Serum Tyrosine Concentrations Research Articles

A novel pathway of levodopa metabolism by commensal Bifidobacteria

The gold-standard treatment for Parkinson’s disease is levodopa (L-DOPA), which is taken orally and absorbed intestinally. L-DOPA must reach the brain intact to exert its clinical effect; peripheral metabolism by host and microbial enzymes is a clinical management issue. The gut microbiota is altered in PD, with one consistent and unexplained observation being an increase in Bifidobacterium abundance among patients. Recently, certain Bifidobacterium species were shown to have the ability to metabolize L-tyrosine, an L-DOPA structural analog. Using both clinical cohort data and in vitro experimentation, we investigated the potential for commensal Bifidobacteria to metabolize this drug. In PD patients, Bifidobacterium abundance was positively correlated with L-DOPA dose and negatively with serum tyrosine concentration. In vitro experiments revealed that certain species, including B. bifidum, B. breve, and B. longum, were able to metabolize this drug via deamination followed by reduction to the compound 3,4-dihydroxyphenyl lactic acid (DHPLA) using existing tyrosine-metabolising genes. DHPLA appears to be a waste product generated during regeneration of NAD +. This metabolism occurs at low levels in rich medium, but is significantly upregulated in nutrient-limited minimal medium. Discovery of this novel metabolism of L-DOPA to DHPLA by a common commensal may help inform medication management in PD.

Long-term low dose nitisinone therapy in adults with alkaptonuria shows no cognitive decline or increased severity of depression.

Little is documented on whether nitisinone‐induced hypertyrosinaemia alters cognitive functioning or leads to worsening depression in alkaptonuria (AKU). Wechsler Adult Intelligence Scale‐IV (WAIS‐IV) and Beck Depression Inventory‐II (BDI‐II) assessments were performed before and annually following treatment with nitisinone 2 mg daily to assess the impact on cognitive functioning and severity of depression. Serum tyrosine concentrations were also measured annually. WAIS‐IV: 63 patients (27 females/36 males: mean age[years] [±standard deviation, range] 55.7[13.7, 26–79]; 60.3[9.6, 19–75]) were included at baseline for assessment of: verbal comprehension (VC), perceptual reasoning (PR), working memory (WM), and processing speed (PS) using separate indices. Over the 6‐year period studied 43, 39, 36, 29, 26 and 15 patients had annual assessments. Using a longitudinal model (age and sex adjusted) no significant differences were observed in any of the indices over this period, apart from VC which showed a significant increase after adjustment for sex (p < 0.05). BDI‐II: 74 patients (32 females/42 males: mean age[years] [±standard deviation, range] 56.1[13.2, 26–79]; 42 males, 51.5[16.3, 19–70]) were included at baseline. Over the 7‐year period studied 48, 47, 38, 34, 32, 24 and 12 patients had annual assessments. No significant differences in BDI‐II scores were observed when compared to baseline. Hypertyrosinaemia was observed in all patients following treatment with nitisinone (p < 0.001, at all annual visits). Serum tyrosine was not correlated with WAIS‐IV sub‐test indices or BDI‐II scores pre‐ or post‐nitisinone therapy. These findings suggest that treatment with nitisinone does not affect cognitive functioning and or lead to increased severity of depression.

Duodenal infusion of soy protein hydrolysate activates cAMP signaling and hypothalamic neurotransmitter synthesis in pigs.

Neurotransmitters in the brain are important for cognition and memory. As bioactive substrates, whether increased soy protein levels in pigs can promote hypothalamic neurotransmitter synthesis remains unclear. The effect of increased soy protein hydrolysate (SPH) levels in the small intestine of pigs on neurotransmitter precursor supply, hypothalamic neurotransmitter synthesis and underlying molecular processes was investigated by using sixteen pigs (35.2 ± 0.3 kg) infused either with SPH (70 g day-1) or sterile saline (control) twice daily for 15 days via a duodenal fistula. It demonstrated that SPH infusion increased the expression of the neutral amino acid transporter B0AT1 in the jejunal mucosa, the serum tyrosine/large neutral amino acid ratio, the concentrations of serum tyrosine, hypothalamic tyrosine, dopamine and brain-derived neurotrophic factor (BDNF) (P < 0.05). It also increased the jejunal and serum choline, hypothalamic choline and acetylcholine levels (P < 0.05). Hypothalamic transcriptome revealed that differential genes were significantly enriched in the cholinergic synapse, dopaminergic synapse and cyclic adenosine monophosphate (cAMP) signalling pathways, and that the expression of key enzyme genes in the synthesis of acetylcholine and dopamine and dopamine receptors 1 (DRD1) was upregulated by SPH (P < 0.05). Western blotting showed that SPH infusion activated the hypothalamic cAMP signalling pathways. Overall, SPH infusion promoted the synthesis of hypothalamic dopamine and acetylcholine, and the synthesised dopamine promoted BDNF production most likely through the activation of the cAMP signalling pathways by the DRD1.

