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© 2005 The American Society for Nutritional Sciences J. Nutr. 135:1585S-1590S, June 2005

4th Amino Acid Assessment Workshop

Tolerance for Branched-Chain Amino Acids in Experimental Animals and Humans1

David H. Baker2

Department of Animal Sciences and Division of Nutritional Sciences, University of Illinois, Urbana, IL 61801

2To whom correspondence should be addressed. E-mail: dhbaker{at}uiuc.edu.


   ABSTRACT
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 ABSTRACT
LITERATURE CITED
 
There is no good evidence for establishing branched-chain amino acid (BCAA) tolerance levels for humans. With pigs, chicks, and rats, data are available concerning excessive intake levels of BCAA, but most of the information is for growing animals instead of for adults. Estimates of maintenance requirements for (high-quality) protein and BCAA in pigs weighing between 43 and 140 kg are 350 mg · kg–1 · d–1 for protein and 28.7 mg · kg–1 · d–1 for total BCAA. In contrast, human adult maintenance requirement estimates are much higher, i.e., 660 mg · kg–1 · d–1 for good quality protein and a range of 68 to 144 mg · kg–1 · d–1 for total BCAA. The human maintenance BCAA requirement estimates range from 10.3 to 22% of the maintenance protein requirement. Whole-body protein of 45-kg pigs contains 14.2 g BCAA/100 g protein, but the maintenance requirement (based on nitrogen balance) for total BCAA is only 8.2% of the total maintenance protein requirement. Conversely, sulfur amino acid (methionine + cysteine), threonine, and tryptophan maintenance requirements of pigs as a percentage of the maintenance protein requirement are much higher than whole-body protein levels of these amino acids. This suggests that the efficiency of using absorbed amino acids of dietary origin or of reusing endogenous amino acids arising from body protein catabolism may vary considerably among the indispensable amino acids. Additionally, work with pigs points to the conclusion that whole-body amino acid concentrations are poor predictors of both maintenance requirements and ideal amino acid profiles. Based on studies with young experimental animals, a rather large dietary excess (above requirement) of an individual BCAA is well tolerated when consumed in diets containing surfeit levels of protein and the other 2 BCAA.

KEY WORDS: • leucine • isoleucine • valine • pig • chick • rat • human

Human branched-chain amino acid (BCAA) (1) requirements, as well as putative benefits and adverse effects of pharmacologic dosing, are in a state of confusion. This review will deal with both requirements and tolerance limits for leucine (Leu),3 isoleucine (Ile), and valine (Val). Human data, though sparse (particularly for adults), will be compared with relevant data available for pigs, rats, and chicks.

BCAA requirements

In defining tolerance limits for BCAAs in the pharmacologic dosing range, it is useful to compare excess levels with some reference point. Most would concur that the best reference point is the estimated average requirement (EAR) for Leu, Ile, and Val. The EAR is deemed a better reference level than the recommended dietary allowance (RDA), because the latter is a calculated instead of an empirical value, i.e., RDA = EAR + 2 SD. Unfortunately, confusion and controversy surround the best estimate of the EAR for BCAA.

The DRI Committee (1) arrived at EAR requirement estimates of 34, 15, and 19 mg · kg–1 · d–1 for Leu, Ile, and Val, respectively. However, recent indicator oxidation work from Riazi et al. (2,3) was interpreted to indicate a total BCAA requirement for adults of 144 mg · kg–1 · d–1, a value more than double the total BCAA requirement estimate of 68 mg · kg–1 · d–1 set by the DRI Committee. The University of Toronto group also reported that the BCAA requirement of young children was 48% higher than the DRI Committee recommendation (4). It is not my intent to interpret the reasons for this disparity. Suffice it to say, there are considerable problems in determining accurate requirements for amino acids (AAs)—in both animal models and humans (5,6). Some of the complicating factors include: a) method of assessment, i.e., direct oxidation, indirect oxidation, nitrogen balance (7); b) energy intake during the study period; c) the extent to which microbial AA biosynthesis in the gut may contribute to meeting the requirement (8); d) the statistical and curve-fitting procedures used to predict an average requirement; e) variability among experimental subjects; and f) the basal dietary ingredients used in the study.

It is well accepted that dietary factors such as energy level, protein (or nitrogen) level, and fiber type and level can impact AA requirement assessment. What is often forgotten is that many so-called nitrogen-free or AA-free diets are not really devoid of either nitrogen or the AAs being studied. This is particularly relevant with adult maintenance studies, where requirements are relatively low. We, for example, were unable to attain negative nitrogen balance in adult female swine that were fed a chemically defined AA diet thought to be totally devoid of Leu (9). We subsequently learned that the cornstarch in our "Leu-free" diet was contributing a meaningful quantity of Leu. Thus, cornstarch was analyzed and found to contain 3 g/kg protein of which 9.63 g/100 g was Leu. Only when we used sucrose instead of cornstarch in our purified diet were we able to arrive at an estimate of the maintenance Leu requirement (10).

