Phenylalanine plasma concentration

The liver is also the principal metabolic center for hydrophobic amino acids, and hence changes in plasma concentrations or metabolism of these molecules is a good measure of the functional capacity of the liver. Two of the commonly used aromatic amino acids are phenylalanine and tyrosine, which are primarily metabolized by cytosolic enzymes in the liver [1,114-117]. Hydroxylation of phenylalanine to tyrosine by phenylalanine hydroxylase is very efficient by the liver first pass effect. In normal functioning liver, conversion of tyrosine to 4-hy-droxyphenylpyruvate by tyrosine transaminase and subsequent biotransformation to homogentisic acidby 4-hydroxyphenylpyruvic acid dioxygenase liberates CO2 from the C-1 position of the parent amino acid (Fig. 5) [1,118]. Thus, the C-1 position of phenylalanine or tyrosine is typically labeled with and the expired C02 is proportional to the metabolic activity of liver cytosolic enzymes, which corresponds to functional hepatic reserve. Oral or intravenous administration of the amino acids is possible [115]. This method is amenable to the continuous hepatic function measurement approach by monitoring changes in the spectral properties of tyrosine pre- and post-administration of the marker. 

L-Dopa is not bound to plasma proteins. It crosses the blood-brain barrier by stereospeciflc saturable facilitated diffusion and competes with LNAA for transport into the brain. High-dose infusions of phenylalanine and leucine decrease the clinical response to L-dopa without altering L-dopa plasma concentrations. This has led to... 

Because the hver metabohzes the aromatic amino acids (i.e., phenylalanine, tyrosine, and tryptophan), methionine, and glutamine, the plasma concentrations of these amino acids are elevated in cirrhotic patients. Plasma concentrations of the branched-chain amino acids (BCAAs) (i.e., valine, leucine, and isoleucine) often are depressed because these amino acids are metabohzed by skeletal muscle. This altered plasma aminogram contributes to the development of hepatic encephalopathy. 

The plasma concentration of LNAA competes with tryptophan for uptake into the brain. The extent of uptake and net utilization influences levels in blood. Like tryptophan, tyrosine and phenylalanine are mainly metabolized in the liver.199 However, the branched-chain amino acids (BCAA) are taken up and metabolized mainly by skeletal muscle and little by the liver.200 Thus, following a meal, the BCAA rise more in peripheral blood than the other LNAA and other indispensable amino acid levels that are influenced by liver metabolism. The BCAA, therefore, have the dominating effect of the LNAA as a group on brain tryptophan uptake. 

Indinavir is a peptidomimetic hydroxyethylene HIV protease inhibitor. It is formulated as the sulfate salt to yield better solubility and more consistent plasma concentrations as compared with the free base. The molecule was based on a renin inhibitor with some similarity to a phenylalanine-proline cleavage site in the HIV polyprotein, although indinavir is not itself a renin inhibitor. Indinavir is tenfold times more potent against the HIV-1 protease than that of HIV-2, and its 95% inhibitory concentration (IC95) for wild-type HIV-1 ranges from 25 to 100 iiM. 

The neutral amino acids alanine, serine, threonine, asparagine, glutamine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, histidine and citrulline share a common transporter at the luminal border of the epithelial cells in the renal tubuli and the epithelial cells in the small intestine [16]. In Hartnup disorder an impairment of this transporter leads to hyperexcretion of these neutral amino acids and to intestinal malabsorption. Excretion of tryptophan metabolites kynurenine and N-methyl-nico-tinamide is reduced. Plasma concentrations of the affected amino acids may be low normal or reduced. The inheritance is autosomal recessive. The hph2-deficient mouse has been postulated as a model for Hartnup disorder [17]. Affected persons may be asymptomatic, while some demonstrate pellagra-like photodermatitis or cerebellar ataxia due to a nicotinamide deficiency and respond well to the administration of nicotinamide [16]. 

In liver failure the plasma concentrations of the aromatic amino acids (AAAs) tyrosine, phenylalanine, and tryptophan increase, probably because they are predominantly broken down in the liver, whereas the plasma levels of BCAAs decrease while they are degraded in excess in muscle as a consequence of hepatic failure-induced catabolism. As AAAs and BCAAs are all neutral amino acids and share a common transporter across the blood-brain barrier (system L carrier), changes in their plasma ratio are reflected in the brain, subsequently disrupting the neurotransmitter profile of the catecholamines and indoleamines (see sections on tyrosine and tryptophan). It has been hypothesized that this disturbance contributes to the multifactorial pathogenesis of hepatic encephalopathy. In line with this hypothesis it has been suggested that normalization of the amino acid pattern by supplementing extra BCAAs counteracts hepatic encephalopathy. 

