Phenylalanine: Its Role in Chronic Stress


Phenylalanine: Its Role in Chronic Stress

Phenylalanine, an essential amino acid, plays a crucial role in the regulation of chronic stress and depression. This state is characterized by a dysregulation of the hypothalamo-pituitary-adrenalan axis (HPA), with a hyperactivity of this axis and a disappearance of the circadian variations of the levels of ACTH and cortisol. Cortisol excess has a deleterious effect on other cells of the hypothalamus and seems to be responsible in part for premature aging of the brain.

Important and repeated stress activates the serotoninergic pathway and the physiologic answer to serotonin. Serotonin activates the HPA at its 3 levels (hypothalamus, pituitary, adrenals). Brain tryptophan is increased during chronic stress and is responsible for the increased turnover of serotonin observed in this state. Studies have shown that by giving a competitive amino acid it is possible to modulate the increase in serotonin during chronic stress and to control the hyperstimulation of the HPA.

Phenylalanine has the lowest Km for the common system (system L) of cerebral transport Of tryptophan and the other large neutral amino acids, so it has the highest affinity for this system of transport, just before tryptophan, and is the most efficient LNAA to counteract the dysregulation of the HPA. Phenylalanine is also the dietary precursor of phenylethylamine, a natural analog of amphetamines (it is one of the mediators of the action of antidepressive agents) which is lowered in depressive states. It is also the dietary precursor of catecholamines (dopamine, noradrenaline).

The kinetics of the conversion of phenylalanine (regulation of phenylalanine hydroxylase) to tyrosine in the liver and its influence by dietary factors, the regulation of cerebral transport of phenylalanine, the influence of the dose of phenylalanine administered on the synthesis of neuroamines, higher doses being repressive on this synthesis, are also examined.

Metabolism of Phenylalanine

Phenylalanine is an essential amino acid. The daily needs are 1-2 g per day, which corresponds to the ingestion of 50 g of dietary proteins per day. High protein value foods as eggs or milk bring 5 g phenylalanine per 100 g proteins. A great part of dietary phenylalanine is hydroxylated to tyrosine by the liver. The reaction is catalysed by phenylalanine hydroxylase.

Regulation of Phenylalanine Hydroxylase

- Phenylalanine is hydroxylated in the liver in tyrosine, the reaction being catalysed by phenylalanine hydroxylase. When the plasmatic levels of phenylalanine rise by 100%, phenylalanine hydroxylase activity is doubled. Each molecule of phenylalanine hydroxylase contains 2 iron atoms. An iron deficiency lowers this enzyme activity. A marginal iron deficiency can reduce by half the conversion of phenylalanine to tyrosine, the ad junction of iron raises its enzymatic activity.

- Copper is essential for the action of phenylalanine hydroxylase.

- Alpha chymotrypsine doubles the activity of phenylalanine hydroxylase for plasmatic concentrations of phenylalanine between 30 and 120 mMol/1. These concentrations are obtained with a supplementation of 10 to 20 mg/kg of phenylalanine per body weight.

- Folic acid activates this enzyme. Biopterine, the cofactor of phenylalanine hydroxylase is activated by folic acid.

- Hepatic disturbances reduce hepatic conversion of phenylala, nine to tyrosine.

Cerebral Transport of Phenylalanine

Phenylalanine is a long chain amino acid (LNAA), a group including aromatic amino acids, tyrosine, tryptophan and phenylalanine and the branched chain amino acids valine, leucine and isoleucine. These amino acids use a common pathway for their transport into the brain. The system of transport of the LNAA through the hemato encephalic barrier has the greatest affinity for phenylalanine (lowest Kin). Km of phenylalanine is 32+/-9, Km of valine is 168+/-72, Km of tryptophan is 52+/-14.

Regulation of Plasmatic Levels of Phenylalanine: The Role of Phe/LNAA Ratio

Immediately after consumption of dietary proteins the plasmatic level of phenylalanine rises while the phenylalanine/LNAA ratio lowers, because of global more important rise in LNAA. Meals rich in carbohydrates lower the LNAA raising the Phe/LNAA ratio.