Effects of a protein-restricted diet on body weight and serum tyrosine concentrations in patients with alkaptonuria.

In an open‐label, controlled study of nitisinone in alkaptonuria (SONIA 2), patients were advised to lower dietary protein intake to reduce serum tyrosine (s‐Tyr) levels and the risk of keratopathy. A body weight increase was observed in the nitisinone‐treated patients but not in the control group. To investigate the effectiveness and consequence of protein restriction in patients with alkaptonuria, a post‐hoc analysis of SONIA 2 was performed. One hundred and thirty‐eight patients were randomised (nitisinone: n = 69, controls: n = 69). Comparison of baseline and Month 12 data on 24‐h urinary excretion of HGA (u‐HGA24) and urea (u‐urea24, used as an approximate protein intake measure), tyrosine and body weight were performed using paired t tests. Comparisons of data between groups were made using 2‐sample t tests. We found that u‐urea24 decreased more in nitisinone‐treated than controls. The study centre with lowest average s‐Tyr and u‐urea24 (nitisinone arm) at Month 12 also had lowest keratopathy incidence (3.1%), while the centre with highest values showed the highest (14.6%). S‐Tyr was generally high in those with keratopathy, but those without keratopathy had similar elevated values. A similar pattern across centres was seen for body weight changes, with a statistically significant weight increase in nitisinone‐treated patients at centres with lower u‐urea24 values. Therefore, in nitisinone‐treated patients, protein restriction led to increased body weight but may also have lowered the risk of developing keratopathies. If introduced, a protein‐restricted diet should be supervised by a dietician and, when appropriate, include amino acid supplements deficient in tyrosine and phenylalanine, to avoid malnutrition and undesired weight increase.

Elevated serum tyrosine concentration is associated with a poor prognosis among patients with liver cirrhosis.

Chronic liver insufficiency is often associated with changes in amino acid metabolism. We evaluated whether change in serum amino acid concentrations had prognostic value among patients with liver cirrhosis. This retrospective study evaluated 158 patients who had been hospitalized with cirrhosis. Baseline serum concentrations of branched-chain amino acids (BCAAs) and tyrosine, as well as the BCAA-to-tyrosine ratio, were evaluated. Cox proportional hazards analysis was used to calculate the hazard ratios for factors that were associated with mortality or liver transplantation. Among the 158 patients, baseline measurements showed decreased serum BCAA concentrations for 59 patients (37.3%), elevated serum tyrosine concentrations for 80 patients (50.6%), and a decreased BCAA-to-tyrosine ratio for 114 patients (72.2%). During a median follow-up period of 3.0years, death or liver transplantation occurred at a rate of 0.136 cases/1 person-year. Multivariable analysis showed that transplant-free survival was independently predicted by older age, male sex, comorbid hepatocellular carcinoma, Child-Turcotte-Pugh score, and serum tyrosine concentration. Receiver operating characteristic curve analysis showed that a serum tyrosine concentration of >110µmol/L was the optimal cut-off value for predicting transplant-free survival (adjusted hazard ratio 1.89, 95% confidence interval 1.15-3.11, p=0.012). Kaplan-Meier analysis showed a significant difference in the 5-year transplant-free survival probability between patients with high and low serum tyrosine concentrations (42.1% vs. 60.7%, p<0.001). Elevated serum tyrosine concentration, but not changes in serum BCAA concentration or the BCAA-to-tyrosine ratio, may indicate a high risk of death or liver transplantation for patients with liver cirrhosis.

Prognostic significance of serum tyrosine concentration in patients with primary biliary cholangitis under ursodeoxycholic acid therapy.

