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Mittwoch, 26. Mai 2010
Inhibition of tryptophan-degrading enzymes enhances central availability of tryptophan
The enzyme tryptophan dioxygenase (TDO), which is primarily found in the liver, breaks down tryptophan. Therefore, if tryptophan is administered in large quantities, the supply of free tryp to be taken up by the CNS does not rise in proportion to the dose ingested (Salter et al. 1995).
There is evidence to suggest that the administration of paracetamol inhibits TDO activity and increases the amount of tryp available for serotonin synthesis (Daya et al. 2000, Maharaj et al. 2004). Likewise, acetylsalicylic acid has been shown to have an inhibitory effect on TDO activity (Maharaj et al. 2004). Treatment with melatonin has also been associated with an inhibitory effect on TDO activity (Walsh et al. 1997). As melatonin, particularly in high doses, may affect the circadian rhythm, a combination with sleep-inducing tryp seems to be inappropriate for long-term treatment.
It should be noted that stress stimulates TDO activity through an increased release of cortisol which in turn contributes to the breakdown of tryp (Hirota T. et al 1985). This mechanism of action may partly explain the occurrence of depression under high-stress conditions as a result of relative serotonin deficiency (Miura et al. 2008). There is evidence suggesting that consumption of alcohol also raises TDO activity. Within two hours after consumption of alcohol a decline in the plasma levels of tryp and an increase in kynurenine metabolites were measured (Badawy et al. 2009). As previously discussed, physiological doses of vitamin B3 stimulate the enzyme TDO, thereby reducing the blood concentrations of tryp (Sainio et al. 1990).
Another important enzyme for the degradation of tryp is indoleamine-2,3-dioxygenase (IDO). A number of natural substances have been associated with the inhibition of IDO.
For example, rosmarinic acid inhibits IDO activity and thus the degradation of tryp (Lee et al 2007). Part of the beneficial effects of lemon balm extract (contains a high percentage of rosmarinic acid, e.g. Gastrovegetalin®) may be due to its influence on the serotonin system.
Likewise, curcumin (Curcuma) has been shown to have an inhibitory effect on IDO activity (Jeong et al. 2009). In the literature an antidepressant effect of curcumin has been described, with the effect being only partly mediated by serotonin receptors (Wang et al. 2008).
A recent study has provided the first evidence that cacao may also have an inhibitory effect on IDO activity (Jenny et al. 2009). Further investigations are required to show that cacao consumed in the usual quantities has a favourable effect on the availability of tryp.
Resveratrol, a substance that occurs naturally in grapes (particularly high concentrations have been found in red wine), also inhibits the enzyme IDO (Banerjee et al. 2008).
An in-vitro study demonstrates suppression of tryptophan degradation in stimulated human PBMC by acetylsalicylic acid. These data suggest that acetylic acid is able to counteract Interferon-γ production and consequently suppression of IDO activity in several cells in which IDO is inducible by Interferon-γ (Schroecksnadel et al. 2005).
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Other agents affecting the central availability of tryptophan
The following substances have an effect on the concentrations of FFA and may therefore indirectly affect the uptake of tryp by the CNS. The administration of chromium (chromium picolinate) leads to an acute and chronic increase in free tryp which is probably due to a rise in FFA (Franklin and Odontiadis 2004).
The administration of heparin as an anticoagulant (to inhibit coagulation) has also been shown to increase the concentration of free tryp due to a rise in FFA levels under heparin (Strüder et al. 1996).
Consumption of caffeine results in an elevation of FFA levels and thus raises the proportion of free (unbound) tryptophan, while showing an inhibitory effect on serotonin synthesis (inhibition of the enzyme tryptophan hydroxylase, Lim et al. 2001). Therefore, it cannot be recommended as adjuvant therapy for depressive symptoms and affective disorders.
There is evidence to suggest that the displacement of albumin-bound tryptophan in rat serum after administration of acetylic acid (aspirin) in vivo led to increased entry of tryptophan into the brain (Maharaj et al. 2004).
Niacin is known to lead to an acute decline in the FFA concentration (at a dose of 500 mg). It is, however, less known that approximately 3 hours after oral administration a rebound effect occurs with a pronounced increase in FFA (Peireira 1967, Kamanna 2007). If tryp is given about 3 hours after the administration of niacin, the concentration of free tryp is likely to rise, thus creating favourable conditions for an optimised bioavailability of tryp.
Treatment with physiological doses of niacin (vitamin B3) has a beneficial effect on serotonin synthesis in individuals with relative vitamin B3 deficiency. As a result of an inadequate supply of vitamin B3, the body uses a considerable proportion of the ingested tryp for the production of vitamin B3. The simultaneous administration of low-dose niacin (vitamin B3) and tryp in order to compensate for deficiencies is not appropriate, as niacin activates the enzyme (TDO) responsible for the breakdown of tryp in the liver (Sainio et al. 1990). Consequently, treatment for a deficient vitamin B3 status needs to be completed prior to the initiation of tryptophan therapy.
High doses of niacin (> 500 mg) have also been shown to have adverse effects on the availability of tryp for serotonin synthesis (Penberthy 2007). In high doses, niacin stimulates another important enzyme system (indoleamine-2,3-dioxygenase) responsible for the degradation of tryp.
