Plasma Tyrosine Concentrations Research Articles

Triketone toxicity

Sulcotrione is a herbicidal agent belonging to the family of triketones. Sulcotrione herbicides are used for weed control in maize and flax crops. To date, no cases of human poisoning had been reported in the literature linked to different herbicidal agents in the triketone family. We report here on two cases of the voluntary ingestion of this substance in the form of the branded product Mikado(TM), which were recorded by the Angers Poison Centre. Both cases of voluntary ingestion constituted attempted suicide, and involved two men aged 30 and 37 years. Their symptoms linked to sulcotrione were limited to vomiting, despite elevated plasma concentrations of sulcotrione. In one case, hypertyrosinemia has been demonstrated. The outcome was favourable in both patients and at follow up, no ocular disorders were observed. In the second case, hypotension and transient renal failure could be linked to the concomitant ingestion of chlorophenoxy herbicides. In animal toxicity studies, sulcotrione inhibit 4-hydro-phenylpyruvate dioxygenase leading to hypertyrosinemia and corneal opacities. In both cases, no ocular disorders were observed despite hypertyrosinemia in one case. These case reports were consistent with the animal toxicology findings concerning triketones, and particularly their relative safety in mammals following acute poisoning. However it seems prudent to monitor plasma tyrosine concentrations and to screen prospectively for corneal deposits if further acute intoxication events occur.

L-Tyrosine administration increases acetylcholinesterase activity in rats

Tyrosinemia is a rare genetic disease caused by mutations on genes that codify enzymes responsible for tyrosine metabolism. Considering that tyrosinemics patients usually present symptoms associated with central nervous system alterations that ranges from slight decreases in intelligence to severe mental retardation, we decided to investigate whether acute and chronic administration of l-tyrosine in rats would affect acetylcholinesterase mRNA expression and enzymatic activity during their development. In our acute protocol, Wistar rats (10 and 30days old) were killed one hour after a single intraperitoneal l-tyrosine injection (500mg/kg) or saline. Chronic administration consisted of l-tyrosine (500mg/kg) or saline injections 12h apart for 24days in Wistar rats (7days old) and rats were killed 12h after last injection. Acetylcholinesterase activity was measured by Ellman’s method and acetylcholinesterase expression was carried out by a semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) assay. We observed that acute (10 and 30days old rats) and chronic l-tyrosine administration increased acetylcholinesterase activity in serum and all tested brain areas (hippocampus, striatum and cerebral cortex) when compared to control group. Moreover, there was a significant decrease in mRNA levels of acetylcholinesterase in hippocampus was observed after acute protocol (10 and 30days old rats) and in striatum after chronic protocol. In case these alterations also occur in the brain of the patients, our results may explain, at least in part, the neurological sequelae associated with high plasma concentrations of tyrosine seen in patients affected by tyrosinemia type II.

Neurocognitive outcome in patients with hypertyrosinemia type I after long‐term treatment with NTBC

The implementation of NTBC into treatment of hypertyrosinemia type I (HT I) greatly improved survival by prevention of acute liver failure and hepatocellular carcinoma. However, there are first reports of cognitive impairment in patients with elevated plasma tyrosine concentrations. We here assess the neurocognitive development using standardized psychometric test batteries with respect to cognition, motor abilities and speech in nine early-treated patients with HT I under long-term NTBC treatment. High plasma tyrosine concentrations were frequently documented resulting in elevated 12-month median plasma tyrosine concentrations in seven out of nine patients. Plasma NTBC concentrations were generally in the lower therapeutic range. Five out of seven patients (71%) above 3 years of age had a total IQ score below the average. In addition, five out of seven patients above 3 years showed an inhomogenous test profile with significant differences between the different testing scales. Motor abilities were subnormal in four out of seven patients(57%). Cerebral MRI revealed no abnormalities. Logopedic evaluation in children at school age documented dysfunction or retardation in language development in all but one of the tested patients (80%), however, all but one patients had a migration background. A high number of patients performed below normal in the assessment of development, motor function and speech. We propose intellectual impairment as long-term complication in HT type I with elevated plasma tyrosine under NTBC treatment as observed in other hypertyrosinemias. These findings remain to be reproduced in greater patient numbers.