Chronic liver insufficiency is often associated with alteration in amino acid metabolism. We evaluated the prognostic value of changes in serum amino acid concentrations in patients with primary biliary cholangitis. A total of 75 primary biliary cholangitis patients who started urusodeoxycholic acid therapy were retrospectively enrolled. Baseline serum concentrations of branched-chain amino acids and tyrosine, and branched-chain amino acid-to-tyrosine ratio were determined. The hazard ratios of factors associated with liver-related events were analyzed by Cox proportional hazard analysis. Of the 75 patients enrolled, 12 showed a decrease in serum branched-chain amino acid levels, and 15 showed an increase in serum tyrosine levels. The branched-chain amino acid-to-tyrosine ratio decreased in 16 patients. During a median 5.6-year follow up, liver-related events occurred in 11 patients. Multivariate analysis showed that high serum tyrosine levels at baseline and high alkaline phosphatase levels 48weeks after starting urusodeoxycholic acid therapy were independent risk factors for event occurrence. From the receiver operator characteristics curve analysis, serum tyrosine concentration >110μmol/L was identified as a cut-off value with an adjusted hazard ratio of 20.9 (95% confidence interval 4.3-101.5, P < 0.001). Kaplan-Meier analysis showed that the 5-year cumulative incidences of event occurrence in patients with high and low serum tyrosine concentration were 56.5% and 5.5%, respectively (P < 0.001). The 10-year survival probabilities also showed significant differences between patients with high and low serum tyrosine concentration (44.9% vs. 92.0%, P < 0.001). Elevation of serum tyrosine concentration indicates a high risk of liver-related events in primary biliary cholangitis patients receiving urusodeoxycholic acid therapy.

Tyrosine Supplementation Does Not Influence the Capacity to Perform Prolonged Exercise in a Warm Environment

Eight young men were recruited to a study designed to examine the effect of tyrosine (TYR) supplementation on the capacity to perform prolonged exercise in a warm environment. Subjects entered the laboratory in the morning and remained seated for 1 hr before cycling to exhaustion at 70% VO2peak. Two 250-ml aliquots of a placebo (PLA ) or a TYR solution were ingested at 30-min intervals before exercise, with an additional 150 ml consumed every 15 min throughout exercise (total TYR dose: 150 mg/kg BM). Cognitive function was assessed before drink ingestion, at the end of the rest period, and at exhaustion. TYR ingestion had no effect on exercise capacity (PLA 61.4 ± 13.7 min, TYR 60.2 ± 15.4 min; p = .505). No differences in heart rate (p = .380), core temperature (p = .554), or weighted mean skin temperature (p = .167) were apparent between trials. Ingestion of TYR produced a marked increase in serum TYR concentrations (+236 ± 46 μmol/L; p < .001), with this difference maintained throughout exercise. No change was apparent during the PLA trial (p = .924). Exercise caused an increase in error rate during the complex component of the Stroop test (p = .034), but this response was not influenced by the drink ingested. No other component of cognitive function was altered by the protocol (all p > .05). Ingestion of a TYR solution did not influence time to exhaustion or several aspects of cognitive function when exercise was undertaken in a warm environment.

Is the polymorphic microsatellite repeat of the dopamine β-hydroxylase gene associated with biochemical variability of the catecholamine pathway in schizophrenia?

Six allelic fragments were typed by a polymerase chain reaction process with a pair of primers specific for a sequence containing the polymorphic (GT)n repeat, a microsatellite repeat, in the human dopamine beta-hydroxylase (DBH) gene. Their frequencies in unrelated patients with schizophrenia were 0.003 (A1), 0.114 (A2), 0.343 (A3), 0.526 (A4), 0.006 (A5), and 0.009 (A6), and in unrelated control subjects, 0.012 (A1), 0.086 (A2), 0.309 (A3), 0.574 (A4), 0.006 (A5), and 0.012 (A6). Kruskal-Wallis analysis revealed significant differences among the three groups, the drug-free and drug-treated patients, and the control subjects, in serum DBH activity of the subjects whose genotype was A2/A3 (H = 6.0, p < .05) or A3/A3 (H = 9.8, p < .01), in serum homovanillic acid concentration of those whose genotype was A3/A4 (H = 7.7, p < .025), and in serum tyrosine concentration of those whose genotype was A4/A4 (H = 8.3, p < .02). Mann-Whitney U test showed that in the subjects carrying the A3/A4 genotype, serum noradrenaline concentration of drug-treated patients was significantly higher than that of control subjects (N = 58, p < .02). These results suggest that genotypic polymorphism of the human DBH is likely to be associated with biochemical variability of the catecholamine pathway in schizophrenia.

