Kynurenine is synthesized by the enzymetryptophan dioxygenase, which is made primarily but not exclusively in theliver, andindoleamine 2,3-dioxygenase, which is made in many tissues in response to immune activation.[1] An important source is theintestine.[2] Kynurenine and its further breakdown products carry out diverse biological functions, including dilatingblood vessels duringinflammation[3] and regulating the immune response.[4] Somecancers increase kynurenine production, which increases tumor growth.[1][5]
Kynurenine protects theeye by absorbingUV light, especially in the UVA region (315–400 nm).[6] Kynurenine is present in the lens and retina as one of multiple tryptophan derivatives produced in the eye, including3-hydroxykynurenine, that together provideUV protection and aid in enhancing visual acuity.[7][8] The use of kynurenine as a UV filter is consistent with itsphotostability and lowphotosensitization, owing to its efficient relaxation from the UV-induced excited state.[9] The concentration of this UV filter decreases with age,[10] 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.[11][12][13]
Evidence suggests that increased kynurenine production may precipitate depressive symptoms associated withinterferon treatment forhepatitis C.[14] Cognitive deficits inschizophrenia are associated with imbalances in the enzymes that break down kynurenine.[15] Blood levels of kynurenine are reduced in people withbipolar disorder.[16] Kynurenine production is increased in Alzheimer's disease[17][18] and cardiovascular disease[19] where its metabolites are associated with cognitive deficits[20] and depressive symptoms.[21] Kynurenine is also associated withtics.[22][23]Myokines regulate it's metabolism.[24][25][26]
Downregulation ofkynurenine-3-monooxygenase (KMO) can be caused by geneticpolymorphisms,cytokines, or both.[34][35] KMO deficiency leads to an accumulation of kynurenine and to a shift within the tryptophanmetabolic pathway towards kynurenine acid andanthranilic acid.[36] Kynurenine-3-monooxygenase deficiency is associated with disorders of the brain (e.g. major depressive disorder, bipolar disorder, schizophrenia, tic disorders)[37] and of the liver.[22][38][39][40][41]
It is hypothesized that the kynurenine pathway is partly responsible for the therapeutic effect oflithium onbipolar disorder. If that is the case, it could be a target of drug discovery.[42][43]
^Bova, L. M.; Sweeney, M. H.; Jamie, J. F.; Truscott, R. J. (January 2001). "Major changes in human ocular UV protection with age".Investigative Ophthalmology & Visual Science.42 (1):200–205.ISSN0146-0404.PMID11133868.
^Tsentalovich, Yuri P.; Sherin, Peter S.; Kopylova, Lyudmila V.; Cherepanov, Ivan V.; Grilj, Jakob; Vauthey, Eric (2011-09-29). "Photochemical properties of UV Filter molecules of the human eye".Investigative Ophthalmology & Visual Science.52 (10):7687–7696.doi:10.1167/iovs.11-8120.ISSN1552-5783.PMID21873681.
^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.doi:10.1038/s41380-020-00913-1.PMID33077852.S2CID224314102.
^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.doi:10.1111/j.1365-2990.2005.00655.x.PMID16008823.S2CID7754894.
^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.PMID12814390.S2CID10300941.
^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.S2CID36687413.
^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.PMID17665285.S2CID39150343.
^Marx W, McGuinness AJ, Rocks T, Ruusunen A, Cleminson J, Walker AJ, Gomes-da-Costa S, Lane M, Sanches M, Diaz AP, Tseng PT, Lin PY, Berk M, Clarke G, O'Neil A, Jacka F, Stubbs B, Carvalho AF, Quevedo J, Soares JC, Fernandes BS (2020). "The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: a meta-analysis of 101 studies".Molecular Psychiatry.26 (8):4158–4178.doi:10.1038/s41380-020-00951-9.PMID33230205.S2CID227132820.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^Hirata Y, Kawachi T, Sugimura T (1967). "Fatty liver induced by injection of L-tryptophan".Biochim. Biophys. Acta.144 (2):233–41.doi:10.1016/0005-2760(67)90153-1.PMID4168935.
^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.PMID29357703.
