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© 2007 American Society for Nutrition J. Nutr. 137:1586S-1590S, June 2007

Supplement: Aromatic Amino Acids and Related Substances: Chemistry, Biology, Medicine, and Application: SESSION 4

Phenylalanine and Tyrosine Metabolism in Chronic Kidney Failure1–3,

Joel D. Kopple*

Division of Nephrology and Hypertension, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502 and David Geffen School of Medicine at UCLA and the UCLA School of Public Health, Los Angeles, CA 90095

* To whom correspondence should be addressed. E-mail: jkopple{at}labiomed.org.


   ABSTRACT
TOP
 ABSTRACT
LITERATURE CITED
 
In chronic kidney failure, there is impairment in the conversion of phenylalanine to tyrosine. As a result, tyrosine and the tyrosine/phenylalanine ratio are reduced in plasma and many tissues, and phenylalanine concentrations tend to be normal or slightly increased. Although animal studies indicate that the kidney is not a major contributor to the conversion of phenylalanine to tyrosine, human studies conducted in the postabsorptive state suggest that the kidney plays a major role in the uptake of phenylalanine and its hydroxylation and release as tyrosine. The human splanchnic bed in the postabsorptive state also displays net uptake of both phenylalanine and tyrosine and hydroxylation of substantial amounts of phenylalanine to form tyrosine. In chronic renal failure (CRF) patients, splanchnic uptake of tyrosine appears to be reduced in the postabsorptive state. After an amino acid meal, there is net release of phenylalanine from the splanchnic bed in normal subjects and to an even greater degree in CRF patients; tyrosine is released postprandially in both normal subjects and CRF patients. In the postabsorptive state, tyrosine release from the kidney is largely derived from the hydroxylation of phenylalanine. In CRF, the release of tyrosine from the kidney is reduced and this reduction may be marked with advanced CRF. These observations, as well as isotope studies indicating normal phenylalanine flux, reduced tyrosine flux and impaired conversion of phenylalanine to tyrosine in CRF patients, raise the possibility that tyrosine may be an essential amino acid in this condition. Further research will be necessary to answer this question. Oxidative stress, which often increases in CRF patients, may lead to increased formation of chlorotyrosine and nitrotyrosine in plasma proteins and of nitrotyrosine in the brain. Increased nitrotyrosine is also found in kidneys of patients with diabetic nephropathy or allograft nephropathy. Increased serum concentrations of oxidation products of phenylalanine have also been observed in patients with CRF. Impaired urinary excretion also may lead to accumulation of metabolic products of both phenylalanine and tyrosine in CRF. It is not known whether the elevated protein chlorotyrosine or nitrotyrosine or increased oxidative products of phenylalanine cause adverse metabolic or toxic effects in patients with CRF.

Human and animal studies indicate that chronic kidney failure is associated with extensive changes in the degradation, synthesis, or excretion of the aromatic amino acids, phenylalanine and tyrosine, and also in the synthesis, metabolism, or urinary excretion of metabolites of these amino acids. This review will attempt to summarize these changes.

Phenylalanine is an essential or indispensable amino acid that cannot be synthesized by humans. Tyrosine is referred to as a semiessential or conditionally indispensable amino acid, because it can only be synthesized by the hydroxylation of phenylalanine. Other than this biochemical action, which is catalyzed by the enzyme phenylalanine hydroxylase, and which generates tyrosine from phenylalanine, the only source of these 2 amino acids is nutritional intake, such as from eating, tube feeding, intravenous nutrition, or amino acids administered through peritoneal dialysate or hemodialysate or from degradation of endogenous proteins with net release of these amino acids (1–3).

In humans, rats, and dogs with chronic renal failure (CRF), plasma, erythrocyte, and skeletal muscle tyrosine concentrations are often decreased, plasma and red cell phenylalanine is normal to slightly increased, and the ratio in plasma, red cells, and muscle of tyrosine/phenylalanine is almost always reduced (4–15). These findings suggested that there may be impairment in the conversion of phenylalanine to tyrosine by phenylalanine hydroxylase. Activity for this enzyme has been found in liver, kidney, and pancreatic cells of mice (16). Because CRF is associated with loss of not only renal excretory function but also metabolic and endocrine actions of the kidney, it would seem likely that the loss of renal phenylalanine hydroxylase activity might account for a reduced conversion of phenylalanine to tyrosine in kidney failure. The difficulty with this hypothesis was that in vitro activity measurements in mouse tissue indicated that the preponderance of phenylalanine hydroxylase activity resides in the liver (16). Both kidneys combined accounted for <10% of the total body enzyme activity, and the pancreatic phenylalanine hydroxylase activity comprised an even lower fraction of total body phenylalanine hydroxylase activity (8,9,16).

