Oxidative and Conjugative Xenobiotic Metabolism in Zebrafish Larvae In Vivo
Oxidative and Conjugative Xenobiotic Metabolism in Zebrafish Larvae In Vivo
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DOI：
10.1089/zeb.2009.0630
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发表时间：
2010-03-01
期刊：
影响因子：
2
通讯作者：
Chipman, J. Kevin
中科院分区：
文献类型：
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作者：
Jones, Huw S.;Panter, Grace H.;Chipman, J. Kevin
随着斑马鱼幼体越来越多地应用于毒性测试，有必要了解这些早期生命阶段生物体的异源物质代谢潜力。在整个胚胎发育过程中，评估了与哺乳动物细胞色素P450（CYP）2B 6、CYP 3A 5和UDP-葡萄糖醛酸转移酶（UGT）1A 1以及斑马鱼CYP 1A相似的基因的表达。在受精后96小时检测到7-乙氧基试卤灵O-脱乙基酶（EROD测定）、7-乙氧基香豆素O-脱乙基酶（ECOD测定）和辛氧基甲基试卤灵（OOMR测定）的活性，在EROD测定中检测到显著的酚结合（p < 0.001）。在暴露于Aroclor 1254（100 μ g/L，24 h）后，观察到CYP 1A、CYP 1A基因zgc：153269和UGT 1A 1的诱导，具有显著的CYP 1A诱导（p < 0.01）。多氯联苯暴露也显著诱导EROD活性（p < 0.005），与α-萘酚酮共暴露也以剂量依赖性方式诱导EROD活性（p < 0.05; 5和10 μ M暴露）。不能证明SKF 525 A（5 μ M）对TNF活性的抑制，因为OOMR活性证明了显著的TNF诱导（p < 0.05）。这项研究表明，斑马鱼幼虫在整个早期发育过程中表达类似于哺乳动物β-内酰胺酶和UGT亚型的基因，并对模型β-内酰胺酶底物具有活性。这些基因和活动的调制，通过cytokine诱导剂也有报道。本研究支持在毒性试验中继续使用这些模式生物。
As zebrafish larvae are being increasingly applied to toxicity testing, there is a need to understand the potential for xenobiotic metabolism by these early life-stage organisms. The expression of genes similar to mammalian cytochromes P450 (CYP) 2B6, CYP3A5, and UDP-glucuronosyl transferase (UGT) 1A1, as well as the zebrafish CYP1A was assessed across embryonic development. Activities toward 7-ethoxyresorufin O-deethylase (EROD assay), 7-ethoxycoumarin O-deethylase (ECOD assay), and octyloxymethylresorufin (OOMR assay) were detected at 96 h postfertilization, as was significant phenolic conjugation in the EROD assay (p < 0.001). The induction of CYP1A, the CYP gene zgc:153269, and UGT1A1 after exposure to Aroclor 1254 (100 mu g/L, 24 h) was observed, with significant CYP1A induction (p < 0.01). Aroclor exposure also significantly induced EROD activity (p < 0.005), as did coexposure of alpha-naphthoflavone in a dose-dependent manner (p < 0.05; 5 and 10 mu M exposures). Inhibition of CYP activity by SKF525A (5 mu M) could not be demonstrated because of significant CYP induction as evidenced by OOMR activity (p < 0.05). This study demonstrates that zebrafish larvae express genes similar to mammalian CYP and UGT isoforms throughout early development and have activities toward model CYP substrates. The modulation of these genes and activities by CYP inducers is also reported. The continued use of these model organisms in toxicity testing is supported by this study.