Whole-body Tyrosine Research Articles

Phenylalanine hydroxylation across the kidney in humans Rapid Communication

Phenylalanine hydroxylation across the kidney in humans. Although phenylalanine hydroxylase activity is detectable in in vitro renal tissue preparations, no data on in vivo phenylalanine hydroxylation across the human kidney, as well as on its possible contribution to whole-body hydroxylation, currently exist. To this aim, we have measured whole-body, renal, and splanchnic phenylalanine hydroxylation to tyrosine, as well as phenylalanine and tyrosine rates of appearance (Ra) and disposal (Rd), in postabsorptive subjects by means of renal and splanchnic arteriovenous catheterization combined with phenylalanine and tyrosine isotope infusions. In the kidney, a relevant phenylalanine hydroxylation activity was detected (3.51 +/- 0.97 micromol/min x 1.73 m2 of body surface), whereas it was 2.48 +/- 1. 35 micromol/min x 1.73 m2 across the splanchnic area. These two sites together accounted for virtually the entire whole-body phenylalanine hydroxylation. Renal production of tyrosine from phenylalanine hydroxylation accounted for approximately 13% of whole-body tyrosine Ra, whereas renal total tyrosine Ra accounted for approximately 34% of whole-body tyrosine Ra. In the splanchnic area, these figures were approximately 9 and 40%, respectively. Hydroxylation accounted for approximately 70% of phenylalanine Rd in the kidney, as opposed to approximately 8% in the splanchnic area. These data indicate that hydroxylation represents the major route of phenylalanine disposal within the kidney. The kidney and the splanchnic bed together account for all of the whole-body phenylalanine hydroxylation. These data also provide a further explanation for the reduced tyrosine pools occurring in uremia.

Twenty-four-hour L-[1-(13)C]tyrosine and L-[3,3-(2)H2]phenylalanine oral tracer studies at generous, intermediate, and low phenylalanine intakes to estimate aromatic amino acid requirements in adults

Daily pattern and rates of whole-body tyrosine oxidation and phenylalanine hydroxylation were determined in young adults (15 men, 1 woman) receiving [13C]tyrosine and [(2)H2]phenylalanine via primed, constant oral infusion and [(2)H4]tyrosine by vein (five subjects also received [(2)H3]leucine simultaneously by vein) continuously for 24 h (12 h fast then 12 h fed). Subjects were given a diet supplying 96.6 (n = 5), 35.6 (the proposed requirement; n = 5), and 18.5 mg phenylalanine x kg(-1) x d(-1) (n = 6) based on an otherwise adequate L-amino acid mixture for 6 d before the 24-h tracer study began. [Each diet was low in tyrosine: 6.79 mg x kg(-1) x d(-1).] Our hypothesis was that subjects would be in tyrosine equilibrium, positive balance, or both, at the 96.6- and 35.6-mg intakes and in distinctly negative balance at the 18.5-mg intake. The diurnal pattern in phenylalanine and tyrosine kinetics was dependent on the intake and, presumably, on the adequacy of dietary phenylalanine. Wholebody tyrosine balances, determined from rates of phenylalanine hydroxylation and tyrosine input and oxidation were negative (0.05 < P < 0.1 from zero balance) with the low (18.5 mg) phenylalanine intake [total aromatic amino acid (AAA) intake: 25.3 mg x kg(-1) x d(-1)] but at equilibrium (P > 0.05 from zero balance) with the two higher phenylalanine intakes. Whole-body AAA balance (AAA intake - tyrosine oxidation) was negative (P < 0.05 from zero balance) with the low intake, at equilibrium with the intermediate intake, and apparently distinctly positive (P < 0.05) with the generous intake. Despite model limitations, as discussed, these findings lend further support for a proposed, tentative value for a total mean requirement of 39 mg AAA x kg(-1) x d(-1).

Effect on whole-body protein synthesis after institution of intravenous nutrition in cancer and non-cancer patients who lose weight

Cancer and non-cancer patients received total parenteral nutrition (TPN) corresponding to either 120% or 200% non-protein energy resting energy expenditure. Whole-body tyrosine flux and leg exchange of various metabolites were measured in the fasted and fed state. Feeding with the moderate TPN rate did not stimulate whole-body protein synthesis in either group, but the high rate did. Both TPN rates switched an efflux of branched-chain aminoacids from the leg to an uptake in both groups, but this did not apply to tyrosine or phenylalanine. Only the high TPN rate stimulated glucose uptake across the leg in both groups. The leg exchanges of lactate, glycerol and free fatty acids were not significantly influenced by moderate or high TPN rates in either group, although changes in arterial concentrations indicated significant exchanges in compartments other than leg tissues. Thus standard TPN is insufficient to stimulate overall protein synthesis in both malnourished cancer and non-cancer patients, which may explain why previous studies have demonstrated insignificant functional effects with nutritional support to cancer patients.