Low concentrations of serum tyrosine in neuroleptic-free schizophrenics with an early onset

The concentrations of serum tyrosine, phenylalanine and tryptophan have been determined in 23 male neurolepticfree patients with schizophrenia and 28 male healthy control subjects. Tyrosine was significantly lower in neurolepticfree patients with an early onset (starting before adulthood) than in healthy control subjects ( p<0.05), and the ratio of tyrosine to phenylalanine was significantly lower in neuroleptic-free patients with an early onset than in those with a late onset (starting at adulthood). No significant differences in these three amino acids were found between the patients with a late onset and healthy control subjects. The present findings suggest that there may be a disturbance of balance between tyrosine and phenylalanine in early-onset patients with schizophrenia.

Metabolic Basis of Hypertyrosinemia in Liver Disease

Serum tyrosine concentrations in patients with liver cirrhosis and with advanced fatty degeneration of the liver were 143 and 140 mumol/L, respectively, as compared with 65 mumol/l in normal controls. In biopsy samples of histologically normal livers, total tyrosine aminotransferase activity was 10.5 +/- 1.8 nmol p-hydroxyphenylpyruvate formed/mg of protein per min (mean +/- SEM; n = 10) whereas the corresponding figures for 7 cirrhotics were 4.95 +/- 0.85. The enzyme activity was normal in moderate adipose degeneration of the liver, but it was reduced when more than 50% of the hepatocytes were occupied by fat. It is suggested that the hypertyrosinemia of cirrhotics is, at least in part, due to decreased tyrosine aminotransferase activity.

Serum-free amino acid concentrations in low birth weight infants during the first 4 weeks of life.

To obtain more information about the correct protein intake in low birth weight children, serum amino acid concentrations were determined. In 59 formula-fed, low birth weight children, serum amino acid concentrations were determined at 3, 24 and 72 h after birth and at the age of 1, 2, 3 and 4 weeks. Mean serum concentrations of all amino acids decreased during the first 24 h of life, except of aspartate and tyrosine. This decrease was followed by an increase during the first weeks of life and a variable pattern afterwards. A hypertyrosinemia (serum-tyrosine concentration > 250 mumol/l) was not found in any case. Taurine concentrations decreased gradually, as was expected because of the low taurine concentrations in cow's milk. Mean concentrations of alanine, glycine, proline and valine were higher in small for date children. Concluding, parenteral supplementation of amino acids is advisable during the first days of life to low birth weight children.

Effects of Dietary Phenylalanine and Tyrosine on Circulating Thyroid Hormone Levels and Growth in the Chick

Studies were conducted to investigate the effects of a phenylalanine-tyrosine deficiency on serum thyroid hormone concentrations and growth in chicks from 0 to 14 days of age. Birds fed diets severely deficient in aromatic amino acids (AAA), lysine or valine were found in most trials to have reduced serum concentrations of either 3,5,3'-triiodothyronine (T3) or 3,5,3',5'-tetraiodothyronine (T4). Approximately one-half of the samples assayed did not show detectable levels of 3,3',5'-triiodothyronine (reverse T3). The reduction in serum thyroid hormone levels was not observed until chick growth was markedly affected and was not specific for AAA deficiency. Phenylalanine alone could not efficiently supply tyrosine when dietary AAA were suboptimal as evidenced by significantly greater weight gains in chicks fed 50:50 or 55:45 (mole:mole) mixtures of phenylalanine and tyrosine as compared with birds fed the same total amount (moles) of AAA supplied solely by phenylalanine. However, at or above requirement levels, phenylalanine could completely meet the chick's demand for tyrosine. Serum tyrosine concentrations generally reflected the dietary levels of AAA.

Metabolic Studies on Two Patients with Nonhepatic Tyrosinemia Using Deuterated Tyrosine Loads

Metabolic studies on two patients with defects in the tyrosine oxidation pathway are reported. Serum tyrosine was greatly elevated in both patients (1.37 and 1.52 mmol/liter, respectively) and both excreted large quantities of p-hydroxyphenylacetic acid, p-hydroxyphenyllactic acid, and p-hydroxyphenylpyruvic acid. Deuterated tyrosine loads were administered to both patients, before and after lowering of the serum tyrosine concentration by dietary treatment, and to a normal adult control subject. In one patient the excretion of the deuterated (D2)-tyrosine load was more than 300 times that found in the control subject whether the test was done at high or low serum tyrosine level and the pattern of metabolites indicated a persistent defect in p-hydroxyphenylpyruvic acid oxidase. Enzyme assays on needle liver biopsy supported this finding. In the second patient excretion of the D2 label was 300 times that of the control at high serum tyrosine levels, but only 5 times normal at low serum tyrosine levels. This finding was interpreted as indicating substrate inhibition of p-hydroxyphenylpyruvic acid oxidase. The primary defect has not been established in this patient, but the findings are compatible with a defect in hepatic-soluble tyrosine aminotransferase.

