Oxenkrug Gregory F
Department of Psychiatry, Tufts University School of Medicine and Tufts Medical Center, Boston, Massachusetts 02111, USA.
Isr J Psychiatry Relat Sci. 2010;47(1):56-63.
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.
1969年发表在《柳叶刀》上的原始论文提出，在抑郁症中，肝脏色氨酸吡咯酶的活性会因血液中皮质类固醇水平升高而受到刺激，色氨酸的代谢会从血清素生成转向犬尿氨酸生成。犬尿氨酸的神经营养活性的发现表明，色氨酸-犬尿氨酸途径的上调不仅加剧了血清素缺乏，还突出了与抑郁症相关的焦虑、精神病和认知衰退。目前对调节色氨酸代谢犬尿氨酸途径的遗传和激素因素的综述表明，该途径介导了抑郁症的遗传和环境机制。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），分别被应激激素（TDO）和/或促炎细胞因子（IDO）激活。促炎细胞因子基因（如干扰素-γ和肿瘤坏死因子-α）的高产生者等位基因同时存在，通过上调IDO决定了抑郁症的遗传易感性，而环境应激的影响则通过TDO的激素激活来介导。色氨酸-犬尿氨酸途径是抑郁症中基因-环境相互作用的主要交汇点，也是药物干预的新靶点。
