Kynurenine metabolic pathway of tryptophan catabolism in healthy and pathological pregnancy
Konstantin G.Gurevich(1*), Senior researcher, Ph.D., M.D.
and Sergey A. Popkov (2), Professor, Dr. Sci., Ph.D., M.D.
1 Pathophysiology Department of Therapy
Faculty, Moscow State Medico-Stomatological University, 20/1 Delegatstaya street,
103473, Moscow, Russian Federation. Fax: +07-095-9733259, Email the author
2 Obstetrics and Gynecology Department, Stomatological Faculty, Moscow State Medico-Stomatological University, Sosonovaya street, 11, Moscow, Russian Federation. Phone: +07-095-1907386
* Corresponding author
Tryptophan to kynurenine transformation is one of alternative tryptophan pathways. It is activated by some immune factors and in pregnancy. One of the key enzymes of kynurenine pathway induction, indoleamine-2,3-dioxygenase (IDO), was found in placenta. Its expression increases with placenta development in healthy pregnancy. This caused decreasing of blood tryptophan concentration in pregnant women and elevation of kynurenine one. In pregnant women with ischemia of placenta, expulsion of fetus, IDO activity suppresses. From an other hand, increasing in IDO activity and kynurenine level in healthy pregnancy result in activation of kynurenine catabolism. One of kynurenine metabolites, kynurenic acid, demonstrates neuroprotective properties. Another metabolites, such as 3-hydroxykynurenin, quinolinic acid, are suggested to be neurotoxic. Elevated quinolinic acid concentration is observed in preeclampsia and toxemia.
Key words: pregnancy, kynurenine, and neuroactive effects.
There are known several tryptophan metabolic pathways, the main of them is degradation to serotonin. Tryptophan to kynurenine transformation is one of alternative tryptophan metabolic pathways (Fig.). At least two enzymes, tryptophan-dioxygenate and indolamine-2,3-dioxygenase (IDO), are known to catalyze L-tryptophan transformation to formyl-kynurenine, which is rapidly metabolized to kynurenine (Moroni, 1999). In healthy men this metabolism does not play essential role, but it can be activated due to stimulation of IDO expression by some immune factors (the main of them is interferon-g) (Taylor and Feng, 1991; Surkina and Gurevich [in press]) and pregnancy (Bonney, and Matzinger, 1998). Induction of tryptophan to kynurenine transformation and biological response of kynurenine metabolites will be in the focus of our review.
In pregnant women changes in tryptophan metabolism are observed since the first weeks of pregnancy. The molecular mechanism for such observation is IDO expression in trophoblast and then in placenta. IDO expression is correlated with placenta development (Tatsumi et al., 2000; Kudo and Boyd, 2000). Its activity is significantly lower in placenta with retarded intrauterine development (Kamimura et al., 1991).
IDO activation plays essential role in the immunological tolerance between the
mother and the fetus. Administration of 1-methyl-tryptophan (IDO inhibitor)
caused allogenic foetal rejection (Munn et al., 1998). Induction of IDO expression
in trophoblast is suppressed T-cell activity against fetus (Tatsumi et al.,
2000). So, it can be suggested that IDO induction in trophoblast and placenta
is sufficient to inhibit the immune system of mother and prevent expulsion of
Due to IDO induction in placenta, in healthy pregnancy, blood tryptophan level decreases and kynurenine one increases. Using high performance liquid chromatography, we demonstrated increasing in kynurenine concentration in blood and urine in pregnant women in comparison with non-pregnant women of the same age (Ahmerova et al., 2000). It was found that in pregnant women tryptophan values significantly decrease with increasing of gestation age (median for the first trimester is 72 mumol/L, the second trimester: 51 mumol/L, the third trimester: 4 mumol/L).
Correlation between ratio of kynurenine to tryptophan and gestation age was observed (r=0.714, p<.001) (Schrocksnadel et al., 1996; Fuchs et al., 1996). Intravenous tryptophan infusion (100 mg/kg) induced kynurenine production in sheep. Non-pregnant sheep demonstrate lower serum kynurenine concentrations then those pregnant. The highest kynurenine levels were observed on the third trimester (Nicholis et al., 1999). In study by Eguchi et al (1992) it was found that levels of tryptophan metabolites in the umbilical vein and artery of fetus were significantly higher then those in the maternal vein.