In vitro measurements in pair-fed CRF rats by Wang et al. (9) indicated that enzyme activities of liver phenylalanine hydroxylase and tyrosine aminotransferase (which catalyzes the first step in the oxidation of tyrosine) were not different from that of sham-operated, pair-fed control rats. The hepatic activity of phenylalanine hydroxylase fell when protein intake was reduced (9). CRF rats had significantly lower hepatic phenylalanine hydroxylase activities compared with control rats when both groups consumed very low (5%) protein diets ad libitum. CRF rats that are allowed to eat spontaneously eat less food than control rats, and thus the lesser phenylalanine hydroxylase activity in the CRF rats may be a response to their diminished nutrient intake. Young and Parsons also found that hepatic phenylalanine hydroxylase activity was similar in CRF rats and sham-operated control rats fed a 16% protein diet, but was significantly lower in CRF rats fed an 8% protein diet compared with CRF rats fed the 16% protein diet or to sham-operated control rats fed the 16 or 8% protein diet (8). These rats were apparently not pair-fed, so the protein intake in the latter CRF rats was probably substantially lower than in each of the 3 other groups. Plasma or plasma ultrafiltrate from CRF patients inhibited rat hepatic phenylalanine hydroxylase activity by 15%, which was not enough to account for the impairment in phenylalanine hydroxylase activity in CRF in the authors' estimation (8).

In normal rats, total phenylalanine hydroxylase activity is much lower in the kidney than in liver (8,9). Enzyme activity in kidney is further diminished in CRF rats in our experience (9), although this was not confirmed by Young and Parsons (8). Clearly, if kidney disease is sufficiently extensive, phenylalanine hydroxylase activity in this organ must be reduced. However, these in vitro studies indicate that the normal contribution of the kidney to total body phenylalanine hydroxylase activity must be small, at least in rats.

The contribution of the normal and diseased kidney to tyrosine and phenylalanine metabolism was also examined in dogs. Mass balances of tyrosine and phenylalanine across the kidney were examined in postabsorptive, female mongrel dogs during both the postabsorptive state when animals were receiving a half-normal saline infusion and during an infusion of 22 amino acids that increased plasma amino acid concentrations to average peak postprandial concentrations (17,18). With the half-normal saline infusion, there was a tendency for net renal release of tyrosine and phenylalanine. With the amino acid infusion, there was a tendency toward net uptake of these 2 amino acids by the kidney. None of these balances were statistically different from 0, and the arithmetic differences from 0 were small. Similar studies were carried out in female mongrel dogs with CRF induced by repeated injections of uranyl nitrate (18,19). Again, amino acid balances of the uptake and release of tyrosine or phenylalanine by the kidney were arithmetically small and not significantly different from 0. Thus, in vitro studies in rats and in vivo studies in dogs suggest that reduction in renal metabolic function in CRF does not contribute importantly to altered tyrosine or phenylalanine metabolism.

Several investigations of phenylalanine or tyrosine metabolism were subsequently carried out in vivo in humans with CRF. Jones and coworkers gave phenylalanine, 100 mg/kg body weight, to 11 normal men, 5 men with advanced CRF (primarily stage 5 chronic kidney disease) not receiving dialysis therapy and 8 men undergoing maintenance hemodialysis (MHD), all of whom were in the postabsorptive state (10). In the CRF and MHD patients, compared with the normal men, plasma phenylalanine rose higher and fell more slowly and plasma tyrosine rose more gradually and to lower levels (Figs. 1 and 2). Other studies have also described lower tyrosine and higher phenylalanine concentrations in plasma after a mixed amino acid or protein meal (20,21). Moreover, after an intravenous infusion of an amino acid solution containing phenylalanine, the half-life of phenylalanine was shown to be increased and its plasma clearance was reduced (22,23).


