Enzyme activities of tryptophan metabolism along the kynurenine pathway in various species of animals

doi:10.1016/S0014-827X(03)00140-X

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Volume 58, Issue 9, September 2003, Pages 829-836

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Abstract

The purpose of this study was to investigate variations in the enzyme activities of the kynurenine pathway in various mammals (rabbit, mouse, rat, guinea-pig). Liver tryptophan 2,3-dioxygenase, small intestine indole 2,3-dioxygenase, liver and kidney kynurenine 3-monooxygenase, kynureninase, kynurenine-oxoglutarate transaminase, 3-hydroxyanthranilate 3,4-dioxygenase and aminocarboxymuconate-semialdehyde decarboxylase were analysed. Small intestine superoxide dismutase activity and free and total serum tryptophan were also measured. Liver tryptophan 2,3-dioxygenase was present as both holoenzyme and apoenzyme only in rat, while in the other species only holoenzyme activity was observed. Also, small intestine indole 2,3-dioxygenase activity was more abundant in rat than in the other animals studied. The highest activity of small intestine superoxide dismutase was found in rat, and the lowest in rabbit. Liver and kidney kynurenine 3-monooxygenase activity was very elevated and higher in mouse, followed by rat; rabbit showed the lowest activity. Kynureninase activity appeared to be much lower among the enzymes of the kynurenine pathway. However, guinea-pig showed higher activity in both liver and kidney in comparison with other species. With regard to kynurenine-oxoglutarate transaminase, all species examined here presented more abundant enzyme activity in kidney, the value being similar between rat and mouse. Guinea-pig was the animal with the lowest activity. 3-Hydroxyanthranilate 3,4-dioxygenase showed the highest activity of all the enzymes evaluated in the study, but with different levels in liver and kidney, varying among species. The most elevated activity of aminocarboxymuconate-semialdehyde decarboxylase was present in kidney of guinea-pig, and the lowest in rabbit. Serum concentrations of tryptophan were higher in rat, followed by mouse, rabbit and guinea-pig. In conclusion, the present study demonstrates that the enzyme activities of the kynurenine pathway are very active in tissues of the four species of mammals investigated. The proposed method of in vitro enzyme determination represents a valid alternative to study of the tryptophan metabolic route.

Introduction

Every day a normal diet in man supplies about 600–900 mg of tryptophan. Besides being partly incorporated into proteins (30% of dietary tryptophan), in man tryptophan is metabolised along various pathways, yielding biologically important compounds [1], [2], [3], [4]. Scheme 1 summarizes the metabolic pathways of this amino acid.

The major metabolic pathway is the kynurenine pathway leading to the biosynthesis of nicotinic acid (niacin) (Scheme 2): 60 mg of tryptophan yields 1 mg of niacin. The sequence of steps that takes place in vivo along this pathway, named kynurenine pathway in order to distinguish it from others, has now been elucidated through the efforts of many researchers. Along this route, only small amounts of tryptophan metabolites are excreted daily by normal human subjects fed a free diet.

The sum of metabolites corresponds to 6.04 mg, about 1–2% of tryptophan ingested with diet [1]. Human subjects convert the largest part of dietary tryptophan to non-aromatic compounds along the glutarate pathway. However, in some diseases and in cases of vitamin deficiency, this pattern can change quantitatively [1].

Along the serotonin pathway, about 1–2% of ingested tryptophan is metabolised to give 5-hydroxy-indoleacetic acid. In patients with carcinoid, however, as much as 60% of dietary tryptophan may be converted to 5-hydroxy-indoleacetic acid [3], [5].

From tryptophan, by the action of intestinal bacteria, 3-indoxysulphate (indican) is formed, which is excreted in relatively large amounts in the urine of healthy subjects, corresponding to about 3% of dietary tryptophan [6]. The excretion of indican may increase in various diseases (Hartnup's disease, schizophrenia, phenylketonuria, malabsorption, pernicious anemia) [3].

Tryptophan is also a precursor of 3-indoleacetic acid, normally excreted in the urine of human subjects up to 100 μmol per day (about 3–4% of dietary tryptophan) [3], [7]. It is formed by both tissue enzymes and bacteria in the intestine. This amount may rise more than 10 times in 24 h in various pathological conditions (such as idiopathic sprue) [3].

The involvement of tryptophan in the biosynthesis of melanins has been demonstrated by our laboratory [8], [9], [10]. How much tryptophan is necessary for this route is not known.

Very little tryptophan is excreted unmodified in urine (0.5%). The kynurenine pathway therefore represents the major metabolic route through which tryptophan is totally degraded along the glutarate pathway, yielding energy (Scheme 1, Scheme 2). This pathway is altered in a great number of diseases [1], [2], [3].

The administration of a loading dose of l-tryptophan is widely used to reveal abnormalities in tryptophan metabolism, by determining the urinary metabolites of the kynurenine pathway [11], [12]. In humans, the enzyme activities of this route were rarely measured, due to the impossibility of obtaining isolated organs or tissues, unless after surgical treatment [13], [14] or death [15], [16]. Therefore, other mammals may be used to provide useful models for investigating enzyme activities along the kynurenine pathway.