Nitisinone improves eye and skin pigmentation defects in a mouse model of oculocutaneous albinism

Mutation of the tyrosinase gene (TYR) causes oculocutaneous albinism, type 1 (OCA1), a condition characterized by reduced skin and eye melanin pigmentation and by vision loss. The retinal pigment epithelium influences postnatal visual development. Therefore, increasing ocular pigmentation in patients with OCA1 might enhance visual function. There are 2 forms of OCA1, OCA-1A and OCA-1B. Individuals with the former lack functional tyrosinase and therefore lack melanin, while individuals with the latter produce some melanin. We hypothesized that increasing plasma tyrosine concentrations using nitisinone, an FDA-approved inhibitor of tyrosine degradation, could stabilize tyrosinase and improve pigmentation in individuals with OCA1. Here, we tested this hypothesis in mice homozygous for either the Tyrc-2J null allele or the Tyrc-h allele, which model OCA-1A and OCA-1B, respectively. Only nitisinone-treated Tyrc-h/c-h mice manifested increased pigmentation in their fur and irides and had more pigmented melanosomes. High levels of tyrosine improved the stability and enzymatic function of the Tyrc-h protein and also increased overall melanin levels in melanocytes from a human with OCA-1B. These results suggest that the use of nitisinone in OCA-1B patients could improve their pigmentation and potentially ameliorate vision loss.

Phenylalanine hydroxylase deficiency

AbstractPhenylalanine hydroxylase deficiency is an autosomal recessive disorder that results in intolerance to the dietary intake of the essential amino acid phenylalanine. It occurs in approximately 1:15,000 individuals. Deficiency of this enzyme produces a spectrum of disorders including classic phenylketonuria, mild phenylketonuria, and mild hyperphenylalaninemia. Classic phenylketonuria is caused by a complete or near-complete deficiency of phenylalanine hydroxylase activity and without dietary restriction of phenylalanine most children will develop profound and irreversible intellectual disability. Mild phenylketonuria and mild hyperphenylalaninemia are associated with lower risk of impaired cognitive development in the absence of treatment. Phenylalanine hydroxylase deficiency can be diagnosed by newborn screening based on detection of the presence of hyperphenylalaninemia using the Guthrie microbial inhibition assay or other assays on a blood spot obtained from a heel prick. Since the introduction of newborn screening, the major neurologic consequences of hyperphenylalaninemia have been largely eradicated. Affected individuals can lead normal lives. However, recent data suggest that homeostasis is not fully restored with current therapy. Treated individuals have a higher incidence of neuropsychological problems. The mainstay of treatment for hyperphenylalaninemia involves a low-protein diet and use of a phenylalanine-free medical formula. This treatment must commence as soon as possible after birth and should continue for life. Regular monitoring of plasma phenylalanine and tyrosine concentrations is necessary. Targets of plasma phenylalanine of 120–360 μmol/L (2–6 mg/dL) in the first decade of life are essential for optimal outcome. Phenylalanine targets in adolescence and adulthood are less clear. A significant proportion of patients with phenylketonuria may benefit from adjuvant therapy with 6R-tetrahydrobiopterin stereoisomer. Special consideration must be given to adult women with hyperphenylalaninemia because of the teratogenic effects of phenylalanine. Women with phenylalanine hydroxylase deficiency considering pregnancy should follow special guidelines and assure adequate energy intake with the proper proportion of protein, fat, and carbohydrates to minimize risks to the developing fetus. Molecular genetic testing of the phenylalanine hydroxylase gene is available for genetic counseling purposes to determine carrier status of at-risk relatives and for prenatal testing.

Brain MRI diffusion-weighted imaging in patients with classical phenylketonuria

The aim of this study was to grade magnetic resonance white matter abnormalities (WMAs) of classical phenylketonuria (cPKU) patients treated from birth and to compare sensitivity and specificity of T2-weighted and diffusion-weighted images (DWI). Twenty early-treated cPKU patients still on a low-phenylalanine diet (12 males; mean age 21.2 years) and 26 normal subjects (ten males; mean age 25.1 years) were enrolled. Typical T2- and diffusion-weighted WMAs were semiquantitatively graded according to Thompson score (TS). Besides, a regional magnetic resonance imaging (MRI) score (mTS) was developed according to extension and intensity of WMAs. Phenylalanine and tyrosine plasma concentrations before performing MRI and the amino acid mean levels collected the year before MRI (Tyr(year) and Phe(year)) were measured. No patient with Phe(year) concentration below 460 mumol/L showed WMAs. In cPKU patients, TS and mTS were significantly higher on DWI than on T2 images (3.50 vs 2.65 and 23.65 vs 15.85, respectively, p < 0.002, Wilcoxon test). All controls were scored 0 on DWI, while in T2 images, TS and mTS were 0.19 and 1.70. DWI evaluated by mTS disclosed a frontotemporal, occipital, and parietal WM progressive involvement. TS and mTS, both on T2 images and on DWI, showed no correlation with tyrosine while they proved to have a strong correlation with phenylalaninemia and an excellent one with Phe(year) levels. Among the different MR sequences, DWI seems to be the most sensitive and reliable in detecting and grading the typical WMAs of cPKU patients.