Total kynurenine concentration does not change in neonatal vein throughout perinatal period. So, authors suggest that tryptophan to kynurenine metabolism play an essential role in foetal development (Eguchi et al., 1992). The similar results were observed by Adachi et al (1990).
Since IDO induction in placenta is correlated with placenta development (Kudo and Boyd, 2000), pathology of placenta or foetal development results in decreasing in kynurenine level in comparison with normal pregnancy. Such decreasing is observed in cases of foetal expulsion (Munn et al., 1998). Placenta ischemia and retarded intrauterine development were demonstrated to suppress placental IDO activity and to decrease serum kynurenine concentration. In pregnant women such differences were significant since 14 week of gestation (in comparison with healthy pregnant women of the same gestation age) (Kamimura et al., 1991).
Changes in tryptophan metabolism in healthy and pathology pregnancy play essential role in neuroprotection and neutoxity. It happens because the most of kynurenine metabolites have neuroactive properties. Kynurenine can be found both in peripheral tissues and brain. Peripheral kynurenine is transported through blood-brain barrier and easily reaches the central nervous system. Glial cells are taken up kynurenine and metabolized it (Fukui et al., 1995). At least two enzymes might to metabolize kynurenine.
The first enzyme of kynurenine metabolism is kynurenine aminotransferase. It is localized in astrocytes (Du et al., 1992), kidney and liver (Okuno and Kido, 1991). Kynurenic acid is physiologically present in brain tissues. It demonstrated to be antagonist of glycine site of NMDA receptors (Stone, 2000). Increasing of its concentration prevents ischemia in hypoxia rats due to suppression of NMDA neurotransmission (Nozaki and Beal, 1992) and increasing in nitric oxide levels (Schimanovskii and Gurevich, 2000). Also kynurenic acid possible to prevent post-ischemia NMDA-induced alteration of neuronal cells (Nozaki and Beal, 1992). Kynurenic acid levels elevate in pregnancy due to kynurenine increasing levels in healthy pregnancy. It causes neuroprotective effects of kynurenic acid (Stone, 2000).
The second enzyme of kynurenine metabolism is kynurenine-3-hydroxylase. It is localized in placenta, brain, spleen, liver and kidney. This is a flavine-containing monooxydase (Erickson et al., 1992). The enzyme has high affinity for substrate, so in physiological conditions the most of free kynurenine transforms to 3-hydroxykynurenine (Bender and McCreanor G.M., 1982). The low concentrations of 3-hydroxykynurenine induce apoptosis in neuronal cells (Okuda et al., 1998). Increasing of 3-hydroxykynurenine levels can be observed in placenta ischemia due to kynurenine-3-hydroxylase suppression. Moreover, vitamin B6 surplus dietary suppresses kynurenine-3-hydroxylase activity both in placenta and liver in pregnant mice. (van der Kamp and Smolen, 1995). From an other hand, pregnancy-induced vitamin B6 deficient results in increasing of kynurenine-3-hydroxylase activity (Guilarte and Wagner, 1987). The elevated concentrations of kynurenic acid have citoxicity effects in cultures of neonatal neuronal cells (Eastman and Guilarte, 1989) or in local indirect injection in brain (Nakagami et al., 1996). 3-hydroxykynurenine and one of its metabolites, quinolinic acid, demonstrated induction of epilepsy-like seizures (Chiarulli et al., 1995).
Kynurenininase catalyses 3-hydroxy-kynurenine transformation to 3-hydroxy-anthranilic acid. The compound able to induce apoptotic process in brain tissues (Okuda et al., 1998) and decreasing in nitric oxide levels (Schimanovskii and Gurevich, 2000). This compound is easy transformed to quinolinic acid, which is interacted with NMDA-receptors (Stone and Perkins, 1981). Indirectly injected into brain, it induced destroys of the most neuronal cells (Perkins and Stone, 1983). The neurotrophic effects of quinolinic acid were observed after intranasal injection. These effects were similar to observed in Huntington's disease: the most intrinsic strial neurons were destroyed, neurons containing peptide Y seem to be spared together (Beal et al., 1989). In preeclampsia (Tanigushi et al., 1994) and toxemia (Tanigushi et al., 1990) the increasing of quinolinic acid plasma concentration is found, so the neurotoxic effects of this compound might be observed.
