Administration Of L-phenylalanine Research Articles

SUN-266 Protein Induced Pancreatic Hormone Secretion Is Modulated by Vagal CaSR

The existence of a vago-vagal entero-pancreatic pathway, where sensory information from the gut can signal via vagal afferents to the brain to mediate changes in pancreatic function, has been recognised for over a century, and investigated extensively with regards to pancreatic exocrine secretions. However, the role of such pathways in pancreatic endocrine secretions has received less attention.The secretion of insulin and glucagon in response to protein and amino acids is conserved across species. This effect is thought to promote amino acid uptake into tissues without concomitant hypoglycaemia. We found that the essential amino acid L-Phenylalanine potently stimulates glucagon secretion, even when administered directly into the gut at small doses unlikely to significantly raise systematic levels. Administration of L-Phenylalanine also increased neuronal activation in the rat and mouse dorsal vagal complex, the central nervous system region directly innervated by vagal afferents.L-Phenylalanine modulates the activity of the calcium sensing receptor (CaSR), a nutrient sensor more commonly known for its role in calcium homeostasis, but which is thought to also act as a sensor of aromatic amino acids. Interestingly, the CaSR is one of the few nutrient sensors expressed in vagal afferents and in vitro calcium imaging revealed CaSR synthetic agonists activate subpopulations of vagal afferents.The role of CaSR in vivo was investigated further by selectively knocking down the CaSR in vagal afferents. Briefly, CaSR floxed mice were bilaterally injected directly into the nodose ganglion, where the cell bodies of vagal afferents are located, with a cre expressing adeno-associated virus. CaSR knockdown did not interfere with normal food intake, nor the vagal-dependent anorectic effects of cholecystokinin, or of L-Phenylalanine. However, it did blunt protein-induced glucagon secretion, suggesting involvement of the CaSR in the vagus nerve in protein sensing and glucose homeostasis.Future studies are required to determine the importance of vagal CaSR in protein induced pancreatic endocrine secretions, and the possibility of exploiting this circuit to develop new anti-diabetic therapies.

Protection by oral phenylalanine against gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats

The effect of oral administration of L-phenylalanine on the incidence and histology of gastric adenocarcinomas induced by N-methyl-N'-nitro-N-nitrosoguanidine was investigated in inbred Wistar rats. Oral administration of 6% phenylalanine after 25 weeks of treatment with the carcinogen significantly reduced the incidence and number of adenocarcinomas of the glandular stomach at experimental week 52. Oral administration of high dose phenylalanine significantly increased the basal serum gastrin level and significantly decreased the norepinephrine concentration in the antral portion of the gastric wall, as well as the labelling indices of antral mucosa. These findings indicate that orally administered phenylalanine inhibits the development of gastric cancers.

In vivo studies on the formation of m-tyrosine and o-tyrosine from L-phenylalanine in rats.

L-Phenylalanine was administered intraperitoneally, intravenously, intramuscularly and orally to rats, and its metabolites were separated and identified by high-performance liquid chromatography (HPLC) with fluorescence detection. Chromatographic peaks were identified on the basis of their retention behavior and the assignment of peaks of HPLC was verified by ion-exchange chromatographic analysis. The three metabolites p-, m- and o-tyrosines were formed in vivo after phenylalanine administration. The extents of formation of m- and o-tyrosines were significantly increased by the administration of L-phenylalanine. However, the concentrations of m- and o-tyrosines in the serum were reduced by the administration of α-methyltyrosine, which is an inhibitor of tyrosine hydroxylase. On the other hand, the inhibition of phenylalanine hydroxylase activity by the administration of p-chlorophenylalanine and ethionine resulted in a marked increase of the concentration of phenylalanine in the serum, and the formation of m- and o-tyrosines was also significantly increased. These results suggest that the formation of m- and o-tyrosines from phenylalanine is caused mainly by tyrosine hydroxylase, but not by phenylalanine hydroxylase.

Use of alpha-methylphenylalanine for studies of brain development in experimental phenylketonuria.

Experimental phenylketonuria was induced in newborn rats by administration of L-phenylalanine and alpha-methylphenylalanine. There was no primary disturbance of myelination, but reduced cell proliferation, early cell death and compensatory hyperplasia were evident in the cerebellum.

Effect of phenylalanine on toxicity of S-(dichlorovinyl)-L-cysteine in the rat and the calf.

SummaryBoth enantiomers of phenylalanine when injected intraperitoneally into rats can greatly reduce the toxicity of S-(1,2-dichlorovinyl)-L-cysteine. To be most effective the DCVC and Phe must be administered simultaneously, a delay of one hour in injection of phenylalanine reducing its effectiveness markedly. Administration of L-phenylalanine to calves failed to reduce the toxic effects of S-(dichlorovinyl)-L-cysteine and development of fatal aplastic anemia.

Pattern of N15-excretion in man following administration of N15-labeled L-phenylalanine.

On the basis of the same dose (in mEq) per unit body weight of N15 administered, the patterns of N15-excretion following oral administration of labeled L-phenylalanine and of ammonium citrate have been compared with those of labeled glycine and aspartic acid in previous studies. In the first few hours, the patterns for ammonia, urea and hippuric acid are markedly different for different amino acids. After 6–8 hours, with the exception of hippuric acid, the patterns are substantially the same, regardless of the particular amino acid administered. The data obtained in the first few hours reflect predominantly the rate of metabolism of the particular amino acid administered. The ratios of the isotope concentration of glycine (calculated from that of hippuric acid) to that of ammonia, following the oral administration of l-phenylalanine, and of ammonium citrate, deviate from theory not only in the early stages of excretion, but in the attainment of a final value of about 0.6; this indicates the possibility that the turnover rate of glycine is higher than the average for ammonia-forming amino acids. Following oral administration of L-phenylalanine and also after ammonium citrate, the isotope concentrations of ammonia and of urea are equal at the maximum point of the latter. From the ammonia-urea relationship, the assumption of a single pool of amino acids in the body seems justified in oral experiments. Note: (With the Assistance of James George and Daisy Yen Wu) Submitted on September 15, 1958