The discovery of the enzyme indoleamine dioxygenase (IDO) [17], [18], [19] in many tissues and organs, cleaving tryptophan via kynurenine, has thrown light on the interpretation of results obtained until now in the abnormal metabolism of tryptophan in various pathological conditions [1], [2], [3]. Hayaishi [20] has suggested that, when some tissues are invaded by viruses, bacteria or endotoxins, interferon is produced, stimulating the synthesis of prostaglandins, inducers of indoleamine dioxygenase. As a consequence of inflammation, superoxide anion is liberated and used by IDO, causing a marked increase in the conversion of tryptophan to kynurenine.

The catabolism of tryptophan along the kynurenine pathway has aroused considerable interest, not only for the role that some metabolites play in several neuropathological conditions [21], [22], [23], [24], but also due to the recent results obtained by Munn and coworkers [25], [26], [27], who have shown that cells expressing IDO are able to inhibit T-cell proliferation in vitro.

The purpose of the present study was to investigate if any difference exists in the enzyme activities of the kynurenine pathway among various species of animals and if the mammalian species considered—rabbit, mouse, rat and guinea-pig—are good animal models for investigating tryptophan metabolism in pathological conditions by measuring enzyme activities along the kynurenine pathway.

The following enzymes were determined: liver tryptophan 2,3-dioxygenase [TDO; l-tryptophan:oxygen 2,3-oxidoreductase (decyclizing), EC 1.13.11.11], small intestine indole 2,3-dioxygenase (indoleamine 2,3-dioxygenase) [IDO; indole:oxygen 2,3-oxidoreductase (decyclizing), EC 1.13.11.17], liver and kidney kynurenine 3-monooxygenase [l-kynurenine, NADPH₂:oxygen oxidoreductase (3-hydroxylating), EC 1.14.13.9], kynurenine-oxoglutarate transaminase [l-kynurenine: 2-oxoglutarate aminotransferase, EC 2.6.1.7], kynureninase [l-kynurenine hydrolase, EC 3.7.1.3], 3-hydroxyanthranilate 3,4-dioxygenase [3-hydroxyanthranilate:oxygen 3,4-oxidoreductase (decyclizing), EC 1.13.11.6], and aminocarboxymuconate-semialdehyde decarboxylase (picolinic carboxylase) [2 amin-3-(3-oxoprop-2-enyl)-but-2-enedioate carboxy-lyase, EC 4.1.1.45]. The activity of small intestine superoxide dismutase (SOD, EC 1.15.1.1) and free and total serum tryptophan concentrations were also determined.

Section snippets

Chemicals

l-Tryptophan, l-kynurenine sulfate, α-ketoglutaric acid, pyridoxal phosphate, 3-hydroxyanthranilic acid, anthranilic acid, haematin hydrochloride, NADPH, catalase, superoxide dismutase (SOD), nitro blue tetrazolium, methylene blue, l-ascorbic acid and xanthine oxidase were purchased from Sigma Chemical Company. Bovine erythrocyte SOD was used as standard. All other chemicals were of analytical R grade.

Animals

Forty adult male animals were considered: 10 New Zealand rabbits (3–4 kg body weight), 10

Results

Table 1 shows the activities of liver TDO and small intestine IDO. TDO activity was present only as holoenzyme in rabbit, mouse and guinea-pig, whereas rat liver also contained TDO-apoenzyme. In addition, rat presented higher activity of TDO in comparison with the other species. Also, IDO activity was more abundant in rat than in the other animals.

Table 1 also shows the activity of small intestine SOD. Among the species of animals considered, the highest activity was found in rat and the lowest

Discussion

Study of tryptophan metabolism along the kynurenine pathway has patho-physiological relevance, as suggested for example by the fact that this route is rapidly induced by IFN-γ in human mononuclear cells [43], [44].

Mammals are very useful animal models for studying this catabolism in pathological conditions, by measuring urinary excretion of metabolites after a load of l-tryptophan or by determining enzyme activities along the kynurenine pathway. In some animals, repeated doses of tryptophan

Conclusions

The present study demonstrates that the enzyme activities of the kynurenine pathway are very active in tissues of the four species of mammals investigated. Study of tryptophan metabolism in vivo through urinary metabolite determination after repeated administration of tryptophan is limited by toxic events. The proposed method of in vitro enzyme determination represents a valid alternative to study of the tryptophan metabolic route.

Acknowledgements

This work was supported by grants from M.I.U.R. (Cofin, 2000), Rome (Italy).

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Enzyme activities of tryptophan metabolism along the kynurenine pathway in various species of animals

Abstract

Introduction

Section snippets

Chemicals

Animals

Results

Discussion

Conclusions

Acknowledgements

Adv. Clin. Chem.

Adv. Metab. Disord.

Am. J. Med.

Am. J. Clin. Nutr.

J. Biol. Chem.

J. Biol. Chem.

Brain Res.

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Methods Enzymol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Anal. Biochem.

J. Biol. Chem.

Biochim. Biophys. Acta

Life Sci.

Int. J. Biochem.

Comp. Biochem. Physiol.

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

Studies on tryptophan metabolism in man

Scand. J. Clin. Lab. Invest. Suppl.

Tryptophan nutrition and metabolism: an overview

Incorporation of d,l-tryptophan-benzene ring-14C (U) and d,l-tryptophan-methylene-14C into the melanin of mouse Harding–Passey melanoma

Gazz. Chim. Ital.

Melanogenesis from tryptophan. Biogenetic experiments with Harding–Passey mouse melanoma

Experientia

Incorporation of d,l-tryptophan-benzene ring-¹⁴C (U) and d,l-tryptophan-methylene-¹⁴C into the melanin of mouse Harding–Passey melanoma