Ronidazole Is a Superior Prodrug to Metronidazole for Nitroreductase-Mediated Hepatocytes Ablation in Zebrafish Larvae
Ronidazole Is a Superior Prodrug to Metronidazole for Nitroreductase-Mediated Hepatocytes Ablation in Zebrafish Larvae
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DOI：
10.1089/zeb.2022.0066
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发表时间：
2023-05-25
期刊：
影响因子：
2
通讯作者：
Zou, Qingliang
中科院分区：
文献类型：
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作者：
Chen, Yuhang;Li, Peipei;Zou, Qingliang
肝脏在人体的生理过程中起着非常重要的作用。肝再生已成为肝病研究的重要领域。MTZ(甲硝唑)/NTR(硝基还原酶)介导的细胞消融系统已被广泛用于研究肝损伤和再生的过程和机制。然而，MTZ的高浓度和毒副作用严重限制了MTZ/NTR系统的应用。因此，筛选新的类似物来替代MTZ已成为优化NTR消融系统的重要手段。在本研究中，我们筛选了五个甲氨蝶呤类似物，包括呋喃唑酮、硝硝唑、奥硝唑、硝胺和替硝唑。我们比较了它们对转基因鱼类Tg(Fabp10a：mCherry-NTR)的毒性和对肝细胞的特异性消融能力。结果表明，较低浓度(2 MM)的罗硝唑对肝细胞的消融能力与甲氨蝶呤(10 MM)相当，对幼鱼几乎没有毒副作用。进一步研究发现，罗硝唑/NTR系统对斑马鱼肝细胞的损伤达到了与MTZ/NTR系统相同的肝脏再生效果。以上结果表明，在斑马鱼肝脏中，罗硝唑可以替代MTZ和NTR，达到更好的损伤和消融效果。
The liver plays a very important role in physiological processes of the human body. Liver regeneration has developed into an important area of study in liver disease. The Mtz (metronidazole)/NTR (nitroreductase)-mediated cell ablation system has been widely used to study the processes and mechanisms of liver injury and regeneration. However, high concentrations and toxic side effects of Mtz severely limit the application of the Mtz/NTR system. Therefore, screening new analogs to replace Mtz has become an important means to optimize the NTR ablation system. In this study, we screened five Mtz analogs including furazolidone, ronidazole, ornidazole, nitromide, and tinidazole. We compared their toxicity on the transgenic fish line Tg(fabp10a: mCherry-NTR) and their specific ablation ability on liver cells. The results showed that Ronidazole at a lower concentration (2 mM) had the same ability to ablate liver cells comparable with that of Mtz (10 mM), almost without toxic side effects on juvenile fish. Further study found that zebrafish hepatocyte injury caused by the Ronidazole/NTR system achieved the same liver regenerative effect as the Mtz/NTR system. The above results show that Ronidazole can replace Mtz with NTR to achieve superior damage and ablation effects in zebrafish liver.