3-hydroxy-DL-Kynurenine

3-hydroxy-DL-Kynurenine is a potential endogenous neurotoxin which significantly inhibited CD4⁺ T-cell proliferation in a dose-dependent manner with IC₅₀ value of approximately 70μM. 3-hydroxy-DL-Kynurenine is a metabolic intermediate of the kynurenine pathway, the major metabolic pathway of tryptophan (Trp). Increased levels of 3-hydroxy-DL-Kynurenine have been described in several neurodegenerative disorders^[1][2].

In vitro, human colon cancer HCT116 cells treated with 3-hydroxy-DL-Kynurenine (0.008-2mM) for 6-48h disrupted TCA cycle metabolism, depleted glutathione levels and reduced cell viability in a dose-dependent manner^[3]. Neuronally derived hybrid cell line (N18-RE-105) was treated with increasing concentration of 3-hydroxy-DL-Kynurenine for 24h. 3-hydroxy-DL-Kynurenine was toxic to greater than 85% of cultured cells at concentrations in excess of 100μM. N18-RE-105 exposed to 500μM 3-hydroxy-DL-Kynurenine for 2h did not induced significant cell lysis, yet marked cell death emerged 22h after harvest^[4]. Human neurons and astrocytes treated with 3-hydroxy-DL-Kynurenine (0.1–1000μM) for 24h significantly increased intracellular NAD⁺ levels at a low concentration of 100nM but substantially decreased NAD⁺ levels at higher concentrations. Treatment with 3-hydroxy-DL-Kynurenine increased extracellular LDH activity at concentrations above 100nM in both cell types^[5].

In vivo, kynurenine 3-monooxygenase (KMO) is a pivotal enzyme in the kynurenine pathway (KP) and normally oxidizes kynurenine (KYN) to 3-hydroxy-DL-Kynurenine in the presence of reduced NADPH and molecular oxygen. Endotoxic shock was induced in KMO^-/- C57BL/6N mice with 15mg/kg LPS. KMO^-/- mice given 10mg/kg 3-hydroxy-DL-Kynurenine i.p. every 12h after LPS survived significantly longer than PBS-treated KMO^-/- mice by inhibiting inflammation via halving serum IL-6 and blocking ATF4 nuclear translocation^[6]. Intrastriatal injection of 1μl of 3-hydroxy-DL-Kynurenine (50nmol) dissolved in DMSO into Wistar rats brain induced lesion at the injected area characterized by a dose-dependent, well-defined cavity surrounded by necrosis and reactive gliosis^[7].

References:
[1] Okuda S, Nishiyama N, Saito N, and Katsuki H. 3-Hydroxykynurenine, an endogenous oxidative stress generator, causes neuronal cell death with apoptotic features and region selectivity. J Neurochem. 1998 Jan;70(1):299-307.
[2] Sarah S Zaher,Germain C, Fu H, et al. 3-hydroxykynurenine suppresses CD4+ T-cell proliferation, induces T-regulatory-cell development, and prolongs corneal allograft survival. Invest Ophthalmol Vis Sci. 2011 Apr 22;52(5):2640-8.
[3] Buchanan J L, Rauckhorst A J, Taylor E B. 3-hydroxykynurenine is a ROS-inducing cytotoxic tryptophan metabolite that disrupts the TCA cycle. bioRxiv. 2023 Jul 10:2023.07.10.548411.
[4] Eastman C L, Guilarte T R. Cytotoxicity of 3-hydroxykynurenine in a neuronal hybrid cell line. Brain Res. 1989 Aug 28;495(2):225-31.
[5] Braidy N, Grant R, Brew B J, et al. Effects of Kynurenine Pathway Metabolites on Intracellular NAD Synthesis and Cell Death in Human Primary Astrocytes and Neurons. Int J Tryptophan Res. 2009:2:61-9.
[6] Hoshi M, Kubo H, Ando T, et al. 3-Hydroxykynurenine Regulates Lipopolysaccharide-Stimulated IL-6 Production and Protects against Endotoxic Shock in Mice. Immunohorizons. 2021 Jun 28;5(6):523-534.
[7] Nakagami Y, Saito H, Katsuki H. 3-Hydroxykynurenine toxicity on the rat striatum in vivo. Jpn J Pharmacol. 1996 Jun;71(2):183-6.