In tryptophan metabolism

Unkila M, Pohjanvirta R, MacDonald E, et al. 1994. Dose response and time course of alterations in tryptophan metabolism by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the most TCDD-susceptible and the most TCDD-resistant rat strain Relationship with TCDD lethality. Toxicol Appl Pharmacol 128 280-292. 

Capuron L, Neurauter G, Musselman DL, Lawson DH, Nemeroff CB, Fuchs D, Miller AH. Interferon-alfa-induced changes in tryptophan metabolism. Relationship to depression and paroxetine treatment. Biol Psychiatry 2003 54 906-14. 

Bender DAand McCreanorGM (1985) Kynurenine hydroxylase a potential rate-limiting enzyme in tryptophan metabolism. Biochemical Society Transactions 13,441-3. 

From the data reported here and the considerations presented, it appears diflScult to accept the hypothesis that a change in tryptophan metabolism, giving an abnormal excretory pattern of o-aminophenolic derivatives of tryptophan, is able to induce bladder tumors. 

It was also observed (W6) that at termination of normal pregnancy, vitamin Be values were significantly depressed in maternal leucocytes and plasma. In blood of women in the last trimester of pregnancy, however, normal average amounts of the vitamin were found, although these individuals had a distinct abnormality in tryptophan metabolism. Amounts of pyridoxal phosphate are high in cord blood. 

According to Terent eva et al., disturbed tryptophan metabolism was not restricted to leukemia and cancer patients. Nevertheless, change in tryptophan metabolism played a definite role in the pathogenesis of leukemia and cancer (Tl). 

No evidence was found (Dl) for immaturity of the enzyme systems involved in tryptophan metabolism, since kynurenine and xanthurenic acid could be detected in the first weeks of life in urine of infants loaded with tryptophan. 

Mongolism. Several authors have pointed out that children affected by mongolism show a defect in tryptophan metabolism which is characterized primarily by a decreased urinary excretion of xanthurenic acid. 

Metabolic modifications in the chain of reactions involved in tryptophan metabolism were studied by Quagliariello et al. (Q2, Q3) and Piazza and Tancredi (P5) by qualitative analysis of urinary metabolites in 24 patients with viral hepatitis in an acute stage and in 34 subjects at least 2 months after recovery in comparison with normal controls. 

The disease is a rare inherited disorder characterized by a progressive degeneration of the lenticular nucleus in the brain and by cirrhosis of the liver. Barbeau et al. (Bl) studied a case of Wilson s disease which presented normal ceruloplasmin and serum copper values but increased excretion of kynurenine, 3-hydroxykynurenine, and conjugated anthra-nilic acid in xurine after an oral dose of 2 g L-tryptophan. This defect in tryptophan metabolism could be related to that of other amino acids and to the actual content of ceruloplasmin in Wilson s disease (Bl). These findings corroborated Marver s (M2) investigations demonstrating a definite excretion of kynurenine and 3-hydroxykynurenine in abnormal proportions after a tryptophan load in a case of Wilson s disease. 

Pla. Pelikw, V., Novosadov4, J., and Kaldb, M., Changes in tryptophan metabolism in diabetic patients. Vnitmi Lekar. 8, 668-673 (1962). 

Some women suffer from mental deprc.ssion when taking estrogen-containing oral contraceptives, and this depression could be due to another malfunction in tryptophan metabolism, leading to S-hydroxytryptamine (serotonin). Some evidence indicates that the decarboxylation of S-hydroxytrypto-phan is inhibited (in vitro) by estfogen conjugates competing with pyridoxal phosphate for the decarboxylase apoenzyme. 

Experiments with mutants of microorganisms and insects, which made it likely that hydroxykynurenine is an intermediate in tryptophan metabolism, have been described above. Further evidence for the occurrence of hydroxykynurenine in insect larvae has siirce been reported (575, 844, 845), and its relation to eye-pigments is discussed below. It is also formed in plants (932). Strong support for participation in mammalian metabolism was provided by its identification in mammalian urine (171, 176, 292, and cf. further discussion later). 

