinary [1-13C]phenylalanine, [1-13C]tyrosine, and breath 13CO2 enrichments (8,20). Attainment of plateau was defined by consideration of the slope and SD of the points on the plotted enrichment curve. The isotopic steady state (Ep) either in mole fraction above baseline x 100 (MF%) for urinary amino acids or in atoms percentage excess (APE) for breath CO2 was calculated according to standard equations (25). Phenylalanine kinetics were determined from the isotope enrichment in urine and breath using standard methods (8,20,25).

Apparent nitrogen retention (mg · kg–1 · d–1) was calculated by subtracting nitrogen losses in urine and estimated losses in stool from nitrogen intake during the 4-d balance study. Nitrogen loss in stool was estimated to represent 15% of nitrogen intake in formula-fed infants and 12% of nitrogen intake in preterm milk–fed infants, based on the results of a study conducted on a similar group of infants fed similar formulas and human milk (11). Fecal excretion of phenylalanine and tyrosine (µmol · kg-1 · d–1) was determined by multiplying fecal phenylalanine and tyrosine (µmol/g of nitrogen) by the estimated fecal nitrogen excretion (g · kg–1 · d–1).

Results are means ± SD. Sample size used in this study was based on the sample of babies for which threonine kinetics is described (8). Since threonine kinetics had never been described, we initially established sample size based on the exploratory nature of the study and on the availability of infants. Analysis of variance was used for comparison among formula groups. If the F value was significant at P < 0.05, then post-hoc comparison of differences between groups was performed using the Student-Newman-Keuls multiple-range test with an {alpha} of 0.05 considered statistically significant. Whenever a nonsignificant difference was found (P > 0.1), results from formula groups were pooled and compared with the group fed own mother’s milk by unpaired Student t test for equal or unequal variances. The relation between phenylalanine intake and oxidation was analyzed by linear regression. Statistical analyses were conducted using SAS software (SAS Institute).


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 LITERATURE CITED
 
Eighteen infants completed the phenylalanine tracer infusion study. The clinical characteristics of the infants did not significantly differ among feeding groups, apart from the greater number of females than males in the 40:60 group (Table 1). Infants received similar daily intakes of energy, total amino acids, and nitrogen (Table 2). By design the infants received higher intakes of phenylalanine in the casein-dominant formula (20:80). The phenylalanine content of the casein-dominant formula (18:82) was 11% higher than that in the whey-dominant formula (60:40), 4115 µmol · L–1 compared with 3717 µmol · L–1, while the actual phenylalanine intake was 8% higher, 650 µmol · kg–1 · d–1 compared with 602 µmol · kg–1 · d–1. Intakes of tyrosine were not different among formula groups. The intake ratio of phenylalanine to tyrosine was lower in the group fed preterm milk (0.93) compared to the 60:40, 40:60, and 20:80 groups (1.14, 1.20, and 1.21, respectively).


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  		TABLE 2 Energy, total amino acid, phenylalanine, tyrosine, and nitrogen intakes, apparent nitrogen balance, and fecal phenylamine and tyrosine excretion of preterm infants fed formulas with varying whey:casein ratios or their mother’s milk (preterm milk)

 
There were no significant differences in apparent nitrogen balance among the 3 formula groups or between the pooled formula group and the preterm milk group (Table 2). When corrected for apparent differences in fecal nitrogen losses between formula-fed (15% of nitrogen intake) and human milk-fed preterm infants (12% of nitrogen intake) (10), fecal excretion of phenylalanine and tyrosine expressed as µmol · kg–1 · d–1 did not differ significantly among formula groups nor between the preterm milk group and the pooled formula group (Table 2).

Mean phenylalanine intake including tracer dose (as intended by the experimental design) tended (P = 0.06) to be higher in the 20:80 group compared to the 2 other formula groups (Table 3). Phenylalanine intake of infants fed preterm milk (35.7–44.1 µmol · kg–1 · d–1) was more variable, and the mean was at the lower range of the formula-fed infants. The mean plasma phenylalanine concentration of infants fed the casein-dominant (20:80) formula was 61% higher than infants fed formulas with lower casein contents (P = 0.05) and was almost double that seen in infants fed preterm milk (Table 3). One infant in the 20:80 group with extremely high plasma tyrosine concentration (409 µmol · L–1), indicative of transient tyrosinemia, had negligible phenylalanine oxidation and was removed from the analysis. Plasma tyrosine concentration of the remaining 11 formula-fed infants tended to increase (P = 0.2) with increasing casein content of the formulas (Table 3). Plasma tyrosine concentration of infants fed preterm milk was mid-range of the formula-fed infants. Of the 14 amino acids for which plasma concentration was measured, there was a significant effect of the whey to casein ratio only for phenylalanine and threonine (results not shown) (8).


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  		TABLE 3 Phenylalanine (Phe) kinetics in preterm infants fed formulas with varying whey:casein ratios or their mother’s (preterm) milk

 
No differences were detected in phenylalanine flux or phenylalanine oxidation among the groups (Table 3). However, phenylalanine oxidation as a percentage of intake was higher (P < 0.05) in infants fed preterm milk compared to formula-fed infants. In addition, the relation between phenylalanine intake and phenylalanine oxidation within the formula-fed group (n = 11) was analyzed by linear regression and a positive (r2 = 0.43 P = 0.03) relation was found. Figure 1 shows the scatter plot of phenylalanine oxidation vs intake for the 12 formula-fed infants and the 6 infants fed their own mother’s milk. It appears that human milk–fed infants do not share the same phenylalanine oxidation-intake relation as the formula-fed infants.



