Requirements and Pathology in Humans: Discussion of Session 4

Paul Pencharz, in response to questions regarding the conditions under which the indicator amino acid technique for determining amino acid requirements were performed, confirmed that the model resembled a continuous feeding situation similar to that found with total parenteral or enteral nutrition. Therefore, he viewed his estimates for requirements to be first approximations that would likely be lesser than those that would be found in the meal-feeding condition characteristic of the normal feeding pattern among humans. Under those conditions he predicted that amino oxidation rates would be somewhat higher in the postprandial state. Knowledge of individual amino acid requirements would be of particular value where proteins of lower biologic value were consumed, such as with cereal grains, where the first limiting amino acid is lysine, or corn, where tryptophan would be limiting, rather than clinical diets containing only high biologic value protein provided at protein requirement levels. Dwight Matthews wanted to clarify further the conditions under which these measurements were made; specifically, that they are generally measured when tyrosine is not present at all or provided in excess to define the maximum and minimum phenylalanine requirement. Because dietary proteins contain both these amino acids, this would mean that phenylalanine requirements under normal dietary conditions would be scaled down somewhat from the maximum requirements determined experimentally. Dr. Pencharz confirmed this interpretation and further opined that in the future additional criteria for amino acid requirements could include functional measures, such as optimal organ function, improved systemic inflammatory response, or work performance. Joel Kopple concurred in this assessment, stating that individual techniques for assessing amino acid and protein requirements each have limitations that can best be overcome by a multifactorial approach, including functional outcomes such as, for example, catecholamine production for an adequate response to hypotensive stress as a measure of phenylalanine or tyrosine needs. However, John Fernstrom raised some of the complexities involved in such measurements when neurotransmitters were the focus, because the state of activation of the neurons was important for the response and that the functional pool was not the storage pool of catecholamines but those newly synthesized. Dr. Fernstrom then extended his discussion to the role of amino acids in malignant cell growth and whether their metabolism or transport differed from that of normal cells, because of the accumulation of tyrosine in melanoma cells. Gary Meadows stated that both melanotic and amelanotic cells were sensitive to tyrosine and phenylalanine restriction and other cancer cells such as prostate respond to amino acid deprivation of phenylalanine and tyrosine. On this basis it was proposed that it might be possible to inhibit tumor growth by interfering with tyrosine or phenylalanine metabolism. Although there was some interest in attempts to control the actual growth or influence the cell cycle by starvation of phenylalanine and tyrosine, Dr. Kopple did express concerns about the ability to accomplish this clinically given the resistance of plasma amino acid levels to changes in intake. Dr. Pencharz did clarify that the dietary manipulation as he proposed would include the other 18 amino acids as well as adequate calories, which would, by reducing whole-body protein catabolism, substantially reduce phenylalanine and tyrosine levels by reducing input from endogenous protein catabolism. John Fernstrom discussed some experience with tryptophan depletion in animals where providing a mixture of other amino acids including both essential and nonessential amino acids lowered tryptophan levels in plasma presumably because of a stimulation of protein synthesis in peripheral tissues by the other amino acids and insulin secretion. Similar results were seen with a phenylalanine and tyrosine depletion paradigm (plasma tyrosine and phenylalanine were depressed), raising the possibility that it might be possible to achieve significant depression of target amino acid levels in cancer cells using such an approach (1). Dr. Kopple did express caution about this proposed therapy except for the short term in human patients, even given the prognosis of metastatic melanoma, due to the obvious potential for severe metabolic consequences by drastically affecting protein metabolism. A final question addressed by Dr. Kopple was his position on practical implications of the conditional essentiality of tyrosine for the care of the chronic renal failure or dialysis patient. Although he thought that an amino acid supplement was the obvious solution, this must be considered in light of the large number of oral medications already consumed by dialysis patients. Important considerations would be frequency of dosing, whether the supplement could be given at the time of dialysis only (which would improve compliance), timing 1 Published in a supplement to The Journal of Nutrition. Presented at the ‘‘Conference on Aromatic Amino Acids and Related Substances: Chemistry, Biology, Medicine, and Application’’ held July 20–21, 2006 in Vancouver, Canada. The conference was sponsored by Ajinomoto Company, Inc. The organizing committee for the symposium and Guest Editors for the supplement were: Katsuji Takai, Dennis M. Bier, Luc Cynober, Sidney M. Morris, Jr., and Yoshiharu Shimomura. Guest Editor disclosure: Expenses to travel to the meeting were paid by Ajinomoto Company, Inc. for K. Takai, D. M. Bier, L. Cynober, S. M. Morris, Jr., and Y. Shimomura; D. M. Bier has consulted for Ajinomoto Company, Inc. on scientific issues. 2 Author disclosure: B. Bistrian’s travel expenses to attend the meeting were paid by the Ajinomoto Company, Inc. * To whom correspondence should be addressed. E-mail: bbistria@bidmc. harvard.edu.