It has been shown by the author that examination of the products excreted after administration of tryptophan to vitamin-deficient animals can give valuable information on the function of that vitamin in tryptophan metabolism (142, 171, 173). When tryptophan is given to the riboflavin-deficient rat there is a large excretion of those substances which lie to the left of line BB in diagram 19 (142, 582). This clearly indicates that this is the step at which riboflavin functions, and this is strongly supported by the fact that riboflavin deficiency can reduce up to ten-fold the conversion of tryptophan to quinolinic acid, whereas similar conversion of hydroxykynurenine is unaffected (385). On the other hand, the excretory pattern... 

Abnormal indole derivatives in the urine and low levels of serotonin (a product of tryptophan metabolism) in blood and brain point to a defect in tryptophan metabolism in PKU. 5-Hydroxytryptophan decarboxylase, which catalyzes the conversion of 5-hydroxytryptophan to serotonin, is inhibited in vitro by some of the metabolites of phenylalanine. Phenylalanine hydroxylase is similar to the enzyme that catalyzes the hydroxylation of tryptophan to 5-hydroxytryptophan, a precursor of serotonin. In vitro, phenylalanine is also found to inhibit the hydroxylation of tryptophan. The mental defects associated with PKU may be caused by decreased production of serotonin. High phenylalanine levels may disturb the transport of amino... 

From 1978 to 1985 renewed interest in tryptophan metabolism via the kynurenine-niacin pathway was generated by the findings of Hayaishi et al. and others of a second enzyme, namely, indoleamine-2,3-dioxygenase (IDO).2 3 This enzyme was found to be present in several nonhepatic tissues (lung, intestine, brain, and epididymis) and cells (blood monocytes, macrophages, and eosinophils). The enzyme normally has very low activity but is induced to very high activity by stimulation of immune systems with interferon-y1-8 or interleukin-2 (cytokines).9 Thus, inflammatory processes, infections, and immune stimulation that induce interferon-y could lead to... 

Whether the altered metabolic parameters described above are related to cause or effect in EMS is not clear. However, based upon animal studies where species and strain differences in response to L-tryptophan have been reported,111113 such differences probably also exist in humans. Thus, it is important to establish whether differences in tryptophan metabolism exist in humans and then possibly to relate the changes to altered host susceptibility to diseases. 

For a long time, the major interest in tryptophan metabolism has been focused on the well-known neurotransmitter 5-hydroxytryptamine which, however, accounts for only 1% of dietary tryptophan metabolism in peripheral human tissues, more than 95% being transformed via the kynurenine pathway. Nowadays, a renewed interest arises as far as kynurenine and related substances is concerned, for example as potential targets for pharmacological therapies [5]. Therefore, it seems well worthwhile to carry out a somewhat detailed discussion about some aspects of the kynurenine pathway enzymology. The whole subject has been recently reviewed [5]. 

Depression has been described in women taking oral contraceptives (Al, Bl, H9, L6, W8) although a causal relationship has not been convincingly demonstrated (L3, W5). There has been interest lately in depression in OCA-users because these women often manifest abnormalities in tryptophan metabolism and because depressive illnesses may be associated with abnormal brain neuroamine metabolism. 

Contraceptive steroids, especially estrogens, produce abnormalities in tryptophan metabolism in the great majority of women who use them. Evidence of absolute Bo deficiency is much less common, and the amount of pyridoxine required to correct urinary output of tryptophan metabolites is much higher than what is found in normal diets. The studies reviewed provide at least a partial understanding of the biochemical basis for these phenomena. 

Research on tryptophan metabolism can be divided into three stages a first in which the end products of tryptophan metabolism were studied by investigating the composition of urine a second in which the intermediates of the various metabolic pathways were studied by following the urinary excretion of injected radioisotopes and a third in which an attempt was made to identify the enzymes involved in tryptophan metabolism. In the middle of the 19th century, it was demonstrated that kynurenine is excreted in dogs urine. Fifty years later, it was shown that kynurenic acid excretion is stimulated by the administration of tryptophan. A variety of other compounds were also found in the urine, including xanthurenic acid and quinolinic-2-carboxylic acid. 

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