Fujigaki Hidetsugu, Yamamoto Yasuko, Saito Kuniaki
Faculty of Health Sciences, Hiroshima International University, 555-36 Kurosegakuendai, Higashihiroshima, Hiroshima, 739-2695, Japan.
Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan.
Neuropharmacology. 2017 Jan;112(Pt B):264-274. doi: 10.1016/j.neuropharm.2016.01.011. Epub 2016 Jan 6.
The kynurenine pathway (KP) is the major route for tryptophan (TRP) metabolism in most mammalian tissues. The KP metabolizes TRP into a number of neuroactive metabolites, such as kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN). Elevated metabolite concentrations in the central nervous system are associated with the pathophysiology of several inflammation-related neuropsychiatric diseases. During an inflammatory response, the initial KP metabolic step is primarily regulated by indoleamine 2,3-dioxygenase 1 (IDO1), which produces KYN from TRP. Following this initial step, the KP has 2 distinct branches; one branch is regulated by kynurenine 3-monooxygenase (KMO) and is primarily responsible for the 3-HK and QUIN production, and the other branch is regulated by kynurenine aminotransferase (KAT), which produces KYNA, an N-methyl-d-aspartate receptor and alpha-7-nicotinic acetylcholine receptor antagonist. Unbalanced KP metabolism has been demonstrated in distinct neuropsychiatric diseases; thus, understanding the mechanisms that regulate KP enzyme expression and activity is important. These enzymes are expressed by specific cell types, and the induction of enzyme expression by inflammatory stimuli also shows cell type specificity. This review provides an overview and discusses the current understanding of the influence of KP enzyme expression and activity in different cell types on the pathophysiological mechanisms of specific neuropsychiatric diseases. Moreover, the potential use of KP enzyme inhibition as a therapeutic strategy for treating neurological diseases is briefly discussed. This article is part of the Special Issue entitled 'The Kynurenine Pathway in Health and Disease'.
犬尿氨酸途径（KP）是大多数哺乳动物组织中色氨酸（TRP）代谢的主要途径。KP将TRP代谢为多种神经活性代谢产物，如犬尿氨酸（KYN）、犬尿酸（KYNA）、3-羟基犬尿氨酸（3-HK）和喹啉酸（QUIN）。中枢神经系统中代谢产物浓度升高与几种炎症相关神经精神疾病的病理生理学有关。在炎症反应期间，KP的初始代谢步骤主要受吲哚胺2,3-双加氧酶1（IDO1）调节，该酶从TRP产生KYN。在这一初始步骤之后，KP有2个不同的分支；一个分支受犬尿氨酸3-单加氧酶（KMO）调节，主要负责3-HK和QUIN的产生，另一个分支受犬尿氨酸转氨酶（KAT）调节，该酶产生KYNA，一种N-甲基-D-天冬氨酸受体和α-7-烟碱型乙酰胆碱受体拮抗剂。在不同的神经精神疾病中已证实KP代谢失衡；因此，了解调节KP酶表达和活性的机制很重要。这些酶由特定的细胞类型表达，炎症刺激对酶表达的诱导也表现出细胞类型特异性。本综述提供了概述，并讨论了目前对不同细胞类型中KP酶表达和活性对特定神经精神疾病病理生理机制影响的理解。此外，还简要讨论了抑制KP酶作为治疗神经疾病的治疗策略的潜在用途。本文是名为“健康与疾病中的犬尿氨酸途径”特刊的一部分。