Estimates have been made of BCAA maintenance requirements for pigs (9–13), albeit determined by nitrogen balance, but more recent work from Heger et al. (14,15) is deemed more relevant to comparisons between human and pig EAR values (Table 1). Heger et al. (14) fed graded levels of Leu, Ile, and Val to 44-kg pigs using casein and AA-based purified diets containing sucrose (relatively AA free) as the carbohydrate source. Dosage levels ranged from near maintenance levels to 85% of the requirement for maximum protein accretion. Straight-line linear regression equations were determined in which protein accretion was regressed on AA intake. Excellent fits (r2) occurred, and this allowed calculation of X (AA intake) values at zero Y (protein accretion), i.e., maintenance requirements. Maintenance requirement estimates for BCAAs were 12.8, 7.0, and 8.9 mg · kg–1 · d–1 for Leu, Ile, and Val, respectively, or a total requirement for BCAAs of 28.7 mg · kg–1 · d–1.


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  		TABLE 1 Comparison of maintenance amino acid and protein requirements of humans and pigs relative to whole-body amino acid levels in pigs

 
Maintenance BCAA requirement estimates for humans and pigs in Table 1 are expressed 3 different ways, and the BCAA (and other AA) requirements expressed as a percentage of either the protein or the lysine requirement are compared with whole-body protein levels of AAs expressed as a percentage of both protein and lysine (16,17). With the exception of threonine, sulfur AAs (methionine + cysteine), and tryptophan, the protein as well as the AA requirements of humans are roughly twice those for pigs. While the nitrogen balance methodology used in the pig work may have underestimated the requirements somewhat, the magnitude of the differences between pig and human BCAA requirement estimates cannot be explained by methodology alone.

The total maintenance BCAA requirement of pigs as a percentage of the maintenance protein requirement is only 8.2%, yet BCAAs as a percentage of whole-body protein in pigs (16) are 14.2% (Table 1). Why the disparity? From pig studies we know that the efficiency of using dietary BCAAs for protein accretion is about 82%, with efficiencies of Leu, Ile, and Val being about the same (14). Relative to efficiencies of utilization for other indispensable AAs, the 82% efficiency for BCAAs is roughly average [tryptophan and phenylalanine are considerably lower (14,15)]. Hence, high efficiency of utilization cannot explain why maintenance BCAA requirements as a percentage of the maintenance protein requirement are so much lower in pigs than the BCAA levels in whole-body protein. It is possible that the maintenance BCAA requirement estimates in pigs are underestimated. It seems also possible, however, that the BCAA requirement estimates in adult humans are overestimated. Regardless, the pig studies clearly suggest that whole-body AA levels are misleading predictors of not only maintenance AA requirements but also of maintenance ideal AA profiles.

Another anomaly in comparing human maintenance AA requirements with pig maintenance requirements is that the pig requirements for threonine, sulfur AAs, and tryptophan are actually higher than in humans. The relatively high maintenance requirements for these AAs in pigs have been found in every pig study that has dealt with maintenance AA requirement assessment (9–15). The high threonine need for replacement of gut mucosal losses, as well as for gut protein synthesis, and the high sulfur AAs (especially cysteine) need for keratoid tissue (hair, epidermis, finger and toe nails) protein synthesis have been used as justification for why these AAs are required at relatively high levels for maintenance in pigs. With rats, maintenance requirement estimates for sulfur AAs and threonine substantially exceed the maintenance requirement estimate for lysine (18–20). Also, even though the human maintenance AA requirement estimates of Rose et al. (21) may represent underestimates, the ratio of requirements between sulfur AAs and lysine suggest a higher requirement for sulfur AAs than for lysine.

The fact that threonine, sulfur AAs, and tryptophan are considerably lower in whole-body pig protein than the maintenance needs for these AAs relative to the maintenance protein requirement seems hard to explain. Also hard to explain is why human sulfur AAs and threonine requirements are roughly one-half of the lysine need, whereas these AAs exceed the maintenance lysine need of pigs and rats. Numerous studies have suggested that sulfur AAs are the first-limiting AAs for endogenous protein synthesis, and threonine is the second limiting (22). Thus, protein-retention responses occur when methionine (or cysteine) is added to a protein-free diet (23), and a further response often occurs when threonine is also supplemented. These findings could be interpreted to suggest that there are inefficiencies in reutilization of the sulfur AAs and threonine that arise from body protein catabolism. It may be that AA oxidation (i.e., CO2 recovery) methodology, in contrast to nitrogen balance and protein accretion methodology, does not totally account for the threonine losses because of gut mucosal sloughing or the cysteine losses resulting from keratoid tissue sloughing.