Altered amino acid homeostasis in subjects affected by fibromyalgia

Objectives To evaluate plasma amino acid (AA) concentrations in patients affected by fibromyalgia (FM) and to study the relationships between their levels and FM clinical parameters. Design and methods 20 AAs were assessed in 34 FM patients and in 18 healthy volunteers by means of a modified version of the Waters picotag method. Results Significant lower plasma taurine, alanine, tyrosine (Tyr), valine, methionine, phenylalanine and threonine concentrations, and the sum of essential AAs were observed in FM patients vs healthy controls ( P < 0.05). Tyr CAA' ratio and the sum of AAs competing with tryptophan for brain uptake were significantly reduced in FM ( P < 0.05). A significant correlation was found between FM clinical parameters and certain AAs. Conclusions Our results suggest probable defects of gut malabsorption of certain AAs in FM patients. Moreover, given the reduced Tyr CAA' ratio in FM patients, a possible impairment of the cathecolaminergic system in the FM syndrome may be suggested.

Dietary carbohydrates and amino acids influence oocyte quality in dairy heifers

The objective of the present experiment was to determine whether increasing plasma insulin by different nutritional regimes affects oocyte quality. Holstein dairy heifers (eight per treatment) were assigned, using a two times two factorial design, to diets containing either low or high dietary leucine and either low or high dietary starch. Each heifer underwent six sessions of ovum pick-up beginning 25 days after introduction of the diets. Oocyte quality was assessed by development to the blastocyst stage in synthetic oviducal fluid following in vitro fertilisation. Feeding diets containing high leucine resulted in significantly higher plasma free leucine and tyrosine concentrations. The high-starch diet significantly increased plasma insulin but not glucagon concentration, whereas high dietary leucine increased plasma glucagon but not insulin. Oocyte cleavage was not influenced by diet. The high-starch diet, which was associated with a high plasma insulin : glucagon ratio, had adverse effects on oocyte quality that were avoided when leucine intake was increased. There was an association between total plasma free amino acid concentration and oocyte cleavage. Therefore, in dairy heifers dietary amino acids and carbohydrates during antral follicle development appear to mediate effects on oocyte quality by different mechanisms. These findings have implications for both diet formulation and feeding regimes.

On the role of tyrosine and peripheral metabolism in 3,4-methylenedioxymethamphetamine-induced serotonin neurotoxicity in rats

The mechanisms underlying 3,4-methylenedioxymethamphetamine (MDMA)-induced serotonergic (5-HT) toxicity remain unclear. It has been suggested that MDMA depletes 5-HT by increasing brain tyrosine levels, which via non-enzymatic hydroxylation leads to DA-derived free radical formation. Because this hypothesis assumes the pre-existence of hydroxyl radicals, we hypothesized that MDMA metabolism into pro-oxidant compounds is the limiting step in this process. Acute hyperthermia, plasma tyrosine levels and concentrations of MDMA and its main metabolites were higher after a toxic (15 mg/kg i.p.) vs. a non-toxic dose of MDMA (7.5 mg/kg i.p.). The administration of a non-toxic dose of MDMA in combination with l-tyrosine (0.2 mmol/kg i.p.) produced a similar increase in serum tyrosine levels to those found after a toxic dose of MDMA; however, brain 5-HT content remained unchanged. The non-toxic dose of MDMA combined with a high dose of tyrosine (0.5 mmol/kg i.p.), caused long-term 5-HT depletions in rats treated at 21.5 °C but not in those treated at 15 °C, conditions known to decrease MDMA metabolism. Furthermore, striatal perfusion of MDMA (100 μM for 5 h) combined with tyrosine (0.5 mmol/kg i.p.) in hyperthermic rats did not cause 5-HT depletions. By contrast, rats treated with the non-toxic dose of MDMA under heating conditions or combined with entacapone or acivicin, which interfere with MDMA metabolism or increase brain MDMA metabolite availability respectively, showed significant reductions of brain 5-HT content. Altogether, these data indicate that although tyrosine may contribute to MDMA-induced toxicity, MDMA metabolism appears to be the limiting step.