In the rat, adding 10% proteins to a carbohydrate meal, suppresses the rise of the ratio phe/LNAA (Yokogoshi & Wurtman 1986). In man, it was not evaluated but is probably similar or a little lower in effect. These studies confirm that a meal rich in proteins raises plasmatic levels of phenylalanine but lowers the phe/LNAA ratio reducing the cerebral transport of phenylalanine. Otherwise the isolate consumption of phenylalanine induces a rise of its plasmatic level up without raising the other amino acids, and so raises the phe/LNAA ratio, favoring the cerebral transport of phenylalanine (Stegink 1977).

fasting: phe plasma 56æM/1

phe/LNAA:0.100 (Caballero 1986)

75 g protein: phe plasma: 61 æMol/l

phe/LNAA:0.087 (Maher 1984)

30 g carbohydrate: phe plasma: 36æMol/l

phe/LNAA:0.110 (Caballero 1987)

19 mg/kg phen: phe plasma: 120æMol/l

phe/LNAA:0.170 (Stegink 1977)

By raising the ratio phe/LNAA from 0.1 to 0.2 the level of brain phenylalanine is doubled in the rat (Yokogoshi 1984). The system of transport in the brain for the LNAA are very similar in the rat and in man (Choi and Pardridge 1986). Comparison of the plasmatic ratios with phenylalanine concentrations in the cerebrospinal fluid shows a positive correlation (Berry 1982). These studies show that a rise in the phe/LNAA ratio is associated with a significant rise of brain phenylalanine.

Studies on the correlation between an isolated supplementation of phenylalanine and its plasmatic concentration shows the following results:

fasting: 56æmol/l

* 5.6 mg/kg phenylalanine: 67.3æmol/l
* 19 mg/kg phenylalanine: 120æMol/l

Relation of Phenylalanine Concentration and Brain Dopamine

In the rat phenylalanine induces a rise in brain dopamine to 200 mg/kg. In the rat the rate of hepatic conversion of phenylalanine to tyrosine is 5 times greater than it is in man. In man it raises brain dopamine for doses until 40 mg/kg. Above it inhibits its synthesis (Matthew 1987). So it means that optimal doses for phenylalanine supplementation are between 10-20 mg/kg 30-40 mg being a maximum.

Phenylalanine and Depression

In depressive illness deficit in phenylalanine plays an important role. (Sandier 1980). Low catecholamine activity is associated with low energy drive, difficult social relationships, low self-esteem and sleep disturbances. Phenylalanine has been used in depressive illness with some success (Sabelli 1986, Fisher 1975, Fisher 1972, Sandler 1980.)

Phenylalanine is the precursor of phenylethylamine a neuroactive agent (Fisher 1972), and an intermediary of the action of amphetamines (Borison 1975). Phenylethylamine causes the release of noradrenaline in the central nervous system (Pharmacological Basis of Therapeutics, 199O, p. 188).

Oral administration of phenylalanine induces a rise of brain phenylalanine and tyrosine (Wurtman, Fernstrom 1983). Amphetamines stimulate synthesis of dopamine from phenylalanine in the brain (Bagchi 1980), by using tyrosine hydroxylase. An excess of noradrenaline inhibits by retrocontrole tyrosine hydroxylase. Phenylethylamine acts in great part by causing the release of noradrenaline from adrenergic nerve terminals. In depression often the liberation of noradrenaline is altered which is reflected by low plasmatic and urinary levels of MHPG its metabolite, and constitutes a good screening test for the etiology of depression and therapeutic approach. It can be coupled with the dosage of the metabolite of serotonin 5 HIAA. Some foods act by releasing noradrenaline from adrenergic nerve terminals, in particular coffee and tyramine-rich foods. Another substance, Yohimbine, acts by suppressing the inhibitory effect of presynaptic alpha 2-adrenergic receptors on the release of noradrenaline.

Phenylalanine can be converted in the brain to catecholamines although its conversion is less efficient than from tyrosine (Kapatos 1977). Narcolepsy is alleviated by phenylalanine (Parker 1974), as well as diurnal sleepiness which is associated with depressive states in chronic stress.

Phenylalanine, The Dietary Precursor of Phenylethylamine

Phenylethylamine 2 PEA is a biogenic amine obtained by decarboxylation of phenylalanine. The coenzyme of this reaction is vitamin B6. Urine analysis of people supplemented with phenylalanine show a rise in phenylacetic acid (PAA), the metabolite of PEA (Sabelli 1986).

Phenylethylamine plays an important part in the central effects of amphetamine. The administration of PEA induces amphetamine-like effects (reduced appetite, euphoria, loss of fatigue) (Borison 1975). Amphetamine induces a rise in the synthesis of PEA. It is an important intermediary of central effects of amphetamine. PEA stimulates attention and reduces depression. A reduction of cerebral concentration of PEA and a reduction of its turnover induces endogenous depression (Sabelli 1986). Damphetamine raises cerebral levels of PEA. A depletion in PEA suppresses the action of amphetamine.