The relation of one BCAA to another (i.e., BCAA ratios) is also of interest in that pharmacologic BCAA dosing for muscle endurance (24–27) or for other purposes (28) generally has involved administration of all 3 BCAAs. The nitrogen balance studies of Rose et al. (21) found requirement ratios of 1.6 (Leu):1.0 (Ile):1.1 (Val) for adult men; the EAR estimates of the DRI Committee (1) are 2.3 (Leu):1.0 (Ile):1.3 (Val). The ratios of BCAAs in whole-body protein of pigs (Table 1) are 1.9 (Leu):1.0 (Ile):1.3 (Val). Maintenance requirement ratios of BCAA in 44-kg pigs (14) are 1.8 (Leu):1.0 (Ile):1.3 (Val). Thus, based on these ratios, most studies involving pharmacologic BCAA administration have used mixtures containing 50 to 100% more Leu than Ile, and generally slightly more Val than Ile.

Adverse effects of excess BCAAs

There are no studies in humans that provide a basis for setting tolerance limits for excess BCAA ingestion (29). Moreover, even with experimental animals, most of the literature dealing with excess BCAAs has involved short-term studies with growing animals instead of with adult animals. Also, most of the animal literature on excess BCAAs has involved supplements to test diets that were either very low in protein and (or) low in one or more of the 3 BCAAs. Illustrations of how protein level and source can affect responses to excess BCAAs in young rats are presented in Tables 2, and 3. Sauberlich (30) showed that 5 g/100 g supplemental DL-Leu was very growth depressing when added to a cystine-fortified casein diet containing only 6 g casein/100 g diet. In contrast, in a diet with 34 g casein/100 g diet, 5 g/100 g added DL-Leu was not growth depressing (Table 2). Likewise in diets with 10 g/100 g of different protein sources (Table 3), 5 g/100 g of supplemental L-Leu was growth depressing in all cases, but the magnitude of the growth depressions were much greater when casein, blood fibrin, or soy protein was fed than when egg albumin or lactalbumin were the dietary protein sources. The latter 2 protein sources are rich in both Ile and Val, whereas casein, blood fibrin, and soy protein contain much lower concentrations of Ile, Val, or both.


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  		TABLE 2 Effect of excess dietary leucine in weanling rats fed low or high protein diets for 4 wk1

 

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  		TABLE 3 Effect of excess dietary leucine in weanling rats fed various sources of protein for 4 wk1

 
With young pigs and chicks fed standard diets containing adequate protein together with surfeit levels of Leu, Ile, and Val, dietary addition of 4 g/100 g of Leu, Ile, or Val either did not depress growth at all, or did so very little (22). There is evidence, also, that older pigs, about 100 kg body weight, are very tolerant to excess dietary Leu. Thus, 45-d feeding of standard corn–soybean meal diets containing 2 g/100 g supplemental L-Leu caused neither anorexia nor growth suppression (31). The diet containing 2 g/100 g added Leu contained about 6 times the required Leu level for this size pig. Pigs fed this level of (excess) Leu deposited more fat in muscle than those fed the control diet. This is deemed desirable (i.e., marbling) in pigs, but how would it be judged if the same thing occurred in humans?

Antagonisms among the BCAAs have been discussed and reviewed in some detail (32–37). Allen (38) and Allen and Baker (36) conducted purified diet studies with young chicks in an attempt to learn which AAs among the 3 BCAAs was most damaging to utilization of each of the other 2 BCAAs (Table 4). Crystalline amino acid diets were fed, with an individual BCAA set at its requirement or at 3 g/100 g above its requirement for the excess BCAA being studied. In both the adequate and excess series of diets, graded (and deficient) levels of each of the other 2 BCAAs were fed in diets that contained the remaining BCAA (i.e., the one that was set to be neither deficient nor in excess) at its exact requirement. Thus, pairs of BCAAs were studied in all possible combinations. A reduction in slope (weight gain/mg of deficient BCAA intake) was taken to indicate that the individual BCAA fed in excess was antagonizing utilization of the individual deficient BCAA. Remarkably, there was little indication that 3 g/100 g of excess dietary Val affected dietary utilization of either Leu or Ile. Excess Leu, in contrast, affected dietary utilization of both Val and Ile, and excess Ile reduced dietary utilization of Val and Leu. These results show that the Leu effects on Ile and Val, and the Ile effects on Leu and Val are representative of AA antagonism. In all cases, 3 g/100 g supplementation of Leu, Ile, or Val caused a reduction in voluntary food intake when one of the remaining BCAAs was deficient in the diet. However, only in the case of excess Leu or Ile was the reduction in food intake and growth, at least in part because of impaired utilization of the growth limiting AAs.