Changes of plasma free amino acid concentrations and myofibrillar proteolysis index by starvation in non‐pregnant dry cows

ABSTRACTThe effects of 5 day starvation on urinary metabolite excretion, plasma metabolites and free amino acid concentrations in four non‐pregnant dry cows were investigated. Starvation significantly reduced (P &lt; 0.05) the bodyweight and feces weight. The plasma glucose concentration decreased (P &lt; 0.05) during days 2–5 of starvation. Starvation significantly increased (P &lt; 0.05) the plasma nonesterified fatty acid concentration. The plasma urea nitrogen concentration and urinary urea nitrogen excretion increased transiently (P &lt; 0.05) at days 1 and 2 of starvation. The plasma 3‐methlhistidine concentration was significantly higher (P &lt; 0.05) at days 2, 3 and 5 of starvation. However, the urinary 3‐methylhistidine excretion was significantly higher (P &lt; 0.05) at days 4 and 5 of starvation, not corresponding to the change in the plasma. Starvation did not change the plasma proline, methionine, lysine and total amino acid concentrations. On the other hand, starvation reduced (P &lt; 0.05) the plasma aspartic acid, serine, asparagine, glutamic acid, glutamine, alanine, tyrosine, tryptophan and histidine concentrations. Plasma glycine increased during starvation. Plasma threonine, isoleucine, leucine and branched‐chain amino acid increased (P &lt; 0.05) by prolonged starvation. The results of this study indicate that prolonged starvation accelerated myofibril protein degradation in non‐pregnant dry cows and apparently consumes most glucogenic amino acids in preference to other amino acids.

Tyrosinemia produced by 2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione (NTBC) in experimental animals and its relationship to corneal injury

2-(2-Nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione (NTBC) is a potent inhibitor of rat liver 4-hydroxyphenylpyruvate dioxygenase (HPPD) leading to tyrosinemia and corneal opacity. We examined the effect of NTBC on the extent of tyrosinemia and production of corneal lesions in the beagle dog, rabbit and rhesus monkey, as part of safety evaluation on this drug. A single oral dose of 10 mg NTBC/kg to beagle dogs or rabbits increased the concentration of tyrosine in plasma and aqueous humour of the eye, the tyrosinemia being both time- and dose-dependent. Hepatic HPPD was markedly inhibited with little effect on the activity of tyrosine aminotransferase (TAT) and homogentisic acid oxidase at the time of peak plasma tyrosine. Daily oral administration of NTBC to beagle dogs at 0.1, 0.5, 1.5 and 5 mg/kg/day produced corneal opacities with an incidence of 34% following 11 weeks of dosing, which reversed upon withdrawal of the drug. Tyrosine in plasma and aqueous humour was increased at all dose levels, 18 weeks after dosing. In contrast, daily oral administration of NTBC to rabbits for 6 weeks and rhesus monkeys for 12 weeks at 10 mg/kg/day produced no evidence of corneal opacities although tyrosine values were markedly increased. Our studies have shown that NTBC is a potent inhibitor of rabbit, beagle dog and by inference rhesus monkey liver HPPD producing a marked tyrosinemia in all species studied, while only beagle dogs show corneal lesions. The production of corneal lesions in experimental animals exposed to NTBC does not appear to be simply related to the concentration of tyrosine in ocular fluid, other as yet unidentified factors appear to be necessary to trigger tissue injury.

Branched-Chain Amino Acids Enhance the Cognitive Recovery of Patients With Severe Traumatic Brain Injury