Distortion of the plasma aminogram in individuals with an aminoaciduria also may lead to a relative failure of brain protein synthesis. Thus, in mice with a deficiency of phenylalanine hydroxylase, the blood concentration of phenylalanine is more than 20 times greater than the control value, leading to partial saturation of the transport system and a diminution in the brain level of neutral amino acids other than phenylalanine. Rates of protein synthesis were concomitantly reduced [8]. 

Plasma and urine samples from atherosclerotic and control rats were comparatively analyzed by ultrafast liquid chromatography coupled with ion trap-time-of-flight (IT-TOF) MS (UFLC-IT/TOF-MS) (16). They identified 12 metabolites in rat plasma and 8 metabolites in rat urine as potential biomarkers. Concentrations of leucine, phenylalanine, tryptophan, acetylcar-nitine, butyrylcamitine, propionylcamitine, and spermine in plasma and 3-0-methyl-dopa, ethyl /V2-acety I -1. -argininate, leucylproline, glucuronate, A(6)-(A-threonylcarbonyl)-adenosine, and methyl-hippuric acid in urine were decreased in atherosclerosis rats ursodeoxycholic acid, chenodeoxycholic acid, LPC (06 0), LPC (08 0), and LPC (08 1) in plasma and hippuric acid in urine were increased in atherosclerosis rats. The altered metabolites demonstrated abnormal metabolism of phenylalanine, tryptophan, bile acids, and amino acids. Lysophosphatidylcholine (LPC) plays an important role in inflammation and cell proliferation, which shows a relationship between LPC in the progress of atherosclerosis and other inflammatory diseases. 

As a rule, cirrhosis patients show reduced plasma BCAA levels and unchanged BCAA concentrations in the brain, whereas methionine and aromatic amino acids (AAA) (phenylalanine, tyrosine, tryptophan) are elevated in the plasma and brain, (s. p. 280) The fall in BCAA ieveis is attributable to its increased degradation, which, in turn, is caused or aggravated by hyperinsulinaemia. 

Routine liver function tests do not rehably indicate hver damage, and they may not become abnormal until there is already considerable hver damage. It is therefore common practice to monitor patients by conducting annual liver biopsies. Measurement of the serum amino-terminal propeptide of type III procoUagen (PHI PI) has been used as an alternative to hver biopsy high concentrations correlate with fibrosis on liver biopsy (49). No patient with a normal serum concentration had an abnormal biopsy. An increase in the plasma phenylalanine/tjrosine ratio in children and adolescents can provide chnical evidence of liver damage before the appearance of symptoms in patients who have taken high doses of methotrexate (50). 

CCK is found in the I cells of the upper small intestinal mucosa. Mixtures of polypeptides and amino acids (especially tryptophan and phenylalanine) stimulate CCK secretion, whereas pure undigested protein does not elicit a response. Secretion is also stunulated by gastric acid entering the duodenum and by fatty acids with chains of nine or more carbons, especially in the form of micelles. Circulating concentrations of CCK are therefore increased following ingestion of a mixed meal. CCK is rapidly cleared from plasma (tv2 - <3 min), predominantly by the kidneys. Secretion of CCK is completely inhibited after somatostatin inftision. 

The criteria for a biochemical diagnosis of untreated classic PKU are (1) a plasma phenylalanine level above 20 mg/dL (1.2mmol/L) (Figure 55-6, A) (2) a phenylalanine/ tyrosine ratio >3 (3) increased urinary levels of metabolites of phenylalanine (i.e., phenylpyruvic and 2-hydroxyphenyl-acetic acids) and (4) a normal concentration of the cofactor... 

The mainstay of the management of phenylketonuria is to reduce the plasma phenylalanine concentration by dietary control. Mental retardation is not present at birth, and can be prevented from cKcurring if plasma phenylalanine concentrations are kept low in the early years of life. It was thought that dietary control need only be follow ed for ten years or so but current views arc that lifelong therapy is neces.sary. 

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