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  		TABLE 4 Effects of excess levels of individual BCAAs on utilization of leucine, isoleucine, and valine by chicks1

 
Harper et al. (32) have demonstrated the antagonizing effect of excess Leu on Ile and Val in rats. Thus, addition of 3 g L-Leu/100 g to a diet containing 9 g casein/100 g resulted in a severe growth depression, and, even though the casein control diet was first limiting in threonine, supplemental Ile and Val largely reversed the growth depression caused by excess Leu. Block and Harper (39) showed that 5 g/100 g Leu added to low-protein diets for rats had no effect on liver or muscle aminotransferase activity, but it caused a more than 2-fold increase in hepatic dehydrogenase activity. May et al. (40) evaluated dehydrogenase activity in muscle of rats fed 10 g/100 g excess Leu; a marked elevation in decarboxylation occurred. Hence, induction of the ketoacid dehydrogenase enzyme by excess Leu or Ile seems to explain, at least in part, the antagonisms caused by plethoric dosing of Leu or Ile.

Tsubuku et al. (41) did 13-wk feeding studies with 6-wk-old rats (Table 5) in which graded levels of L-Leu, L-Ile, or L-Val were incorporated into a standard rat diet containing 23.1 g protein/100 g. The 13-wk feeding period was followed by a 5-wk recovery period. Pathological examination was performed after both periods. With male rats, Leu, Ile, or Val supplements up to 5 g/100 g diet did not depress growth rate. Results with the slower growing female rats were similar, except the 5 g/100 g level of added Val was growth depressing in females. There was no mortality in any of the treatment groups. The highest dose of Ile (5 g/100g) had some effects, though small, on urinary electrolytes, protein, ketone bodies, glucose, and urobilinogen. Findings on hepatology and ophthalmology were not considered toxicologically relevant. The no observed adverse effect level (NOAEL) was set at 2.5 g/100 g for Ile, 5.0 g/100 g for Leu, and 5.0 g/100 g and 2.5 g/100 g for Val in males and females, respectively. A subsequent study by Mawatari et al. (42) involved giving gravid female rats an aqueous solution of Leu that provided either 300 or 1,000 mg · kg–1 · d–1 during d 7 to 17 of gestation. A normal (high-protein) diet was fed throughout pregnancy. Neither body weight of the dam nor gestational outcome was affected by the Leu dosing. Likewise, no fetotoxicity was evident in the offspring.


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  		TABLE 5 Ad libitum feeding of excess dietary levels of leucine, isoleucine, or valine to rats for 13 wk1

 
A much larger dietary excess of Leu was studied in pregnant rats by Cohlan and Stone (43). Diets containing either 9 or 27 g casein/100 g were supplemented with either 10 or 25 g L-Leu/100 g during d 5 to d 15 of gestation (Table 6). Maternal weight gain from d 5 to d 20 of gestation (body weight not measured at d 15) was reduced markedly in dams receiving the diets with added Leu, and the magnitude of weight gain depression was considerably greater in dams fed the lower protein diet. Matsueda and Niiyama (44) added 5 g/100 g of different AAs to a diet containing only 6 g casein/100 g; diets were fed from d 1 to d 14 or d 21 of gestation. Diets containing 5 g/100 g supplemental methionine resulted in no pregnancies (0 of 12) being maintained, and 5 g/100 g Leu supplementation allowed only 2 of 10 pregnancies to be maintained. Remarkably, similar dietary additions of tyrosine, phenylalanine, threonine, lysine, Val, or Ile did not affect maintenance of pregnancy. Reduced maternal weight gain occurred relative to ad libitum–fed control or pair-fed control rats in all cases where a single excess AA was fed. Gestation weight loss occurred, however, only in rats consuming diets with excess methionine (–54 g) or Leu (–7 g). The fact that 10 g Leu/100 g diet at a dietary casein level of 9 or 27 g/100 g (43) was better tolerated than 5 g Leu/100 g diet at a dietary casein level of only 6 g/100 g (44) again illustrates the profound effect of dietary protein level on the extent to which excess dietary BCAA are tolerated. Thoemke and Huether (45) bred rats for 3 consecutive generations on (standard) diets containing 3 g/100 g of supplemental BCAA (1 g/100 g diet of Leu, Ile, and Val). Neurotransmitter levels in brainstem tissue of rats receiving the BCAA supplement were reduced in all 3 generations relative to those of control rats. No mention was made in this report of whether excess BCAAs affected reproductive performance or progeny development.