Aquilani R, Iadarola P, Contardi A, Boselli M, Verri M, Pastoris O, Boschi F, Arcidiaco P, Viglio S. Branched-chain amino acids enhance the cognitive recovery of patients with severe traumatic brain injury. Objective To investigate whether supplementation with branched-chain amino acids (BCAAs) in patients with severe traumatic brain injury (TBI) improves recovery of cognition and influences plasma concentrations of tyrosine and tryptophan, which are precursors of, respectively, catecholamine and serotonin neurotransmitters in the brain. Design Forty patients with TBI were randomly assigned to 15 days of intravenous BCAA supplementation (19.6g/d) (n=20) or an isonitrogenous placebo (n=20). Setting Tertiary care rehabilitation setting in Italy. Participants Forty men (mean age, 32±15y) with TBI and 20 healthy subjects (controls) matched for age, sex, and sedentary lifestyle. Intervention Supplementation with BCAAs. Main Outcome Measures Disability Rating Scale (DRS) and plasma concentrations of BCAAs, tyrosine, and tryptophan. Results Fifteen days after admission to the rehabilitation department, the DRS score had improved significantly in both the placebo group ( P<.05 vs baseline) and in the BCAA-supplemented group ( P<.01 vs baseline). The difference between the 2 groups was significant ( P<.004). Plasma tyrosine concentration improved in the group given BCAA supplementation, and tryptophan concentration increased in patients receiving placebo. Conclusions Supplemental BCAAs enhance the retrieval of DRS without causing negative effects on tyrosine and tryptophan concentration.

Plasma Amino Acid Concentrations in Patients with Coronary Heart Disease: A Comparison between UK Indian Asian and Caucasian Men

The pattern of plasma free amino acids (PFAAs) of subjects with coronary heart disease (CHD) and controls was investigated. PFAA concentrations of CHD patients (29 Caucasian, 20 U.K. Indian Asian) and controls (36 Caucasian, 27 U.K. Indian Asian) were analyzed by high-performance liquid chromatography (HPLC). Plasma free alanine, tyrosine, and isoleucine concentrations were higher in U.K. Indian Asians compared with Caucasians. Plasma free alanine concentration was higher in CHD patients compared with controls, and the difference was mainly related to the presence of diabetes or elevated blood glucose in the former. Plasma free cysteine concentration was higher in CHD patients compared with controls; this does not seem to be affected by the eating habits of the two races, and seems to be a good marker for CHD and better than that of homocysteine. The data obtained in the present study showed no major alteration in PFAAs pattern in CHD patients except for that of cysteine.

Use of nitisinone in patients with alkaptonuria

Alkaptonuria, a rare autosomal recessive disorder caused by mutations in the HGD gene and deficiency of homogentisate 1,2 dioxygenase, is characterized by ochronosis, arthritis, and daily excretion of gram quantities of homogentisic acid (HGA). Nitisinone, an inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase, can drastically reduce urinary excretion of HGA in individuals with alkaptonuria. We investigated the safety and the HGA-depleting efficacy of nitisinone in an open-label, single-center study of 9 alkaptonuria patients (5 women, 4 men; 35-69 years of age) over the course of 3 to 4 months. Each patient received nitisinone in incremental doses, 0.35 mg bid followed by 1.05 mg bid, and remained on this dosage and a regular diet for 3 months. Nitisinone reduced urinary HGA levels from an average of 4.0 ± 1.8 (SD) g/day to 0.2 ± 0.2 g/day ( P < .001). The average plasma tyrosine concentration, initially 68 ± 18 μmol/L, rose to 760 ± 181 μmol/L ( P < .001). During the final week of the study, 5 patients adhered to a protein-restricted diet (40 g/day), and their mean plasma tyrosine level fell from 755 ± 167 to 603 ± 114 μmol/L. Six of the 7 patients who received nitisinone for more than 1 week reported decreased pain in their affected joints. Weekly ophthalmologic examinations showed no signs of corneal toxicity. Adverse events included the passing of kidney stones, the recognition of symptoms related to aortic stenosis, and elevation of liver transaminase levels. We conclude that low-dose nitisinone effectively reduced urinary HGA levels in patients with alkaptonuria. Future long-term clinical trials are planned to determine the benefits of nitisinone in preventing joint deterioration and providing pain relief, and its long-term side effects.