Let's remark that activation of tryptophan to kynurenine catabolism in pregnancy might cause decreasing in serotonin concentration and depression development. It usually observes in case of placental IDO hyperactivation or/and tryptophan-deficient diet. It is more character for the third trimester. For such depression tricycle anti-depressive agents administration have no significant effect, while treatment with selective serotonin re-uptake inhibitors is effective and results in reduction of kynurenine serum concentration (Stone, 2000).
Observed in pregnancy and described above changes in tryptophan to kynurenine transformation has an essential role in mechanisms of fetus and mother protection and alteration. Due to IDO expression in placenta, in pregnant women kynurenine levels increase in comparison with those in non-pregnant women. Elevation of kynurenine concentration causes increasing in kynurenic acid concentration, which affects in neuroprotection. Activation of alternative kynurenine metabolism to 3-hydroxy-kynurenine and quinolinic acid results in neurotoxic effects.
To prevent neurotoxic effects and to potent neuroprotective effects of tryptophan metabolites, enzyme regulators (inhibitors and activators) have to be used. There are nonselective and selective inhibitors.
Since IDO expression in placenta correlate with its development, and IDO suppression is observed in ischemia of placenta, we used anti-aggregate drug dipiridamol (75 mg 3 times in day, per os) to normalize placental microcirculation in pregnant women with placental blood circulation deficient. In these women we observed decreasing in kynurenine levels with comparison with healthy pregnant women of the same age of gestation (control group). After 2-3 weeks dipiridamol treatment, placental circulation was normalized in 73% of women. In these women kynurenine concentration increases to those in control group (Ahmerova et al., 2000). So, it might be suggested that dipiridamol administration non-specificity stimulates IDO activity due to prevention of placental ischemia development.
Moreover, nonspecific inhibition of kynurenine-3-hydroxylase can be reached by vitamin B6 dietary. In pregnant mice surplus of this vitamin suppresses activity of kynurenine-3-hydroxylase and decreases both 3-hydroxykynurenine and quinolinic acid concentration (van der Kamp and Smolen, 1995). So, vitamin B6 dietary in pregnancy might be suggested to be neuroprotective.
But, from our point of view, the most perspective is a selective enzyme regulator using. Such regulators have to be very specific enzyme inhibitors (activators), because to reach the same biological response the most higher concentrations on nonspecific inhibitors are needed that those of specific inhibitors (Varfolomeyev, Gurevich, 1999), and it is more probably that the higher concentration of enzyme inhibitor will be more toxic.
The most useful of selective enzyme regulators might be kynurenine-3-hydroxylase inhibitors. One of these inhibitors is nicotinylalanine. Its injection with kynurenine surplus into brain prevents neuronal cell alteration and has anticonvulsant activity (Connick et al., 1992). Another kynurenine-3-hydroxylase inhibitors, m-nitrobenoylalanine and o-methoxybenzoylalanine, prevent seizures induced by electroshock (Chiarugi et al., 1995). The kynurenine-3-hydroxylase inhibition by m-nitrobenoylalanine results in decline of 3-hydroxykynurenine and 3-hydroxyanthranilic acid concentrations. o-methoxybenzoylalanine is decreased 3-hydroxykynurenine level but not 3-hydroxyanthranilic acid one. This data is suggested that there are some alternative pathways of kynurenine to 3-hydroxyanthranilic acid transformation. Therefore the new series of kynurenine-3-hydroxylase inhibitors are synthesized (Stone, 2000).
Unfortunately, kynurenine-3-hydroxylase inhibitors safety and influence on foetal development are not still discovered. All knew inhibitors have behavioral effects in animals, the main of them is reduction of free locomotion activity. These inhibitors possible to reduce NMDA-receptor functions (Moroni, 1999). Only in the new century really widely application of kynurenine-3-hydroxylase inhibitors might appear. We hope that such drugs will be able to prevent neurotoxic effects of kynurenine metabolites.