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  		TABLE 6 Excess leucine and rat pregnancy1

 
Clearly, the Ajinomoto work of Tsubuku et al. (41) provides the kind of animal work that is needed to set NOAEL values for AA supplements. Questions nonetheless remain. Are growing rats a good model for humans? Should rats in these kinds of studies be fed ad libitum or should they be trained to meal eat? Does coprophagy influence responses to excess AA ingestion? Why are the Ile and Val requirements higher than the Leu requirement for rat maintenance (18,46–48), whereas the EAR values for Ile and Val in humans are much lower than the Leu EAR value? Does AA oxidation methodology overestimate AA requirements, or does nitrogen balance methodology underestimate AA requirements? Does indirect (phenylalanine) oxidation yield the same requirement as direct (limiting AA) oxidation? Are BCAAs needed for purposes other than protein synthesis, e.g., for muscle metabolism, insulin signaling, and/or provision of nitrogen in muscle for alanine biosynthesis and its use in the glucose–alanine cycle (49)? Do high intakes of BCAAs affect neurotransmitter levels in the brain? With high intakes of BCAAs, how much of the absorbed dose is absorbed as Leu, Ile, and Val compared with that absorbed as their respective keto analogs? Gut BCAA transaminase exists, even in the stomach (50,51), so it seems possible that some portion of the (excess) BCAA intake may be absorbed into portal blood as the keto analog of Leu ({alpha}-ketoisocaproic acid, KIC), Ile ({alpha}-keto-ß-methylvaleric acid, KMV), and Val ({alpha}-ketoisovaleric acid, KIV). If this occurs, it is important to keep in mind that rats use these BCAA precursors with <100% efficiency. Relative to the L-AA, efficacy values for KIC are 50% for rats and 100% for chicks; for L-KMV the values are 65% for rats and 85% for chicks; for KIV the values are 50% for rats and 80% for chicks (52,53). There is no good basis for establishing whether the rat or the chick efficacy values for keto analogs of the BCAAs are representative of human efficacy values (54,55).

Animal studies are both necessary and useful for establishing NOAEL values for humans. However, because excess BCAAs may reduce brain concentrations of tryptophan, phenylalanine, and tyrosine, as well as the neurotransmitters noradrenalin, dopamine, and serotonin (45,56–58), effects of excess BCAAs on behavior and psychological state need more work. Ultimately, therefore, studies with humans are necessary.

Human studies

No definitive graded dosing studies with humans exist, but there are a few instances where BCAA dosing of 2 to 3 times the EAR have been reported. Marchesini et al. (59) treated 20 chronic hepatic encephalopathy patients for 6 mo, with an enteral supplement providing 240 mg · kg–1 · d–1 of BCAA. The enteral supplement was given 3 times daily. This report contains no reference to either toxicity or adverse effects. Patients with sepsis, stress, or injury have likewise been treated with parenteral solutions containing up to 50% of the AA nitrogen as BCAAs, with no apparent adverse side effects (60). Blomstrand et al. (61) gave 6 female soccer players either a placebo (6% carbohydrate) or a drink providing 9.75 g BCAA. Psychological testing was done both before and after each game. No adverse effects of BCAA dosing were noted, and psychological benefits of BCAAs were reported after exercise. DeLorenzo et al. (26) used 10 healthy male subjects to evaluate the efficacy of providing 14.4 g/d (i.e., about 3 times the EAR) of BCAA for 30 d. The investigators reported that hand-grip strength was increased in subjects given BCAAs relative to those receiving the placebo. No adverse effects of BCAA dosing were noted.

It appears based on both animal and human studies that BCAAs are among the best tolerated of all AAs when intakes well above the requirement are consumed. Although human studies have not included graded dosing experiments, animal graded dosing studies together with human single dosing studies suggest that BCAA intake levels of at least 3 times the requirement level are well tolerated. The most important dietary factor impacting BCAA tolerance levels is protein level. Studies with rats, pigs, and chicks suggest that dietary Leu levels exceeding 20 to 25% of the dietary protein level will likely result in anorexia.


   FOOTNOTES
 
1 Published in a supplement to The Journal of Nutrition. Presented at the conference "The Fourth Workshop on the Assessment of Adequate Intake of Dietary Amino Acids" held October 28–29, 2004, Kobe, Japan. The conference was sponsored by the International Council on Amino Acid Science. The Workshop Organizing Committee included Dennis M. Bier, Luc Cynober, David H. Baker, Yuzo Hayashi, Motoni Kadowaki, and Andrew G. Renwick. Guest editors for the supplement publication were David H. Baker, Dennis M. Bier, Luc Cynober, John D. Fernstrom, Yuzo Hayashi, Motoni Kadowaki, and Dwight E. Matthews. Back

3 Abbreviations used: AA, amino acid; DRI, dietary recommended intake (a committee); EAR, estimated average requirement; Ile, isoleucine; KIC, {alpha}-ketoisocaproic acid; KIV, {alpha}-ketoisovaleric acid; KMV, {alpha}-keto-ß-methylvaleric acid; Leu, leucine; NOAEL, no observed adverse effect level; RDA, recommended dietary allowance; Val, valine. Back


   LITERATURE CITED
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 ABSTRACT
 LITERATURE CITED
 

1. Food and Nutrition Board, Institute of Medicine (2002) Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients): Preliminary Report 2002 National Academy Press Washington, DC.