The relation between plasma tyrosine concentration and fatigue in primary biliary cirrhosis and primary sclerosing cholangitis

BackgroundIn primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) fatigue is a major clinical problem. Abnormal amino acid (AA) patterns have been implicated in the development of fatigue in several non-hepatological conditions but for PBC and PSC no data are available. This study aimed to identify abnormalities in AA patterns and to define their relation with fatigue.MethodsPlasma concentrations of tyrosine, tryptophan, phenylalanine, valine, leucine and isoleucine were determined in plasma of patients with PBC (n = 45), PSC (n = 27), chronic hepatitis C (n = 22) and healthy controls (n = 73). Fatigue and quality of life were quantified using the Fisk fatigue severity scale, a visual analogue scale and the SF-36.ResultsValine, isoleucine, leucine were significantly decreased in PBC and PSC. Tyrosine and phenylalanine were increased (p < 0.0002) and tryptophan decreased (p < 0.0001) in PBC. In PBC, but not in PSC, a significant inverse relation between tyrosine concentrations and fatigue and quality of life was found. Patients without fatigue and with good quality of life had increased tyrosine concentrations compared to fatigued patients. Multivariate analysis indicated that this relation was independent from disease activity or severity or presence of cirrhosis.ConclusionIn patients with PBC and PSC, marked abnormalities in plasma AA patterns occur. Normal tyrosine concentrations, compared to increased concentrations, may be associated with fatigue and diminished quality of life.

Liquid chromatography–tandem mass spectrometry method for the simultaneous determination of δ-ALA, tyrosine and creatinine in biological fluids

Background Several acquired and congenital human disorders perturb the concentrations of delta-aminolevulinate (δ-ALA), creatinine and tyrosine in biological fluids. There is currently no facile, sensitive and specific method to measure these analytes simultaneously. Method We developed an LC-MS/MS method to quantify δ-ALA, creatinine and tyrosine in urine that requires minimal sample preparation and no derivatization. The method is also applicable to the analysis of tyrosine in plasma. Results All calibration plots were linear, with R 2≥0.996. Intra- and interday CVs were <10%. The limit of quantitation for δ-ALA was ∼0.1 μmol/l, and for creatinine and tyrosine it was well below the lowest measured physiological concentrations. The method was applied to analyze urine from 75 healthy volunteers and 43 patients with hereditary tyrosinemia type I (HT I). The mean urinary concentration of δ-ALA in patients (38±35 μmol/l, 53±30 mg/g creatinine) was higher than that measured in healthy subjects (5.5±2.6 μmol/l, 0.9±0.2 mg/g creatinine; p<0.001). Treatment with 2-(2-nitro-4-trifluoromethylbenzyl)-1,3-cyclohexanedione (NTBC), an inhibitor of an early step in tyrosine catabolism, decreased urinary δ-ALA (6.4±4.8 μmol/l, 13±24 mg/g creatinine; p<0.001). The average plasma tyrosine concentration in healthy volunteers (56±14 μmol/l) was within normal reference interval used in clinical practice. Conclusions The method is simple, specific and precise and allows simultaneous quantitation of δ-ALA, creatinine and tyrosine at concentrations present under physiological or pathophysiological conditions.

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

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 micromol . 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 micromol . L(-1)). Using [1-(13)C]phenylalanine tracer and (13)CO(2) production in breath we found that although there was a significant positive relation between phenylalanine oxidation and phenylalanine intake in formula-fed infants (r(2) = 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.

Plasma precursors of brain catecholaminergic and serotonergic neurotransmitters in rehabilitation patients with ischemic stroke

Aquilani R, Verri M, Iadarola P, Arcidiaco P, Boschi F, Dossena M, Sessarego P, Scocchi M, Arrigoni N, Pastoris O. Plasma precursors of brain catecholaminergic and serotonergic neurotransmitters in rehabilitation patients with ischemic stroke. Arch Phys Med Rehabil 2004;85:779–84. Objective To determine levels of plasma amino acid tyrosine and tryptophan, precursors of brain catecholamine and serotonin neurotransmitters, respectively, in rehabilitative patients with ischemic stroke. Design Controlled, pre-post analysis, consecutive sample. Setting Rehabilitation center. Participants Twenty men with ischemic stroke (age, 68±11.3y) consecutively admitted into rehabilitation 15±10 days (range, 7–28d) after an acute cerebrovascular insult; 15 healthy sedentary subjects (controls 1); and 13 healthy hypoactive individuals who had recently had knee arthroplasty (controls 2). Both control groups were matched to stroke subjects for age, gender, and body weight. Interventions At 8:00 am, after overnight fasting, venous blood samples were drawn from patients to determine plasma tyrosine and tryptophan levels. A nutritional evaluation, including nitrogen balance, was made. The same procedures were repeated after 45 days of rehabilitation. Amino acid data were compared with those obtained from the controls. Main outcome measure Plasma concentrations of amino acids. Results Patients with ischemic stroke, on admission, had lower plasma tyrosine concentration than did both controls 1 ( P<.0005) and controls 2 ( P<.001), but a similar tryptophan level. The plasma content of tyrosine was similar between the 2 control groups. After 45 days of rehabilitation, the stroke patients’ tyrosine and tryptophan levels remained virtually unchanged, as did nutritional parameters. Nutritional intakes were adequate to meet body needs but insufficient to correct plasma tyrosine. Conclusions Patients experiencing a recent stroke may have low plasma tyrosine levels and, therefore, reduced brain catecholamine formation. It is possible that an imbalance of brain neurotransmitters may occur.

