Kynurenine is synthesized by the enzyme
tryptophan dioxygenase, which is made primarily but not exclusively in the liver, and
indoleamine 2,3-dioxygenase, which is made in many tissues in response to immune activation.[1] Kynurenine and its further breakdown products carry out diverse biological functions, including dilating blood vessels during inflammation[2] and regulating the immune response.[3] Some cancers increase kynurenine production, which increases tumor growth.[1]
Kynurenine protects the eye by absorbing
UV light, especially in the UVA region (315-400 nm).[4] Kynurenine is present in the lens and retina as one of multiple tryptophan derivatives produced in the eye, including
3-hydroxykynurenine, that together provide UV protection and aid in enhancing visual acuity.[5][6] The use of kynurenine as a UV filter is consistent with its photostability and low photosensitization, owing to its efficient relaxation from the UV-induced excited state.[7] The concentration of this UV filter decreases with age,[8] and this loss of free kynurenine and the concomitant formation of relatively more photosensitizing kynurenine derivatives and kynurenine-protein conjugates may contribute to the formation of cataracts.[9][10][11]
Evidence suggests that increased kynurenine production may precipitate depressive symptoms associated with
interferon treatment for
hepatitis C.[12] Cognitive deficits in
schizophrenia are associated with imbalances in the enzymes that break down kynurenine.[13] Blood levels of kynurenine are reduced in people with
bipolar disorder.[14] Kynurenine production is increased in Alzheimer's disease[15] and cardiovascular disease[16] where its metabolites are associated with cognitive deficits[17] and depressive symptoms.[18] Kynurenine is also associated with
tics.[19][20]
Downregulation of
kynurenine-3-monooxygenase (KMO) can be caused by genetic
polymorphisms,
cytokines, or both.[28][29] KMO deficiency leads to an accumulation of kynurenine and to a shift within the tryptophan
metabolic pathway towards kynurenine acid and
anthranilic acid.[30] Kynurenine-3-monooxygenase deficiency is associated with disorders of the brain (e.g. major depressive disorder, bipolar disorder, schizophrenia, tic disorders) [31] and of the liver.[19][32][33][34][35]
Drug development
It is hypothesized that the kynurenine pathway is partly responsible for the therapeutic effect of
lithium on
bipolar disorder. If that is the case, it could be a target of drug discovery.[36][37]
^
abBartoli, F; Misiak, B; Callovini, T; Cavaleri, D; Cioni, RM; Crocamo, C; Savitz, JB; Carrà, G (19 October 2020). "The kynurenine pathway in bipolar disorder: a meta-analysis on the peripheral blood levels of tryptophan and related metabolites". Molecular Psychiatry. 26 (7): 3419–3429.
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^Guillemin GJ, Brew BJ, Noonan CE, Takikawa O, Cullen KM (2005). "Indoleamine 2,3 dioxygenase and quinolinic acid Immunoreactivity in Alzheimer's disease hippocampus". Neuropathology and Applied Neurobiology. 31 (4): 395–404.
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^Wirleitner B, Rudzite V, Neurauter G, Murr C, Kalnins U, Erglis A, Trusinskis K, Fuchs D (2003). "Immune activation and degradation of tryptophan in coronary heart disease". European Journal of Clinical Investigation. 33 (7): 550–4.
doi:
10.1046/j.1365-2362.2003.01186.x.
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^Gulaj E, Pawlak K, Bien B, Pawlak D (2010). "Kynurenine and its metabolites in Alzheimer's disease patients". Advances in Medical Sciences. 55 (2): 204–11.
doi:
10.2478/v10039-010-0023-6.
PMID20639188.
^Swardfager W, Herrmann N, Dowlati Y, Oh PI, Kiss A, Walker SE, Lanctôt KL (2009). "Indoleamine 2,3-dioxygenase activation and depressive symptoms in patients with coronary artery disease". Psychoneuroendocrinology. 34 (10): 1560–6.
doi:
10.1016/j.psyneuen.2009.05.019.
PMID19540675.
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^
abHoekstra PJ, Anderson GM, Troost PW, Kallenberg CG, Minderaa RB (2007). "Plasma kynurenine and related measures in tic disorder patients". European Child & Adolescent Psychiatry. 16: 71–7.
doi:
10.1007/s00787-007-1009-1.
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^Fornaro, Michele; Kardash, Lubna; Novello, Stefano; Fusco, Andrea; Anastasia, Annalisa; De Berardis, Domenico; Perna, Giampaolo; Carta, Mauro Giovanni (4 March 2018). "Progress in bipolar disorder drug design toward the development of novel therapeutic targets: a clinician's perspective". Expert Opinion on Drug Discovery. 13 (3): 221–228.
doi:
10.1080/17460441.2018.1428554.