2. Riazi, R., Wykes, L. J., Ball, R. O. & Pencharz, P. B. (2003) The total branched-chain amino acid requirement in young healthy adult men determined by indicator amino acid oxidation by use of L-[1-13C]phenylalanine. J. Nutr. 133:1383-1389.[Abstract/Free Full Text]

3. Riazi, R., Rafii, M., Wykes, L. J., Ball, R. O. & Pencharz, P. B. (2003) Valine may be the first limiting branched-chain amino acid in egg protein in men. J. Nutr. 133:3533-3539.[Abstract/Free Full Text]

4. Mager, D. R., Wykes, L. J., Ball, R. O. & Pencharz, P. B. (2003) Branched-chain amino acid requirements in school-aged children determined by indicator amino acid oxidation (IAAO). J. Nutr. 133:3540-3545.[Abstract/Free Full Text]

5. Baker, D. H. (1986) Problems and pitfalls in animal experiments designed to establish dietary requirements for essential nutrients. J. Nutr. 116:2339-2349.

6. Fuller, M. F. & Garlick, P. J. (1994) Human amino acid requirements: can the controversy be resolved?. Annu. Rev. Nutr. 14:217-241.[Medline]

7. Pencharz, P. B. & Ball, R. O. (2003) Different approaches to define individual amino acid requirements. Annu. Rev. Nutr. 23:101-116.[Medline]

8. Torrallardona, D., Harris, C. I. & Fuller, M. F. (2003) Pigs’ gastrointestinal microflora provide them with essential amino acids. J. Nutr. 133:1127-1131.[Abstract/Free Full Text]

9. Baker, D. H., Becker, D. E., Norton, H. W., Jensen, A. H. & Harmon, B. G. (1966) Some qualitative amino acid needs of adult swine for maintenance. J. Nutr. 88:382-390.

10. Baker, D. H. & Allee, G. L. (1970) Effect of dietary carbohydrate on assessment of the leucine need for maintenance of adult swine. J. Nutr. 100:277-280.

11. Baker, D. H., Becker, D. E., Norton, H. W., Jensen, A. H. & Harmon, B. G. (1966) Quantitative evaluation of the threonine, isoleucine, valine and phenylalanine needs of adult swine for maintenance. J. Nutr. 88:391-396.

12. Baker, D. H., Becker, D. E., Norton, H. W., Jensen, A. H. & Harmon, B. G. (1966) Quantitative evaluation of the tryptophan, methionine and lysine needs of adult swine for maintenance. J. Nutr. 89:441-447.

13. Fuller, M. F. (1994) Amino acid requirements for maintenance, body protein accretion and reproduction in pigs. D’Mello, J.P.F. eds. Amino Acids in Farm Animal Nutrition 1994:155-184 CAB Intl. Wallingford, Oxon, UK. .

14. Heger, J., Van Phung, T., Krizova, L., Sustala, M. & Simecek, K. (2003) Efficiency of amino acid utilization in the growing pig at suboptimal levels of intake: branched-chain amino acids, histidine and phenylalanine + tyrosine. J. Anim. Physiol. Anim. Nutr. 87:52-65.[Medline]

15. Heger, J., Van Phung, T. & Krizova, L. (2002) Efficiency of amino acid utilization in the growing pig at suboptimal levels of intake: lysine, threonine, sulphur amino acids and tryptophan. J. Anim. Physiol. Anim. Nutr. 86:153-165.[Medline]

16. Bikker, P., Verstegen, M.V.A. & Bosck, M. W. (1994) Amino acid composition of growing pigs is affected by protein and energy intake. J. Nutr. 124:1961-1969.

17. Mahan, D. C. & Shields, R. G., Jr (1998) Essential and nonessential amino acid composition of pigs from birth to 145 kilograms of body weight, and comparison to other studies. J. Anim. Sci. 76:513-521.[Abstract/Free Full Text]

18. National Research Council (1995) Nutrient Requirements of Laboratory Animals 4th rev. ed. 1995 National Academy Press Washington, DC.

19. Shin, S., Owens, F. N., Pettigrew, J. E. & Oltjen, J. W. (1994) Apportioning threonine requirements for maintenance versus growth for rats. Nutr. Res. 14:93-104.