Figure 1
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  		FIGURE 1  Mean plasma phenylalanine concentrations in normal subjects (white circles, n = 11), patients with CRF (black circles, n = 5), and MHD patients (x's, n = 8) during the postabsorptive state and after an oral load of phenylalanine, 100 mg/kg body weight. Vertical lines indicate SD. Superscripts indicate that values are significantly different from those of normal subjects: aP < 0.05, bP < 0.01, cP < 0.005, and dP < 0.001, respectively. Reprinted with permission of Kidney International (10).

 

Figure 2
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  		FIGURE 2  Mean plasma tyrosine concentrations in normal subjects (white circles, n = 11), patients with CRF (black circles, n = 5), and MHD patients (x's, n = 8) during the postabsorptive state and after an oral load of phenylalanine, 100 mg/kg body weight. Vertical lines indicate SD. Superscripts indicate that values are significantly different from normal subjects: aP < 0.05, bP < 0.02, cP < 0.01, dP < 0.005, and eP < 0.0001, respectively, or that values are significantly different from CRF patients: fP < 0.02 and gP < 0.01, respectively. Reprinted with permission of Kidney International (10).

 
In the study by Jones et al. (10), 5 normal men and 5 MHD patients also ingested L-[14C]-phenylalanine with the oral phenylalanine load. During the subsequent 15 h, there was greater expiration of the ingested radioactive label as 14CO2 (P < 0.05) in the normal subjects (28.4%) compared with the MHD patients (20.2%) (Fig. 3). Moreover, in the postabsorptive state, plasma phenyllactic acid, p-hydroxyphenylacetic acid, and p-hydroxybenzoic acid were elevated in the CRF and MHD patients and plasma phenylpyruvic acid and mandelic acid were detected only in the MHD patients. After the phenylalanine load, plasma-conjugated phenylacetic acid increased in the CRF patients and phenylpyruvic acid rose transiently only in some MHD patients. In urine of the MHD patients compared with the normal or CRF subjects, after the phenylalanine load, some metabolites of phenylalanine were decreased and phenylpyruvic acid excretion was sometimes increased (10). These data, taken collectively, indicate that in CRF and MHD patients, there is mild impairment in the conversion of phenylalanine to tyrosine and there is some accumulation in plasma of metabolites of phenylalanine and tyrosine, probably due at least partly to impaired urinary excretion of these metabolites (10) and possibly also to enhanced metabolism through other biochemical pathways [e.g. for phenylpyruvic acid (1)].


Figure 3
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  		FIGURE 3  Mean cumulative expiration of 14CO2 in normal subjects (white circles, n = 5) and MHD patients (x's, n = 5) after an oral load of phenylalanine, 100 mg/kg body weight, and an oral dose of L-[14C]- phenylalanine (uniformly labeled), 0.3 µCi/kg of body weight, given concurrently. Statistical differences between the 2 groups are indicated by asterisks (P < 0.05). Vertical lines indicate SD. Reprinted with permission of Kidney International (10).

 
Mass balance studies (i.e. the net uptake or release of phenylalanine or tyrosine) across an individual organ or organ system or isotopic kinetic studies were also conducted in humans with results that were surprisingly different from the animal studies (24–30). Organ balance studies were performed across the kidney, limb, and/or splanchnic bed, which included both the liver and also other abdominal viscera, such as pancreas, that drain into the liver and hence the hepatic veins. As indicated above, mouse pancreas also contains a small amount of phenylalanine activity (16). In general, catheters were placed into an artery, such as the femoral artery, and also a renal vein and/or hepatic vein and 1 or 2 peripheral veins for infusions and blood sampling. Blood flow rates across the organs were measured using organ extraction of indicator compounds. Sometimes, isotope kinetic studies of phenylalanine and tyrosine were combined with mass balance measurements across organs (28–30).

