Aspects of tryptophan metabolism in health and disease: a review.

Abstract

In recent years, considerable interest has been developed in the effect of various diseases upon the metabolic pathway by which L-tryptophan is converted to nicotinic acid derivatives. As the list of diseases associated with abnormal tryptophan metabolism has grown, there has been mounting scepticism abc;ut the specificity and clinical significance of many of the observed changes. The aim of this article is to review some of the more recent developments which have taken place in the study of tryptophan metabolism in man, and to show that many of the reported abnormalities may have as their origin the influence of hormonal and nutritional factors upon the metabolic pathway. Recognition of these factors should help to distinguish between non-specific changes brought about by the metabolic response to the 'stress' of any severe illness, and abnormalities of tryptophan metabolism that are of pathological or clinical significance.Clinical research into tryptophan metabolism in man has been largely concerned with the levels of intermediate metabolites that are present in urine collected after the patient has received an oral dose of L-tryptophan. The techniques involved have been discussed by Price, Brown, and Yess (1965), and by Musajo and Benassi (1964), who also reviewed the published results obtained in a variety of diseases. Biochemistry of Tryptophan Metabolism and the Effect of HormonesThe steps involved in the biosynthesis of nicotinic acid and 5-hydroxytryptamine from L-tryptophan are summarized in Figure 1. Some of these enzymatic reactions require pyridoxal 5-phosphate, the coenzyme derived from the various forms of vitamin B6, as a cofactor. Impaired function of this coenzyme results in an elevated urinary excretion ofkynurenine, 3-hydroxykynurenine, and xanthurenic acid, apparently because the kynureninase which is responsible for the conversion of 3-hydroxykynurenine

Possible roles of excess tryptophan metabolites in cancer

“…But the alternate explanation was that they showed that the simple injection of the 8-methyl ether of xanthurenic did not produce bladder tumor, but tumors did occur if the metabolite was administered by injection to mice that have previously had pure cholesterol pellets whether the metabolite was present or not. The results suggested that tryptophan metabolites might act as tumor inducers and that for tumor to occur a local abnormality within the bladder such as the presence of a foreign body is necessary to function as a promoter [Rose, 1972]. This was indeed the case, Abdel-Tawab et al [1968] showed that protozoan infection would cause bladder tumors.…”

“…The initial step of KN pathway involves degradation of the tryptophan into formylkynurenine by tryptophan dioxygenase (TDO) [L-tryptophan:oxygen 2,3-oxidoreductase (decyclizing), EC. 1.13.11.11] or called tryptophan pyrrolase, which is induced by adrenocorticosteroides, oestrogen, and androgens [Rose, 1972]. The activity of this enzyme is elevated by glucocortocoid [Knox, 1951], its own substrate, and heme cofactor [Bertazzo et al, 2001].…”

“…This relatively low number of patients with abnormal tryptophan metabolism was because there were higher number bladder cancer patients exposed to industrial carcinogens than people with abnormal tryptophan diet. A consensus of all these studies indicates that a large number of bladder cancer patients who had no exposure to industrial carcinogens are reported to have abnormal tryptophan metabolism [Rose, 1972].…”

“…Some of the tryptophan metabolites tested including 5-hydroxyindole, 5-hydroxytryptamine, and 3-OHKN induced the highest number of revertants (11,000, 5,200, and 2,700 per lmol, respectively) after the nitrite treatment, compared to their nonhydroxylated counter parts (1,000, 1,700, and negligible, respectively) in the Ames Salmonella/microsome mutagenicity test of tester strain TA100 [Hashizume et al, 1991]. These results suggest that the hydroxyl group of the molecule may have a functional role in mutagenicity caused by these compounds [Rose, 1972]. Because stomach mucosa is rich in nitrite and has low pH, it would be the ideal site for nitrosation to take place [Hashizume et al, 1991].…”

Identification of quinoline, carboline and glycinamide compounds in cow milk using HRMS and NMR

“…Various quinolines such as kynurenic, xanthurenic and quinaldic acids are known to be biosynthesized from tryptophan (Rose, 1972). It is also known that 2,6-and 2,8-quinolinediols can result from the hydroxylation of quinoline by different bacterial strains (Cui, Chen, Fu, Sheng, & Sun, 2004;Kaiser, Feng, & Bollag, 1996).…”