20. Shin, S., Owens, F. N., Pettigrew, J. E. & Oltjen, J. W. (1994) Apportioning methionine requirements for maintenance versus growth of rats. Nutr. Res. 14:229-239.

21. Rose, W. C., Wixom, R. L., Lockhart, H. B. & Lambert, G. F. (1955) The amino acid requirements of man. XV. The valine requirement; summary and final observations. J. Biol. Chem. 217:987-995.[Free Full Text]

22. Baker, D. H. (2004) Animal models of human amino acid responses. J. Nutr. 134:1646S-1650S.[Abstract/Free Full Text]

23. Webel, D. M. & Baker, D. H. (1999) Cysteine is the first-limiting amino acid for the utilization of endogenous amino acids in chicks fed a protein-free diet. Nutr. Res. 19:569-577.

24. Ohtani, M., Maruyama, K., Sugita, M. & Kobayashi, K. (2001) Amino acid supplementation affects hematological and biochemical parameters in elite rugby players. Biosci. Biotechnol. Biochem. 65:1970-1976.[Medline]

25. Smriga, M., Kameishi, M., Tanaka, T., Kondoh, T. & Torii, K. (2002) Preference for a solution of branched-chain amino acids plus glutamine and arginine correlates with free running activity in rats: involvement of serotonergic-dependent processes of lateral hypothalamus. Nutr. Neurosci. 5:189-199.[Medline]

26. DeLorenzo, A., Petroni, M. L., Masala, S., Melchiorri, G., Pietrantuono, M., Perriello, G. & Andreoli, A. (2003) Effect of acute and chronic branched-chain amino acids on energy metabolism and muscle performance. Diabetes Nutr. Metab. 16:291-297.[Medline]

27. Shimomura, Y., Murakami, T., Nakai, N., Nagasaki, M. & Harris, R. A. (2004) Exercise promotes BCAA catabolism: effects of BCAA supplementation on skeletal muscle during exercise. J. Nutr. 134:1583S-1587S.[Abstract/Free Full Text]

28. FASEB, Life Sciences Research Office (1992) Safety of Amino Acids Used As Dietary Supplements 1992:39-49 Life Sciences Research Office of FASEB FDA Contract no. 223–88-2124, Task Order no. 8.

29. Garlick, P. J. (2004) The nature of human hazards associated with excessive intake of amino acids. J. Nutr. 134:1633S-1639S.[Abstract/Free Full Text]

30. Sauberlich, H. E. (1961) Studies on the toxicity and antagonism of amino acids for weanling rats. J. Nutr. 75:61-72.

31. Hyun, Y., Kim, J. D., Ellis, M., Baker, D. H. & McKeith, F. K. (2005) Effect of dietary lysine and leucine levels on carcass composition, meat quality, and growth performance in finishing pigs. J. Anim. Sci. (in press).

32. Harper, A. E., Miller, R. H. & Block, K. P. (1984) Branched-chain amino acid metabolism. Annu. Rev. Nutr. 4:409-454.[Medline]

33. D’Mello, J.P.F. & Lewis, D. (1970) Amino acid interactions in chick nutrition. 2. The interrelationship between leucine, isoleucine, and valine. Br. Poult. Sci. 11:313-323.[Medline]

34. Hargrove, D. M., Rogers, Q. R., Calvert, C. C. & Morris, J. G. (1988) Effects of dietary excesses of the branched-chain amino acids on growth, food intake and plasma amino acid concentrations of kittens. J. Nutr. 118:311-320.

35. Smith, T. K. & Austic, R. E. (1978) The branched-chain amino acid antagonism in chicks. J. Nutr. 108:1180-1191.

36. Allen, N. K. & Baker, D. H. (1972) Quantitative efficacy of dietary isoleucine and valine for chick growth as influenced by variable quantities of excess dietary leucine. Poult. Sci. 51:1292-1298.[Medline]

37. Baker, D. H. & Mavromichalis, I. (2000) The role of branched-chain amino acids in swine and poultry nutrition. Biokyowa Tech. Rev. 12:1-20.

38. Allen, N. K. (1971) Quantitative interrelationships between excesses and deficiencies of single essential amino acids in the nutrition of the chick. Doctoral thesis 1971 University of Illinois Urbana, IL.

39. Block, K. P. & Harper, A. E. (1984) Valine metabolism in vivo: effects of high dietary levels of leucine and isoleucine. Metabolism 33:559-566.[Medline]

40. May, R. C., Piepenbrock, N., Kelly, R.A. & Mitch, W. E. (1991) Leucine-induced amino acid antagonism in rats: muscle valine metabolism and growth impairment. J. Nutr. 121:293-301.