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  		FIGURE 1 Scatter plot of the relation between phenylalanine intake and oxidation in 6 human milk–fed infants and 12 infants fed 3 formulas with differing whey:casein ratios.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
LITERATURE CITED
 
We previously reported that human milk–fed infants can increase their threonine catabolism via the threonine dehydratase pathway, but not seemingly through the threonine dehydrogenase pathway (8). Further, the formula-fed infants had a limited capacity to increase threonine catabolism in response to an increased load of threonine. In the present study, our objective was to determine phenylalanine kinetics (flux, oxidation, and plasma concentration) in preterm infants fed formulas with various whey:casein ratios and in preterm infants fed their mother’s milk. We postulated that there would be differences in phenylalanine metabolism between formula-fed and preterm human milk–fed infants, as we found earlier in these same infants for threonine.

Infants fed preterm mother’s milk had generous phenylalanine intakes that varied across the range of intakes of the 3 formula-fed groups, yet their mean plasma phenylalanine concentration remained low and was close to that of the whey-dominant 60:40 formula group. We found an increase in plasma phenylalanine concentration with increasing casein content of formula, which was reported earlier in a study with larger numbers of infants in each group (26). Previous studies in preterm infants also found prominent and significant increases in plasma tyrosine concentration with increasing casein content of the formulas (15,26). Although the increase in plasma tyrosine concentration was not significant (P = 0.2), possibly due to sample size limitation, we did identify 1 baby with transient tyrosinemia, which has been reported to occur only with casein-dominant formula feeding (15). Priolisi et al. (16) earlier reported that preterm infants fed human milk had significantly lower plasma phenylalanine concentration compared to formula-fed infants. We did find evidence that phenylalanine oxidation as a percentage of intake is higher in infants fed preterm milk vs. formula (P < 0.05), which suggests that human milk–fed infants have an up-regulated phenylalanine degradative capacity compared to formula-fed infants. Nonetheless, formula-fed infants were able to partially increase their phenylalanine oxidation in response to the increased load, but not sufficiently to prevent a rise in plasma phenylalanine. Tracer dose oxidized (see Table 3) increased from 7.8% to 10.4% in infants receiving whey:casein ratio formulas of 60:40 and 40:60, respectively, but numerically showed no further increase when receiving the higher phenylalanine load from the 20:80 ratio formula (10.0% of dose). In contrast to the significant linear regression between phenylalanine oxidation and intake, we found no significant linear relation between tracer dose oxidized (%) and phenylalanine intake (results not shown). Tracer dose oxidized (%) is essentially an end-product parameter and does not require measurement of the precursor pool from which oxidation arises and therefore may provide a better indication of oxidative capacity (27). The changes in plasma phenylalanine concentration (Table 3) appear to parallel the changes in percentage of the tracer dose oxidized in that the increase in plasma phenylalanine occurs only in the 20:80 ratio formula group, at a point when the rise in tracer oxidation appears to have flattened. Therefore, and bearing in mind the limited sample size, it appears that formula-fed infants can partially increase their oxidation but are unable to do so in response to the increased load present in a casein-dominant (20:80 ratio) formula.

Van Toledo-Eppinga et al. (28) studied phenylalanine kinetics in human milk–fed and in formula-fed preterm infants. However, they did not measure phenylalanine oxidation; rather they measured phenylalanine hydroxylation, which did not differ between the 2 groups.

Our finding of a higher phenylalanine oxidation in infants fed preterm milk vs. formula parallels in part our earlier observation in these same infants in terms of threonine metabolism. These data support our previous conclusion (8) and extend our interpretation in that human milk may contain a substance or hormone, which is lacking in formula, which stimulates the maturation or activity of both threonine and phenylalanine degradative enzymes (29,30).

We previously showed that at intakes above the requirement level, adult males increase their oxidation of phenylalanine (31). Further, parenterally fed neonatal piglets increase their phenylalanine oxidation in response to an increasing load. However, there was a maximum phenylalanine load above which the neonatal piglets did not further increase their oxidation of phenylalanine (27).

Overall our results show that preterm neonates have a limited ability to handle the higher phenylalanine loads delivered by casein-dominant formulas. When the present results are considered together with the inability of these same infants to handle a threonine load from the whey-dominant formulas (8) it is clear that human preterm infants fed formulas may have an immaturity in their ability to catabolize a load of at least these 2 dietary essential amino acids. These direct kinetic in vivo studies are consistent with some of the findings of the in vitro studies of Raiha (4).


   ACKNOWLEDGMENTS
 
The authors thank Dr L. Marai for his expertise and assistance with mass spectrometry analysis and Constance Williams for her nursing assistance.


   FOOTNOTES
 
1 Supported by grant MOP-12928 from the Canadian Institute for Health Research. The experimental formulas were provided by Wyeth-Ayerst International. Back

Manuscript received 21 April 2004. Initial review completed 8 June 2004. Revision accepted 12 July 2004.


   LITERATURE CITED
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 

1. American Academy of Pediatrics, Committee on Nutrition (1985) Nutritional needs for low birthweight infants. Pediatrics 75:976-986.[Abstract/Free Full Text]

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20. Zello, G. A., Menendez, C. E., Rafii, M., Clarke, R., Wykes, L. J., Ball, R. O. & Pencharz, P. B. (2003) Protein kinetics in the preterm neonate studied at differing short-term protein intakes using various stable amino acid isotopic tracers. Pediatr. Res. 53:338-344.[Medline]

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28. Van Toledo-Eppinga, L., Kalhan, S. C., Kulik, W., Jakobs, C. & Lafeber, H. N. (1996) Relative kinetics of phenylalanine and leucine in low birth weight infants during nutrient administration. Pediatr. Res. 40:41-46.[Medline]

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