Max-Delbrück Center for Molecular Medicine (MDC), Robert-Rössle-Straße 10, 13125 Berlin-Buch, Germany; University of Lübeck, Institute for Biology, Ratzeburger Allee 160, 23562 Lübeck, Germany.
Max-Delbrück Center for Molecular Medicine (MDC), Robert-Rössle-Straße 10, 13125 Berlin-Buch, Germany; University of Lübeck, Institute for Biology, Ratzeburger Allee 160, 23562 Lübeck, Germany; Berlin Institute of Health (BIH), Anna-Louisa-Karsch-Straße 2, 10178 Berlin, Germany; Charité University Medicine, Charitéplatz 1, 10117 Berlin, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany.
Trends Pharmacol Sci. 2018 Jun;39(6):560-572. doi: 10.1016/j.tips.2018.03.004. Epub 2018 Apr 5.
The first step in serotonin (5-HT) biosynthesis is catalyzed by tryptophan hydroxylase (TPH). There are two independent sources of the monoamine that have distinct functions: first, the TPH1-expressing enterochromaffin cells (ECs) of the gut; second, TPH2-expressing serotonergic neurons. TPH1-deficient mice revealed that peripheral 5-HT plays important roles in platelet function and in inflammatory and fibrotic diseases of gut, pancreas, lung, and liver. Therefore, TPH inhibitors were developed which cannot pass the blood-brain barrier to specifically block peripheral 5-HT synthesis. They showed therapeutic efficacy in several rodent disease models, and telotristat ethyl is the first TPH inhibitor to be approved for the treatment of carcinoid syndrome. We review this development and discuss further therapeutic options for these compounds.
5-羟色胺（5-HT）生物合成的第一步由色氨酸羟化酶（TPH）催化。有两种独立的单胺来源，具有不同的功能：首先是肠道表达 TPH1 的肠嗜铬细胞（EC）；其次是表达 TPH2 的 5-羟色胺能神经元。TPH1 缺陷型小鼠揭示了外周 5-HT 在血小板功能以及肠道、胰腺、肺和肝脏的炎症和纤维化疾病中发挥重要作用。因此，开发了不能通过血脑屏障特异性阻断外周 5-HT 合成的 TPH 抑制剂。它们在几种啮齿动物疾病模型中显示出治疗效果，而替洛曲特乙酯是第一种被批准用于治疗类癌综合征的 TPH 抑制剂。我们回顾了这一发展，并讨论了这些化合物的进一步治疗选择。