Protein synthesis measured in vivo in muscle and liver of cachectic tumor-bearing mice : Emery P, Lovell L, Rennie M. Cancer Res 44:2779, 1984

Protein synthesis has been measured in vivo in liver and muscle of mice bearing the XK1 tumor, an appropriate model for cancer cachexia. Two different methods were used involving measurement of tracer incorporation into tissue protein either at the end of a 4-hr constant infusion of [14C]tyrosine or 10 min after i.v. injection of a flooding dose of [3H]phenylalanine. Whole-body tyrosine flux was decreased by 60% in cachectic tumor-bearing mice, and protein synthesis was depressed by 70% in muscle and by 40% in liver. The depression of protein synthesis in muscle was due to a reduction in both RNA content (i.e., protein-synthesizing capacity) and RNA activity (i.e., protein synthesized per g of RNA per hr). In liver, the depression of protein synthesis was due entirely to a decrease in RNA activity. The results also suggest that the synthesis of export proteins was affected more than the synthesis of fixed liver protein. Restriction of food intake in normal mice by up to 50% caused a loss of body weight and reductions in protein synthesis in liver and muscle which were less severe than those caused by the presence of the tumor. It is concluded that the wasting which is associated with advanced malignant disease is brought about by a reduction in the rate of protein synthesis in the tissues, and that this cannot be explained by depression of food intake alone.

Whole-body tyrosine flux in relation to energy expenditure in weight-losing cancer patients

Whole-body tyrosine flux was measured in seven weight-losing cancer patients and compared with that of seven noncancer patients with malnutrition. L[U- 14C] tyrosine was infused intravenously (IV) after an overnight fast under resting conditions and flux rates, oxidation, and incorporation into proteins of tyrosine were calculated from plateau values of specific activity of tyrosine in plasma and of labeled expired carbon dioxide. Rates of protein synthesis were calculated from the flux rate of tyrosine after subtracting the proportion oxidized. Simultaneous measurements of whole-body carbon dioxide production and oxygen uptake were also performed in each subject. Cancer patients had elevated whole-body tyrosine flux, protein synthesis, and energy expenditure when expressed in relation to body weight and whole-body potassium while the differences in tyrosine kinetics became of borderline significance when expressed in relation to energy expenditure. Tyrosine incorporation into whole-body proteins corresponded to a synthesis rate of 2.70 ± 0.17 protein/kg/d in cancer patients and 2.18 ± 0.17 in control patients ( P < 0.025). The results show that elevated protein synthesis in weight-losing cancer patients may explain not more than one third of the elevated energy expenditure. Therefore, other systems that utilize energy must increase in activity.

The contribution of phenylalanine to tyrosine metabolism in vivo. Studies in the post-absorptive and phenylalanine-loaded rat.

1. Rates of appearance and oxidation of plasma L-leucine, L-phenylalanine and L-tyrosine, as well as conversion of plasma phenylalanine into plasma tyrosine, were determined in 90-120 g rats after overnight starvation and while receiving 115-120 mumol of L-phenylalanine/h. 2. In the post-absorptive state, plasma tyrosine and phenylalanine appearances were similar, despite the fact that 22% of plasma tyrosine appearance could be attributed to the hydroxylation of phenylalanine. 3. A constant infusion of 115-120 mumol of L-phenylalanine/h did not significantly alter plasma leucine kinetics, but increased appearance of plasma phenylalanine and tyrosine. The percentage of phenylalanine and tyrosine appearance that was oxidized increased from 12.1% and 24.4% to 37.3% and 48.0% respectively. In phenylalanine-loaded rats, 72% of plasma tyrosine appearance could be attributed to the conversion of phenylalanine. 4. Whole-body tyrosine oxidation measured from a continuous infusion of either L-[14C]tyrosine or L-[14C]phenylalanine differed by 165%. 5. It can be concluded that, in the post-absorptive state, phenylalanine hydroxylation makes a substantial contribution to the plasma appearance of tyrosine and is significantly increased when phenylalanine is administered. The disposal of excess infused phenylalanine is a result of a greater percentage of plasma phenylalanine being converted into tyrosine and a greater proportion of tyrosine being further oxidized. However, apparent tyrosine oxidation rates estimated from plasma tyrosine specific radioactivities and appearance of expired 14CO2 during administration of [14C]tyrosine are underestimates of true rates, in part because tyrosine generated from phenylalanine hydroxylation is catabolized without freely equilibrating with the plasma compartment.

O.73 Whole-body tyrosine flux and energy expenditure in weight-losing cancer and non-cancer patients

O.73 Whole-body tyrosine flux and energy expenditure in weight-losing cancer and non-cancer patients