41. Tsubuku, S., Hatayama, K., Katsumata, T., Nishimura, N., Mawatari, K., Smriga, M. & Kimura, T. (2004) Thirteen-week oral toxicity study of branched-chain amino acids in rats. Int. J. Toxicol. 23:119-126.[Abstract/Free Full Text]

42. Mawatari, K., Katsumata, T., Uematsu, M., Katsumata, T., Yoshida, J., Smriga, M. & Kimura, T. (2004) Prolonged oral treatment with an essential amino acid L-leucine does not affect female reproductive function and embryo-fetal development in rats. Food Chem. Toxicol. 42:1505-1511.[Medline]

43. Cohlan, S. Q. & Stone, S. M. (1961) Effects of dietary and intraperitoneal excess of L-lysine and L-leucine on rat pregnancy and offspring. J. Nutr. 74:93-95.

44. Matsueda, S. & Niiyama, Y. (1982) The effects of excess amino acids on maintenance of pregnancy and fetal growth in rats. J. Nutr. Sci. Vitaminol. 28:557-573.

45. Thoemke, F. & Huether, G. (1984) Breeding rats on amino acid imbalanced diets for three consecutive generations affects the concentrations of putative amino acid transmitters in the developing brain. Int. J. Dev. Neurosci. 2:567-574.

46. Owens, F. N., Shin, S., Oltjen, J. W. & Pettigrew, J. E. (1994) Apportioning isoleucine requirements for maintenance versus growth of rats. Nutr. Res. 14:105-115.

47. Owens, F. N., Shin, S., Pettigrew, J. E. & Oltjen, J. W. (1994) Apportioning leucine requirements for maintenance versus growth for rats. Nutr. Res. 14:73-82.

48. Shin, S., Owens, F. N., Pettigrew, J. E. & Oltjen, J. W. (1994) Apportioning valine requirements for maintenance versus growth for rats. Nutr. Res. 14:117-126.

49. Layman, D. K. (2003) Role of leucine in weight loss diets and glucose homeostasis. J. Nutr. 133:261S-267S.[Abstract/Free Full Text]

50. Ichihara, A., Yamasaki, Y., Masuji, H. & Sato, J. (1975) Isozyme patterns of branched-chain amino acid transaminase during cellular differentiation and carcinogenesis. Markett, C. L. eds. Isozymes. III. Developmental Biology 1975:875-889 Academic Press New York, NY. .

51. Hutson, S. M., Wallin, R. & Hall, T. R. (1992) Identification of mitochondrial branched-chain aminotransferase and its isoforms in rat tissues. J. Biol. Chem. 267:15681-15686.[Abstract/Free Full Text]

52. Boebel, K. P. & Baker, D. H. (1982) Comparative utilization of {alpha}-keto and D- and L-{alpha}-hydroxy analogs of leucine, isoleucine and valine by chicks and rats. J. Nutr. 112:1929-1939.

53. Baker, D. H. (1994) Utilization of precursors for L-amino acids. D’Mello, J.P.F. eds. Amino Acids in Farm Animal Nutrition 1994:37-64 CAB Intl Wallingford, Oxon, UK. .

54. Close, J. H. (1974) The use of amino acid precursors in nitrogen accumulation diseases. New Engl. J. Med. 290:663-667.

55. Giordano, C. (1980) Amino acids and ketoacids-advantages and pitfalls. Am. J. Clin. Nutr. 33:1649-1653.[Abstract/Free Full Text]

56. Anderson, G. H. (1981) Diet, neurotransmitters and brain function. Br. Med. Bull. 37:95-100.[Free Full Text]

57. Harrison, L. M. & D’Mello, J.P.F. (1986) Large neutral amino acids in the diet and neurotransmitter concentrations in the chick brain. Proc. Nutr. Soc. 45:72A (abs.).

58. Fernstrom, J. D. (2005) Branched-chain amino acids and brain function. J. Nutr. 135:1539S-1546S.[Abstract/Free Full Text]

59. Marchesini, G., Dioguardi, F. S., Bianchi, G. P., Zoli, M., Bellati, G., Roffi, L., Martines, & Abbiati, R. (1990) Long-term oral branched-chain amino acid treatment in chronic hepatic encephalopathy: a randomized double-blind casein controlled trial. J. Hepatol. 11:92-101.[Medline]

60. Brennan, M F., Cerra, F., Daly, J. M., Fischer, J. E., Moldawer, L L., Smith, R. J., Vinnars, E., Wannemacher, R. & Young, V. R. (1986) Report of a research workshop: branched-chain amino acids in stress and injury. JPEN. J. Parenter. Enteral Nutr. 10:446-452.[Free Full Text]

61. Blomstrand, E., Hassmén, P., Ekblom, B. & Newsholme, E. A. (1991) Administration of branched-chain amino acids during sustained exercise—effects on performance and on plasma concentration of some amino acids. Eur. J. Appl. Physiol. 68:83-88.




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