An Investigation of the Bioactivation Potential and Metabolism Profile of Zebrafish versus Human
An Investigation of the Bioactivation Potential and Metabolism Profile of Zebrafish versus Human
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DOI：
10.1177/1087057112447305
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发表时间：
2012-08-01
影响因子：
--
通讯作者：
Chan, Eric Chun Yong
中科院分区：
文献类型：
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作者：
Chng, Hui Ting;Ho, Han Kiat;Chan, Eric Chun Yong
斑马鱼模型作为药物毒性筛选的替代模型已被越来越多地探索。然而，与人类相比，人们对斑马鱼体内药物对活性代谢物的生物活化和化学物质的I、II期代谢的了解甚少。本研究的主要目的是利用对乙酰氨基酚作为探针底物，建立斑马鱼的生物激活电位。我们的第二个目的是在斑马鱼中对CYP3A探针底物睾酮进行代谢物谱分析实验，并将代谢物谱与人类的代谢物谱进行比较。n -乙酰-对苯醌亚胺谷胱甘肽捕获试验表明，斑马鱼在对乙酰氨基酚的生物活化过程中产生与人类相同的反应性代谢物。斑马鱼具有功能性cyp3a4 /5样和udp -葡萄糖醛基转移酶对睾酮的代谢活性。睾酮代谢在两个物种中存在差异。硅对接研究表明，斑马鱼CYP3A65负责对乙酰氨基酚的生物活化和睾酮的I期羟基化。我们的研究结果表明，在斑马鱼模型能够充分发挥其作为药物研究中替代毒性筛选模型的潜力之前，需要进一步表征斑马鱼的药物代谢表型。
The zebrafish model has been increasingly explored as an alternative model for toxicity screening of pharmaceutical drugs. However, little is understood about the bioactivation of drug to reactive metabolite and phase I and II metabolism of chemical in zebrafish as compared with human. The primary aim of our study was to establish the bioactivation potential of zebrafish using acetaminophen as a probe substrate. Our secondary aim was to perform metabolite profiling experiments on testosterone, a CYP3A probe substrate, in zebrafish and compare the metabolite profiles with that of human. The glutathione trapping assay of N-acetyl-p-benzoquinone imine demonstrated that zebrafish generates the same reactive metabolite as humans from the bioactivation of acetaminophen. Zebrafish possesses functional CYP3A4/5-like and UDP-glucuronosyltransferase metabolic activities on testosterone. Differential testosterone metabolism was observed among the two species. In silico docking studies suggested that the zebrafish CYP3A65 was responsible for the bioactivation of acetaminophen and phase I hydroxylation of testosterone. Our findings reinforce the need to further characterize the drug metabolism phenotype of zebrafish before the model can fully achieve its potential as an alternative toxicity screening model in drug research.