It would seem that the higher the amount of tryp substituted, the higher the amount of tryp available for serotonin synthesis, but this is unfortunately not the case. Repeated administration of tryp does not produce high blood levels of tryp as expected. This is due to two enzymes that break down tryp. The activities of both enzymes are induced by a high intake of tryp. The enzyme tryptophan dioxygenase (TDO) is primarily found in the liver. As repeated high doses of tryp stimulate this enzyme it seems to be advisable to give tryp in several divided low doses and to schedule for regular tryp-free days. This treatment regimen is supported by pharmacokinetic studies of tryp which indicate that tryp plasma levels may return to normal 4-6 hours after administration at the latest (Green et al. 1980, Möller 1981). It should be noted that the single dose needs to be high enough that adequate levels of free tryp are produced (≥ 1.5 g of tryp) (Green et al. 1980). In summary, an intermittent dosage regimen with breaks in between to allow for periodic normalisation of TDO enzyme activity seems to be more beneficial than continuous therapy with tryp.
Another way to enhance the supply of tryp to the brain would be to administer substances that inhibit the TDO enzyme.
The second important enzyme for the degradation of tryp is indoleamine-2,3-dioxygenase (IDO). Unlike TDO, this enzyme can be found in numerous tissues and plays a special role in the development of tolerance to foreign antigens. IDO activity is also increased by a high supply of tryp, thus reducing the availability of tryp for serotonin synthesis.
Link: Tryptophan Literature
The following substances have an effect on the concentrations of FFA and may therefore indirectly affect the uptake of tryp by the CNS. The administration of chromium (chromium picolinate) leads to an acute and chronic increase in free tryp which is probably due to a rise in FFA (Franklin and Odontiadis 2004).
The administration of heparin as an anticoagulant (to inhibit coagulation) has also been shown to increase the concentration of free tryp due to a rise in FFA levels under heparin (Strüder et al. 1996).
Consumption of caffeine results in an elevation of FFA levels and thus raises the proportion of free (unbound) tryptophan, while showing an inhibitory effect on serotonin synthesis (inhibition of the enzyme tryptophan hydroxylase, Lim et al. 2001). Therefore, it cannot be recommended as adjuvant therapy for depressive symptoms and affective disorders.
There is evidence to suggest that the displacement of albumin-bound tryptophan in rat serum after administration of acetylic acid (aspirin) in vivo led to increased entry of tryptophan into the brain (Maharaj et al. 2004).
Niacin is known to lead to an acute decline in the FFA concentration (at a dose of 500 mg). It is, however, less known that approximately 3 hours after oral administration a rebound effect occurs with a pronounced increase in FFA (Peireira 1967, Kamanna 2007). If tryp is given about 3 hours after the administration of niacin, the concentration of free tryp is likely to rise, thus creating favourable conditions for an optimised bioavailability of tryp.
Treatment with physiological doses of niacin (vitamin B3) has a beneficial effect on serotonin synthesis in individuals with relative vitamin B3 deficiency. As a result of an inadequate supply of vitamin B3, the body uses a considerable proportion of the ingested tryp for the production of vitamin B3. The simultaneous administration of low-dose niacin (vitamin B3) and tryp in order to compensate for deficiencies is not appropriate, as niacin activates the enzyme (TDO) responsible for the breakdown of tryp in the liver (Sainio et al. 1990). Consequently, treatment for a deficient vitamin B3 status needs to be completed prior to the initiation of tryptophan therapy.
High doses of niacin (> 500 mg) have also been shown to have adverse effects on the availability of tryp for serotonin synthesis (Penberthy 2007). In high doses, niacin stimulates another important enzyme system (indoleamine-2,3-dioxygenase) responsible for the degradation of tryp.
It would seem that the higher the amount of tryp substituted, the higher the amount of tryp available for serotonin synthesis, but this is unfortunately not the case. Repeated administration of tryp does not produce high blood levels of tryp as expected. This is due to two enzymes that break down tryp. The activities of both enzymes are induced by a high intake of tryp. The enzyme tryptophan dioxygenase (TDO) is primarily found in the liver. As repeated high doses of tryp stimulate this enzyme it seems to be advisable to give tryp in several divided low doses and to schedule for regular tryp-free days. This treatment regimen is supported by pharmacokinetic studies of tryp which indicate that tryp plasma levels may return to normal 4-6 hours after administration at the latest (Green et al. 1980, Möller 1981). It should be noted that the single dose needs to be high enough that adequate levels of free tryp are produced (≥ 1.5 g of tryp) (Green et al. 1980). In summary, an intermittent dosage regimen with breaks in between to allow for periodic normalisation of TDO enzyme activity seems to be more beneficial than continuous therapy with tryp.
Another way to enhance the supply of tryp to the brain would be to administer substances that inhibit the TDO enzyme.
The second important enzyme for the degradation of tryp is indoleamine-2,3-dioxygenase (IDO). Unlike TDO, this enzyme can be found in numerous tissues and plays a special role in the development of tolerance to foreign antigens. IDO activity is also increased by a high supply of tryp, thus reducing the availability of tryp for serotonin synthesis.
Link: Tryptophan Literature
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