Mutations in monoamine oxidase (MAO) genes in mice lead to hypersensitivity to serotonin-enhancing drugs: implications for drug side effects in humans.
Mutations in monoamine oxidase (MAO) genes in mice lead to hypersensitivity to serotonin-enhancing drugs: implications for drug side effects in humans.
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小鼠单胺氧化酶（MAO）基因突变导致对血清素增强药物过敏：对人类药物副作用的影响。
DOI：
10.1038/tpj.2012.35
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Murphy,DL
中科院分区：
文献类型：
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作者：
Fox,MA;Panessiti,MG;Moya,PR;Tolliver,TJ;Chen,K;Shih,JC;Murphy,DL
血清素增强药物的一个可能的副作用是血清素综合症，这可能是致命的。在这里，我们检查了缺乏单胺氧化酶 A (MAOA) 和 MAOB 基因的小鼠对两种此类药物（血清素前体 5-羟基-L-色氨酸 (5-HTP) 和非典型阿片曲马多）可能的过敏情况。 MAOA/B 敲除 (KO) 小鼠表现出基线血清素综合征行为，并且与基线和野生型 (WT) 同窝小鼠相比，在使用 5-HTP 或曲马多后这些行为反应高度夸大。与 MAOA/B-WT 小鼠相比，MAOA/B-KO 小鼠的基线组织血清素水平增加约 2.6-3.9 倍。 5-HTP 后，MAOA/B-KO 小鼠的血清素水平进一步增加约 4.5-6.2 倍。这些夸张的反应与我们之前在缺乏血清素转运蛋白（SERT）的小鼠中观察到的血清素增强药物后的夸张反应一致。这些发现提供了第二种基因小鼠模型，表明人类可能对 MAO 或 SERT 多态性表达较少的个体易患血清素综合征，这些多态性会导致血清素能系统发生变化。
A possible side effect of serotonin-enhancing drugs is the serotonin syndrome, which can be lethal. Here we examined possible hypersensitivity to two such drugs, the serotonin precursor 5-hydroxy-L-tryptophan (5-HTP) and the atypical opioid tramadol, in mice lacking the genes for both monoamine oxidase A (MAOA) and MAOB. MAOA/B-knockout (KO) mice displayed baseline serotonin syndrome behaviors, and these behavioral responses were highly exaggerated following 5-HTP or tramadol versus baseline and wild-type (WT) littermates. Compared with MAOA/B-WT mice, baseline tissue serotonin levels were increased∼ 2.6–3.9-fold in MAOA/B-KO mice. Following 5-HTP, serotonin levels were further increased∼ 4.5–6.2-fold in MAOA/B-KO mice. These exaggerated responses are in line with the exaggerated responses following serotonin-enhancing drugs that we previously observed in mice lacking the serotonin transporter (SERT). These findings provide a second genetic mouse model suggestive of possible human vulnerability to the serotonin syndrome in individuals with lesser-expressing MAO or SERT polymorphisms that confer serotonergic system changes.