Heterozygote detection in phenylketonuria.

Phenylalanine loading was carried out on 105 parents of children with phenylalanine hydroxylase deficiency and 33 apparently normal individuals with no family history of phenylketonuria. The best discriminant was found to be the logarithmic transformation of the slope of the rise in serum tyrosine multiplied by the maximum serum tyrosine concentration over the maximum serum phenylalanine concentration obtained after an oral load with a pure solution of L-phenylalanine. The overlap between heterozygotes for penylketonuria and normal homozygotes was 2.4 percent. The distribution of the discriminant values suggested three heterozygous phenotypes for phenylalanine hydroxylase deficiency, and the phenotypic combination of parents could be correlated to the phenotype of their affected offspring, i.e. classical phenylketonuria, mild phenylketonuria of hyperphenylalaninemia. The probability of heterozygosity for phenylketonuria was determined by means of the distribution of the discriminant values of the heterozygotes and that of normal homozygotes. The likelihood of being a heterozygote was corrected for the genetic background of the person requiring genetic counseling, and was finally expressed as the percentage probability of being a heterozygote for phenylketonuria.

Serum tyrosine within the first hour after an oral load of phenylalanine.

Twenty-seven heterozygotes for phenylketonuria (PKU) and sixteen normal homozygotes were loaded with an amount of L-phenylalanine per body mass = 0.6 mmol/kg. Serum tyrosine concentration increased significantly within 15 min after the intake and the increase was rectilinear within the first 30 min. The initial rate of increase in serum tyrosine in heterozygotes was 0.47 mumol/l/min (range 0.20-0.98 mumol/l/min) and in normal homozygotes 1.2 mumol/l/min (range 0.80-1.9 mumol/l/min). The median serum tyrosine concentration increased within the first hour after an oral phenylalanine load (0.6 mmol/kg) of twelve infants with persistent hyperphenylalaninaemia (HPA), whereas serum tyrosine showed a decrease in forty infants with classical PKU. In ninetten infants with mild PKU serum tyrosine remained unchanged within the first hour after the load and then declined.

Different phenotypes for phenylalanine hydroxylase deficiency.

Abnormalities related to the hydroxylation of phenylalanine to tyrosine are classified into three phenotypes based on the amount of dietary phenylalanine tolerated to keep serum phenylalanine within therapeutic levels, i.e., 180-425 micronmol/l(3-7 mg/100 ml) : (1) Classical phenylketonuria (PKU) tolerating approximately 17% of a normal intake of phenylalanine or approximately 0.12 mmol per kg body weight; (2) mild PKU with a tolerance some 50% higher; and (3) persistent hyperphenylalaninaemia (HPA) with serum phenylalanine values within therapeutic levels on a daily intake of greater than or equal to 0.7 mmol phenylalanine per kg body weight. Oral phenylalanine loading was performed on 100 heterozygotes for these abnormalities and 33 normal homozygotes. The slope of the rise in serum tyrosine multiplied by the maximum serum tyrosine concentration over the maximum phenylalanine concentration was the most powerful discriminant (D/-s, 3.54; overlapping 2.4%). Three heterozygous phenotypes were distinguished by this discriminant, and a significant correlation was observed between the phenotypic combination of the parents and the phenotype of their affected child. In particular, parents of children with classical PKU were clearly distinguished from heterozygotes for the other two abnormalities.

Hormonal influences on the concentration of tyrosine in blood

Serum tyrosine is not a good indicator of thyroid function. Levels are lower in men than in women and still lower in pregnancy. Administration of glucose lowers serum tyrosine both in the presence and absence of insulin. Insulin-induced hypoglycemia has the same effect. In active acromegaly serum tyrosine is normal. Mesterolone, Lyndiol 2.5®, glucagon and epinephrine lower serum tyrosine concentration.

Tyrosinemia Induced by a Pyridoxine Antagonist, Desoxypyridoxine

Abstract Tyrosinemia was produced in Wistar rats by feeding a diet deficient in vitamin B6, and containing 1 mg of 4-desoxypyridoxine (DOP) per 100 g of diet. Concentrations of serum tyrosine were greatest in lactating rats, with smaller increases in nonpregnant, nonlactating females and adult males. Paper chromatography of urine indicated that DOP feeding also probably inhibits formation of most normal urinary metabolites of tyrosine. Livers of several rats showed no evidence of cirrhosis after 18 days on the diet containing DOP, indicating that this experimentally produced tyrosinemia is not a true model of tyrosinosis.