Adachi, N., Ogasawara, T., Nishijima, M. (1990) Tryptophan metabolism during perinatal period. Nippon Snaka Fujinka Gakka Zasshi [Japanese] 42, 1203-1210.
Ahmerova, A.E., Gal'sova, N.E., Gurevich, K.G., Dorogokulya, Yu.A., Zaev, A.P., Korolevskaya, L.I., Maev, I.V., Pirogova, A.I., Popkov, S.A., Popkova, I.F., Pustovalov, D.A., Ravin, B.F., Siemina, A.A., Smirnova, S.O., Soldatenko, I.V., Firsova, T.A. (2000) The international system of units using in a rating of results of the laboratory analyses at the pregnant and non-pregnant women. In: Urgent questions of clinical railway medicine. Number 4. [Russian]. Moscow, Reprocenter publish, 525-552.
Beal ,M.F., Kowakk, N.W., Swartz, K.J., Ferrante, R.J., Martin, J.B. (1989) Differential sparing of somastatin-neuropeptide Y and cholinegric neurones following striatal exotoxin lesions. Synapse 3, 38-47.
Bender, D.A., McCreanor, G.M. (1982)The preferred route of kynurenine metabolism in rat. Biochim. Biophys. Acta 717, 56-60.
Bonney, E.A., Matzinger, P. (1998) Much IDO about pregnancy. Nature Medicine 4, 1178-1179.
Chiarugi, A., Carpenedo, R., Molina, M.T. Mattoli, L., Pelliciari, R., Moroni, F. (1995) Comparison of the neurochemical and behavioural effects resulting from inhibition of kynurenine hydroxilase and/or kynureninase. J Neurochem. 65, 1176-1183.
Connick, J.H., Heywood, G.C., Sills, G.J., Thomson, G.G., Brodie, M.J., Stone, T.W. (1992) Nicotinylalanine increases cerebral kynurenic acid and has anticonvulsant activity. Gen Pharmacol. 23, 235-239.
Du, F., Schmidt, W.D., Okuno, E., Kido, R., Koehler, R.C., Schwarcz, R. (1992) Localization of kynurenine amitotransferase immunoreactivity in rat hyppocampus. J. Comp. Neurol. 312, 477-487.
Eastman, C.L., Guilarte, T.R. (1989) Citoxicity of 3-hydroxykynurenine in a neuronal hybrid cell line. Brain Res. 495, 225-231.
Eguchi, K, Kamimura, S., Yonezawa, M., Mitsui, Y., Mizutani, Y., Kudo, I. (1992) Tryptophan and its metabolite concentrations in human plasma during the perinatal period. Nippon Snaka Fujinka Gakka Zasshi [Japanese] 44, 663-668.
Erickson, J.B., Reinhard, J.F.J., Flanagan, E.M., Russo, S. (1992) A radiometric assay for kynurenine-3-hydroxylase based on the release of 3H2O during hydroxylation of L-[3,5-3H]-kynurenine. Anal. Biochem. 205, 257-262.
Espey, M.G., Tang, Y., Morse, H.C., Moffet, J.R., Namboodiri, M.A.A., Guilarte, T.R., Wagner, H.W. (1987) Increasing concentrations of 3-hydroxykynurenine in vitamin B6 deficient neonatal rat brain. J. Neurochem. 49, 1918-1926.
Fuchs, D., Schrocksnadel, H., Baier-Bitterlich, G., Dapunt, O., Wachter, H. (1996) Activated cellular immunity and decreased serum tryptophan in healthy pregnancy. Adv. Exp. Med. Biol. 398, 149-153.
Fukui, S., Schwarcz, R., Rapoport, S.I., Takada, Y., Smith, Q.R. (1995) Blood-barrier transport of kynurenines: implications for brain synthesis and metabolism. J. Neurochem.. 56, 2007-2017.
Kamimura, S., Eguchi, K., Yonezawa, M., Sekiba, K. (1991) Localization and developmental change of indolamine 2,3-dioxygenase activity in the human placenta. Acta Med. Okayama 45, 135-139.
Kudo, Y., Boyd, C.A. (2000) Human placental indolamine 2,3-dioxygenase: cellular localization and characterisation of en enzyme preventing foetal rejection. Biochim Biophys. Acta 1500, 119-124.