The mass balance studies indicate that in both normal individuals and people with CRF in the postabsorptive state, there was net uptake of both phenylalanine and tyrosine by the splanchnia (24,25). After ingestion of a meal of mixed amino acids containing both phenylalanine and tyrosine, there was a release of phenylalanine from the splanchnic bed in normal subjects and CRF patients, but the release of phenylalanine from the splanchnia and the increment in whole blood phenylalanine were significantly greater in the CRF patients than in the normal subjects (25). After the amino acid meal, the normal subjects displayed a transient release of tyrosine from the splanchnia, whereas the CRF patients displayed a nonsignificant trend for splanchnic tyrosine output and their blood tyrosine tended to not increase as much as in normal adults. The normal human kidney also displays a net uptake of phenylalanine and net release of tyrosine (26–30), which tend to persist during a mixed amino acid infusion containing phenylalanine and tyrosine (27). In humans with stage 4 or 5 chronic kidney failure, and usually with stage 3 chronic kidney failure, the metabolic activity as well as the excretory activity of the kidney is impaired. In 1 study, postabsorptive patients with CRF show a release of tyrosine but no significant uptake of phenylalanine by the kidney (26). Clearly, if CRF is sufficiently advanced, there will be no renal uptake or release of either phenylalanine or tyrosine. In both normal adults and CRF patients, during the postabsorptive state, there is net release of both phenylalanine and tyrosine from the limb, which is interpreted to indicate net protein breakdown in skeletal muscle with release of phenylalanine and tyrosine (28,31,32).

Isotopic studies, often combined with measurements of uptake and release of total and isotope-labeled phenylalanine and tyrosine across the kidney, splanchnia, or arm, confirm that normally, in the postabsorptive state, the splanchnia takes up phenylalanine and tyrosine (i.e. presumably almost entirely in the liver) and the kidney takes up phenylalanine and releases tyrosine (28–30,32,33). In the postabsorptive state, ~35% of free phenylalanine provided to the splanchnia is removed by these organs. Roughly 11% of the phenylalanine taken up by the splanchnia is hydroxylated to tyrosine (presumably primarily in liver and to a lesser extent in pancreas) (32). Hence, most phenylalanine disposal in the splanchnia is through other pathways rather than hydroxylation. In contrast, during the postabsorptive state, ~16–18% of phenylalanine in the renal arterial blood flow is taken up by the normal kidney (30,32) and more than two-thirds of the phenylalanine disposed by the kidney is hydroxylated to tyrosine and released into renal venous blood as this latter amino acid. About 36% of tyrosine in blood entering the splanchnia is removed, whereas ~12% of renal arterial tyrosine is taken up by the kidney (32).

In normal humans, the absolute rate of phenylalanine hydroxylation in the splanchnia and kidney is actually similar (32). However, because the splanchnia also disposes of tyrosine, the kidney may actually contribute at least as much new tyrosine to the body's free tyrosine pools. Whole-body isotope studies confirm that phenylalanine flux (an indicator of protein degradation) is similar in normal subjects and CRF patients; however, the synthesis of tyrosine from phenylalanine and the net production of tyrosine is reduced in CRF (33). These findings were observed in the postabsorptive state and during the infusion of an amino acid solution containing both phenylalanine and tyrosine (33). In patients with CRF, splanchnic uptake of tyrosine is also decreased (25,32). Other pathways of disposal of phenylalanine and tyrosine by the splanchnia and kidney include incorporation into newly formed proteins and peptides, metabolism to other compounds, and excretion of small amounts of both amino acids into urine.

Only about 6–41 mg/d of phenylalanine and 7–27 mg/d of tyrosine are excreted in the urine of normal men and women (34). Urinary losses of these amino acids can increase substantially in the congenital amino acidurias (35) or in normal pregnancy (36). In patients with advanced CRF, the fractional renal excretion (i.e. the ratio of the clearance of the respective amino acid to the glomerular filtration rate) of both tyrosine and phenylalanine is increased, even markedly so, and the absolute excretion of these amino acids tends to remain within the normal range until the glomerular filtration rate is markedly reduced (5). In end stage renal failure, the urinary excretion of amino acids is reduced or absent. However, the normal excretion of these amino acids is so low that the diminished or absent excretion of phenylalanine and tyrosine in renal failure does not add much to the total body economy of these amino acids. Moreover, in maintenance dialysis patients, the reduction in the urinary excretion of phenylalanine and tyrosine is offset by the losses of these amino acids into dialysate (3,13,37,38). Postabsorptive MHD patients lost into dialysate an average of ~213 mg of phenylalanine and 124 mg of tyrosine with a hemodialysis treatment using lower flux hemodialyzer membranes (cellulose triacetate, CT 190 G (R), 1.9 m2 dialyzers) (3). Patients who were postprandial lost ~270 mg of phenylalanine and 170 mg of tyrosine into dialysate with hemodialysis treatments using high flux hemodialyzer membranes (polysulfone, 1.8 m2) (37). Patients lost slightly more of these amino acids during hemodialysis if they were postprandial (39) or if they received an intravenous infusion containing the respective amino acids (40). Patients who underwent continuous ambulatory peritoneal dialysis lost 87 ± 36 (SD) and 70 ± 30 mg/d of phenylalanine and tyrosine, respectively (13). Similar results were obtained by other investigators (38).

