Tryptophan kynurenine metabolism as a common mediator of genetic and environmental impacts in major depressive disorder: the serotonin hypothesis revisited 40 years later.
Tryptophan kynurenine metabolism as a common mediator of genetic and environmental impacts in major depressive disorder: the serotonin hypothesis revisited 40 years later.
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发表时间：
2010
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通讯作者：
G. Oxenkrug
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作者：
G. Oxenkrug
1969年《柳叶刀》的原始论文提出，抑郁症患者的肝脏中色氨酸吡咯酶的活性受到血液皮质类固醇水平升高的刺激，色氨酸的代谢从5-羟色胺的产生转向犬尿氨酸的产生。犬尿氨酸的亲神经活性的发现表明，Dahan-犬尿氨酸途径的上调不仅增强了5-羟色胺缺乏症，而且强调了抑郁症相关的焦虑、精神病和认知能力下降。本文综述了影响色氨酸代谢犬尿氨酸途径的遗传和激素因素，认为该途径在抑郁症的遗传和环境机制中起重要作用。犬尿氨酸形成的限速酶色氨酸2，3-双加氧酶（TDO）和吲哚胺2，3-双加氧酶（IDO）被应激激素（TDO）和/或促炎细胞因子（IDO）激活。同时存在促炎细胞因子基因的高生产者等位基因（例如，干扰素-γ和肿瘤坏死因子-α）通过IDO的上调决定抑郁症的遗传倾向，而环境应激的影响通过TDO的激素激活介导。色氨酸-犬尿氨酸通路是抑郁症基因-环境相互作用的重要交汇点，也是药物干预的新靶点。
The original 1969 Lancet paper proposed in depression the activity of liver tryptophan-pyrrolase is stimulated by raised blood corticosteroids levels, and metabolism of tryptophan is shunted away from serotonin production, and towards kynurenine production. Discovery of neurotropic activity of kynurenines suggested that up-regulation of the tryptophan-kynurenine pathway not only augmented serotonin deficiency but also underlined depression-associated anxiety, psychosis and cognitive decline. The present review of genetic and hormonal factors regulating kynurenine pathway of tryptophan metabolism suggests that this pathway mediates both genetic and environmental mechanisms of depression. Rate-limiting enzymes of kynurenine formation, tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) are activated by stress hormones (TDO) and/or by pro-inflammatory cytokines (IDO). Simultaneous presence of high producers alleles of proinflammatory cytokines genes (e.g., interferon-gamma and tumor necrosis factor-alpha) determines the genetic predisposition to depression via up-regulation of IDO while impact of environmental stresses is mediated via hormonal activation of TDO. Tryptophan-kynurenine pathway represents a major meeting point of gene-environment interaction in depression and a new target for pharmacological intervention.