Moroni, F. (1999) Tryptophan metabolism and brain function: focus on kynurenine and other indole metabolites. Eur. J. Pharmacol. 375, 87-100.
Munn, D.H., Zhou, M., Attwood, J.T., Bondarev, I., Conway, S.J., Marshall, B., Brown, C., Mellor, A.L. (1998) Prevention of allogenic foetal rejection by tryptophan catabolism. Science 281, 1191-1194.
Nakagami, Y., Saito H., Katsuki, H. (1996) 3-hydroxykynurenine toxicity on the rat striatum in vivo. Jpn. J. Pharmacol. 71, 181-186
Nicholis, T., Nitsos, I, Walker, D.W. (1999) Tryptophan metabolism in pregnant sheep: increased foetal kynurenine production in response to maternal tryptophan loading. Am. J. Obstet. Gynecol. 181, 1452-1460.
Nozaki, K., Beal, M.F. (2000) Neuroprotective effects of L-kynurenine on hypoxia-ischemia and NMDA lesions in neonatal rats. J. Cereb. Blood Flow Metab. 12, 400-407.
Okuda, S., Nishiama, N., Saito, H., Katsuki, H. (1998) 3-hydroxykynurenine, an endogenous oxidative stress genetator, caused neuronal cell death with apoptotic features and region selectivity. J. Neurochem. 70, 299-307.
Okuno, E., Kido, R. (1991) Kynureninase and kynurenine 3-hydroxylase in mammalian tissue. In: Schwecz, R. (ed.) Kynurenine and serotonin pathways. New York, Plenum, 167-175.
Perkins, M.N., Stone, T.W. (1983) Pharmacological and regional variations of quinolic acid-evoked excitations in the rat central nervous system. J. Pharmacol Exp. Ther. 226, 551-557.
Schimanovskii, N.L., Gurevich, K.G. (2000) Nitric oxide in molecular mechanisms of drug action. Internat. Med. J. [Russian] 6: 104-107.
Schrocksnadel, H., Baier-Bitterlich, G., Dapunt, O., Wachter, H, Fuchs, D. (1996) Decreased tryptophan in pregnancy. Obstet. Gynecol. 88, 47-50.
Stone, T.W. (2000) Development and therapeutic potential of kynurenic acid and kynurenine derivatives for neuroprotection. TiPS 21, 149-154.
Stone, T.W., Perkins, M.N. (1981) Quinolic acid: a potent, endogenous excitant at amino acid receptors in CNS. Eur. J. Pharmacol. 72, 411-412.
Surkina, I.D., Gurevich, K.G. [in press] Kynurenine pathway of tryptophan metabolism. Regulation by immune factors. J. Nevrologii i Psichiatrii imeni S.S. Korasokova [Russian].
Tanigushi, K., Okatani, Y, Sagara, Y. (1994) Serotonin metabolism in fetus in preeclampsia. Asia Oceania J. Obstet. Gynaecol. 20, 77-86.
Tanigushi, K., Okatani, Y, Sagara, Y. (1990) Study on serotonin metabolism in toxemia of pregnancy. Nippon Sanka Fujinka Gakkai Zasshi [Japanese] 42, 1217-1223.
Taylor, M.W., Feng, G. (1991) Relationship between interferon gamma, indolamine-2,3-dioxygenase, and tryptophan catabolism. FASEB J. 5, 2516-2522.
Tatsumi, K., Higuchi, T., Fujiwara, H., Nakayama, T., Egawa, H., Itoh, K., Fujii, S., Fujita, J. (2000) Induction of tryptophan 2,3-dyoxygenase in the mouse endometrium during implantation. Biochem.Biophys. Res. Communic. 274, 166-170.
van der Kamp J.L., Smolen A. (1995) Response of kynurenine pathway enzymes to pregnancy and dietary level of vitamin B6. Phamacol. Biochem. Behav. 51, 753-758.
Varfolomeyev, S.D., Gurevich K.G. (1999). Biokinetics. Moscow, Fair-press [Russian]. 720 pages.
Figures of metablism pathways can be found here:
First Published 27/12/2000