Reduced plasma levels of tyrosine, precursor of brain catecholamines, and of essential amino acids in patients with severe traumatic brain injury after rehabilitation

Aquilani R, Iadarola P, Boschi F, Pistarini C, Arcidiaco P, Contardi A. Reduced plasma levels of tyrosine, precursor of brain catecholamines, and of essential amino acids in patients with severe traumatic brain injury after rehabilitation. Arch Phys Med Rehabil 2003;84:1258–65. Objective: To investigate whether levels of plasma tyrosine and tryptophan, precursors of brain catecholamine and serotonin neurotransmitters, respectively, and other essential amino acids (EAA) may return to normal in patients with severe traumatic brain injury (TBI) after 2 months in a hospital rehabilitation center. Design: Peripheral plasma concentrations of tyrosine, tryptophan, and other EAAs in subjects with severe TBI, both at admission (44±11d postinjury) and at discharge from the center (110±15d after acute event) were compared with concentrations in control subjects. Setting: Tertiary care rehabilitation setting in Italy. Participants: Ten men (26.6±12.6y) with TBI and 6 healthy subjects (controls) matched for age, sex, voluntary loss of body weight, and sedentary lifestyle. Interventions: Not applicable. Main Outcome Measures: Concentrations of brain neurotransmitter precursor amino acids and of EAA. Results: On admission, patients had lower plasma tyrosine, leucine, valine, methionine, and phenylalanine concentrations than did control subjects. The plasma concentrations of tryptophan were similar in the 2 groups. These amino acid abnormalities were still present at discharge. Conclusion: The levels of plasma tyrosine and many EAA in patients with TBI did not recover by discharge (110±15d) from rehabilitation. Plasma tryptophan concentrations were similar in patients and controls.

Umbilical Threonine Uptake during Maternal Threonine Infusion in Sheep

Objective: The infusion into the maternal circulation of amino acid solutions failed to increase umbilical threonine (THR) uptake above normal even when THR was present in the infusate at a relatively high concentration. The purpose of the present study was to determine whether umbilical THR uptake can be increased by infusing a THR solution that does not contain any other amino acids.Study design: Five pregnant sheep (130±1.0 days after conception) were infused for 2h with a threonine solution (4.4±0.2μmol·kg−1·min−1). Plasma amino acids, glucose and lactate, hematocrit, blood O2 content in maternal arterial, uterine venous, umbilical arterial and venous blood were measured. Uterine and umbilical blood flows were measured before and during the infusion and were used to calculate uterine and umbilical uptakes. Maternal and foetal plasma insulin and glucagon concentrations were also measured.Results: The THR infusion increased maternal plasma THR (904 vs 236μm , P< 0.001), foetal plasma THR (539 vs 334μm , P< 0.01), and both uterine (20.4 vs 4.7μmol·min−1·kg−1fetalweight, P< 0.05) and umbilical (8.6 vs 3.8μmol·min−1·kg−1fetalweight, P< 0.001) THR uptakes. The uterine-umbilical THR uptake difference increased significantly (11.8 vs 0.9μmol·min−1·kg−1fetalweight, P< 0.05). There were significant (P< 0.001) decreases in the foetal arterial plasma concentrations of tyrosine and the branched chain amino acids, as well as in isoleucine umbilical uptake (P< 0.05). There was a significant increase in maternal plasma glucagon (P< 0.01).Conclusion: A maternal THR infusion that causes a 3.8-fold increase in maternal plasma THR concentration above normal, with no significant increase in the concentration of other amino acids, leads to a 2.3-fold increase in umbilical THR uptake. This contrasts with the absence of a significant increase in umbilical THR uptake when THR was infused as part of an amino acid mixture in previous studies. The evidence supports the hypothesis that, in vivo, THR flux from placenta to foetus is mediated by a saturable, rate limiting transport system which is subject to inhibition by other neutral amino acids.