Studies show a reduction of urinary levels of PEA (Sabelli 1974). PAA being formed from PEA by type B monooxydase, studies have investigated the levels of PAA in biological fluids. PAA levels have been found lowered in the LCR of depressed people (Sandler 1979). The 24 h urinary elimination of PAA is lowered in the patients having unipolar depression (Sabelli 1983) and bipolar depression (Sabelli 1983). Antidepressants raise the turnover of PEA, and urinary excretion of PEA.

Phenylalanine is the precursor of PEA and these studies confirm that a deficit of this stimulating amine (PEA) is associated with depressive illness and that the metabolism of phenylalanine is altered in affective disorders. The rise in the turnover of serotonin in chronic stress reinforces this consideration by altering the cerebral transport of phenylalanine by competition with tryptophan.

Role of the Hypothalamo-Pituitary-Adrenal Axis (HPA) in the Endocrine Response to Stressful Conditions

Bruce McEwen, PhD, Director of the neuroendocrinology laboratory at the Rockefeller University of New York is the pioneer in this field. He began to publish on this topic in 1968 in Nature.

The neuroendocrine responses to stress have two characteristics:

- The liberation of adrenalin by the chromaffin cells of the medulloadrenal.

- The liberation of glucocorticoids by the cells of the corticoadrenal.

The increase of secretion of the adrenal steroids results mainly in the activation of a population of hypothalamic neurons which produce a neuropeptide, the corticoliberin (CRF), which stimulates the release of ACTH, the coticotrope hormone, by the cells of the pituitary.

The dysregulation of the hypothalamo-pituitary-adrenal axis which is characteristic of the states of depression and stress is the subject of many studies. The depressed or stressed patient presents an hyperactivity of the HPA and a disappearance of the circadian variation of the levels of ACTH and cortisol. The levels of cortisol of the depressed are less sensible to the suppression by Dexamethasone than the normal patient. Serotonin (5 HT) plays a fundamental role in the dysregulation of the HPA during stress. Serotonin plays a role at 3 distinct levels:

- It stimulates the release of CRF by the hypothalamic neurons.

- It stimulates the release of ACTH at the pituitary level.

- It stimulates the release of glucocorticoids by directly acting on the pituitary and adrenals.

The depressed subjects show a hyperactivity of the HPA which is attributed to a hypersecretion of CRF.

The serotonin neurones have a stimulating effect on the CRF neurones (de Souza & Van Loo made the demonstration that a stress-produced by immobilization induced an increase of the turnover of serotonin).

The depletion of serotonin in hypothalamus after the injection of a selective neurotoxine,5,7 DHT, in the nucleus of the raphé induces a marked reduction of the corticoadrenalian answer to a neurogenic stress. Calogero et al. showed that serotonin agonists stimulate in vivo the release of ACTH independently of a direct effect on the liberation of endogenous CRF.

Serotonin acts directly on adrenals by stimulating the secretion of glucocorticoids. The studies show that serotonin is present in chromaffin cells of the medulloadrenal. Different studies showed the existence of a serotoninergic control for the secretion of 5HT.

Deleterious Effects of Glucocorticoids on the Brain, In Particular on the Hippocampus

Repeated stress activates by the intermediary of the corticoids, the serotoninergic pathway and the physiologic answer to serotonin. Glucocorticoids maintain under control the dopaminergic system of awake, and inhibit the potency of noradrenaline (Stone et al "Regulation of and á coùponents of noradrenergic cyclic AMP response in cortical stress" Eur J Pharm 1987 141:347-356). On the contrary, the activity of tyrosine hydroxylase is raised, which as we already said allows the conversion of phenylalanine to noradrenaline and reverses the inhibitory effect of glucocorticoids on noradrenaline. Glucocorticoids have a deleterious effect on the brain. The studies show a premature destruction of the hippocampus neurones inducing a phenomenon of premature ageing with a loss of pyramidal neurones. Repeated stress inhibits the capacity of noradrenalin to stimulate the production of its second messenger, the cyclic AMP via the á-adrenergic receptors. The glucocorticoids maintain under control the noradrenergic system of wakefulness.

The Hyperserotoninemia of Chronic Stress

Important and repeated stress activates the serotoninergic system and the physiologic answer to serotonin. It induces an increase of the turnover of serotonin which characterizes the early physiological answer to stress. The studies showed that during chronic stress there is an increase in the turnover of serotonin and an increase of cerebral tryptophan.