The foregoing metabolic disorders in the synthesis of tyrosine have raised the question of whether tyrosine may be an essential or indispensable amino acid in patients with CRF. In favor of this hypothesis are: 1) the low plasma and tissue concentrations of tyrosine observed in CRF patients who are postabsorptive or postprandial or who are receiving an amino acid infusion; and 2) evidence that the kidney is a major source of new tyrosine and that this function of the kidney is impaired or obliterated in CRF. Possible evidence against tyrosine being an essential amino acid include the frequent finding that plasma tyrosine levels are generally not markedly reduced in CRF patients. It is possible that tyrosine may be conditionally essential so that when CRF patients ingest only small amounts of its precursor, phenylalanine, or when they have certain co-morbid conditions, such as liver disease, a dietary requirement for tyrosine emerges. Because tyrosine deficiency could lead to protein depletion and also to impaired synthesis of critical tyrosine metabolites, such as epinephrine or norepinephrine, this would seem to be an important area for fruitful study.

The foregoing review indicates that in CRF there is impaired hydroxylation and removal of phenylalanine, decreased synthesis of tyrosine from phenylalanine, and accumulation of metabolites of phenylalanine and tyrosine, which are at least partly due to impaired urinary excretion. There are also other disorders in the biochemistry of these amino acids in chronic kidney failure. Individuals with chronic kidney disease are frequently subjected to oxidative stress, which is engendered by the hemodialysis procedure (41) as well as by a number of other metabolic disorders that occur in CRF (42). This results in increased generation or decreased removal of reactive oxygen species (42), free radicals (42,43), hypochlorous acid (41), and NO2 (44). These compounds are reactive with tyrosine, and increased quantities of 3-chlorotyrosine and nitrotyrosine in plasma proteins have been described in maintenance dialysis patients (41,44). Nitrotyrosine is also increased in kidneys of patients with diabetic nephropathy, particularly in the proximal tubular cells and the thin limb of the loop of Henle (43). Increased protein nitrotyrosine is also reported in brain of patients with CRF (45) and in chronic allograft nephropathy (46). Several oxidative products of phenylalanine metabolism are also reported to be increased in patients with CRF. These include increased serum protein-bound 3,4 dihydroxyphenylalanine (47) and urine orthotyrosine (48). It is not clear whether the foregoing oxidative-induced changes in tyrosine or phenylalanine have biochemical, metabolic, or toxic effects.


   FOOTNOTES
 
1 Published in a supplement to The Journal of Nutrition. Presented at the "Conference on Aromatic Amino Acids and Related Substances: Chemistry, Biology, Medicine, and Application" held July 20–21, 2006 in Vancouver, Canada. The conference was sponsored by Ajinomoto Company, Inc. The organizing committee for the symposium and Guest Editors for the supplement were: Katsuji Takai, Dennis M. Bier, Luc Cynober, Sidney M. Morris, Jr., and Yoshiharu Shimomura. Guest Editor disclosure: Expenses to travel to the meeting were paid by Ajinomoto Company, Inc. for K. Takai, D. M. Bier, L. Cynober, S. M. Morris, Jr., and Y. Shimomura; D. M. Bier has consulted for Ajinomoto Company, Inc. on scientific issues. Back

2 Supported by NIH grants 5 R01 DK061389-04 and M01-RR00425. Back

3 Author disclosures: J. Kopple's travel expenses to attend the meeting were paid by the Ajinomoto Company, Inc. Back


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