The metabolites could not be ignored: A comparative study of the metabolite norfluoxetine with its parent fluoxetine on zebrafish (Danio rerio)
The metabolites could not be ignored: A comparative study of the metabolite norfluoxetine with its parent fluoxetine on zebrafish (Danio rerio)
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DOI：
10.1016/j.aquatox.2023.106467
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发表时间：
2023-03-02
影响因子：
4.5
通讯作者：
Lu，Guanghua
中科院分区：
文献类型：
--
作者：
Yan，Zhenhua;Chen，Yufang;Lu，Guanghua
水环境中无处不在的药物因其对人类和生态系统的重大风险而引起了人们的极大关注。然而，尽管对母体药物的负面影响的了解相当广泛，但长期以来对其代谢物的了解却很少。本研究对代谢产物诺氟西汀及其母体氟西汀对斑马鱼(Danio Rerio)早期的潜在毒性提供了系统的认识。结果表明，代谢物氟西汀对鱼类的急性毒性与亲本氟西汀相似。对于改变的鱼类发育，在大多数情况下，两种药物之间没有显著差异。与对照相比，该代谢物显著抑制了小鼠在明暗转换下的运动行为，与亲本相当。与氟西汀相比，氟西汀在鱼体中容易蓄积，但很难消除。此外，斑马鱼体内积累的氟西汀可能会迅速代谢成诺氟西汀，然后通过不同的代谢途径被消除。与5-羟色胺能过程(5-HT1aa、5-HT2C、slc6a4b和vmat)、早期生长(Egr4)和昼夜节律(PER2)相关的功能基因均被去氟西汀和氟西汀下调，表明去氟西汀在这些功能中的作用模式与其亲本相同。同时，氟西汀引起的5-HT2C、slc6a4b、VMAT和per2基因的改变比氟西汀更明显。分子对接也证实了诺氟西汀与5-羟色胺转运蛋白的结合能与氟西汀相同，结合自由能更低。总体而言，代谢产物诺氟西汀对斑马鱼具有相同的作用模式，可引起类似甚至更大的毒性效应。代谢产物氟西汀与母体氟西汀在斑马鱼上的不同结合能可能是导致斑马鱼分化的原因之一。它突显了代谢物去氟西汀在水环境中的风险不容忽视。
The ubiquitous pharmaceuticals in aquatic environments have attracted huge attention due to their significant risks to humans and ecosystems. However, even though the knowledge of the negative effects induced by the parent pharmaceuticals is quite extensive, little is known about their metabolites for a long time. This study provides systematical knowledge about the potential toxicity of metabolite norfluoxetine and its parent fluoxetine on zebrafish (Danio rerio) at the early life stage. The results showed that the metabolite norfluoxetine had similar acute toxicity in fish with the parent fluoxetine. For the altered fish development, there was no significant difference in most cases between the two pharmaceuticals. Compared to the control, the metabolite markedly inhibited the locomotor behavior under light-to-dark transitions, which was comparable to the parent. Norfluoxetine could easily accumulate but hardly eliminate from fish, relative to fluoxetine. In addition, the accumulated fluoxetine in zebrafish may rapidly metabolize to norfluoxetine and then be eliminated through different metabolic pathways. The functional genes related to serotonergic process (5-ht1aa, 5-ht2c, slc6a4b,andvmat), early growth (egr4), and circadian rhythm (per2) were downregulated by both the norfluoxetine and fluoxetine, indicative of the same mode-of-action of norfluoxetine with its parent in these functions. Meanwhile, the alterations caused by norfluoxetine were more pronounced than that of fluoxetine in the genes of5-ht2c, slc6a4b, vmat,andper2. The molecular docking also confirmed that norfluoxetine could bind with serotonin transporter protein in the same as fluoxetine with a lower binding free energy. Overall, the metabolite norfluoxetine could induce similar and even more toxic effects on zebrafish with the same mode of action. The different and binding energy of the metabolite norfluoxetine and its parent fluoxetine on zebrafish may be responsible for the differentiated effects. It highlights the risks of the metabolite norfluoxetine in the aquatic environment could not be ignored.