The synthesis of serotonin depends on its dietary precursor, tryptophan. Tryptophan is hydroxylated at the cerebral level in 5 hydroxytryptophan and then decarboxylated in 5 hydroxytryptamine or serotonin. An increase in the neuronal concentration of tryptophan (or a lowering) induces an increase (or a decrease) of the synthesis of serotonin.

The primary increase in synthesis of serotonin in stress is essentially a consequence of an increase in cerebral tryptophan. Cerebral tryptophan comes exclusively from plasma where it is present in 2 forms, free (10%) and bound (90%) to albumin. The concentration of free tryptophan depends upon lipolysis, because free fatty acids displace tryptophan from albumin. So physical exercise and caloric restriction raise free tryptophan by raising free fatty acids; cerebral tryptophan concentration and serotonin is directly related to the plasmatic concentration of free tryptophan.

The stimulation of the glucocorticoid synthesis in stress stimulates serotonin turnover in different ways:

- Raises free fatty acids and so raises free tryptophan

- Has an hyperglycemic effect and so stimulates the cerebral transport of tryptophan

- Activates tryptophan pyrrolase which in turn activates serotonin synthesis (Curzon et al. "effects of immobilization on rat liver tryptophan pyrrolase and brain 5 hydroxytryptamine metabolism: Br J Pharmacol 1969;37:689-697)

Prevention of the Increase of Serotonin in the Regulation of Chronic Stress

It has been clearly demonstrated that the prevention of the serotonin increase during stress suppresses concomitantly the hypercorticosteronemia of stress.

The cerebral transport of tryptophan is regulated by a competitive system between tryptophan and other neutral amino acids; tryptophan, valine, leucine, tryrosine, isoleucine, are the main amino acids sharing this common pathway (system L) (Wurtman, Fernstrom).

Serotonin secretion rises following a primitive rise of the cerebral transport of tryptophan. Tryptophan lowers the transport of the other large neutral amino acids (LNAA) sharing the same system. Studies have shown that by increasing one competitive amino acid it was possible to reduce the hyperserotoninemia of chronic stress, and prevent the increased transport of tryptophan in the brain. These preventive effects are reversed by the concomitant administration of tryptophan with the competitive amino acid. Phenylalanine is among the competitive large neutral amino acids, the one which shows the greatest affinity (lower Km) for the system of transport across the cerebral barrier, greater than tryptophan. By decreasing order of affinity we find: phenylalanine, tryptophan, tyrosine, leucine, isoleucine, valine.

It should be noticed that the increase in serotonin turnover observed in chronic stress could often be the origin of "chronic fatigue" so often observed, since an increase in serotonin is associated with increased fatigue (Anderson "Diet neurotransmitters and brain function" Br Med Bull 1981,37, 95-100).

Chronic Stress and Thyroid Hormones

The rise in the cerebral transport of tryptophan inhibits thyroid hormone secretion. Tryptophan inhibits the pituitary liberation of TSH. The rise in serotonin observed in chronic stress, inhibits the hypothalamic liberation of TRH (Mueller 1976).

Phenylalanine has to be taken in the first part of the day in order to avoid inhibiting the physiological increase of serotonin at the end of the day, promoting a good sleep. The hyperserotoninemia of the state of chronic stress is responsible for the drowsiness in the first part of the day, with a need to take excitants like coffee, and also sugar to increase the cerebral supply of tryptophan needed for the synthesis of serotonin.

The recovery of a physiologic rhythm of secretion of cortisol and serotonin allows a physiologic re-equilibration of sleep, an increase of cerebral catecholamines which were reduced under the influence of chronic stress and are the roots of depression, with an increased energy, concentration, self-esteem and regulation of appetite (suppresses the need for sugar necessary to entertain the facilitated transport of tryptophan to the brain).

Of course the purpose of this article is to insist on modulation of the HPA and the hyperserotoninemia of chronic stress, not to suppress it, as it is essential for general adaptation of the organism. Serotonin, having of course, important physiological benefits on the organism. There is in Europe a specialty called tianeptine which acts in the purpose of controlling hyperserotoninemia and dysregulation of the HPA of chronic stress.

Correspondence and References

Available Upon Request from Author:

Dr. Kathy Bonan


* 52, Rue Etienne Marcel
* 75002 Paris, France

Tel: (1)42-36-48-87

Fax. (1)45-08-19-48


By Kathy Bonan

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