Chlebowski Anna C, La Du Jane K, Truong Lisa, Massey Simonich Staci L, Tanguay Robert L
Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, 97331.
Department of Chemistry, Oregon State University, Corvallis, OR, 97331.
Toxicol Rep. 2017;4:202-210. doi: 10.1016/j.toxrep.2017.04.005. Epub 2017 Apr 27.
Nitroreductase enzymes are responsible for the reduction of nitro functional groups to amino functional groups, and are found in a range of animal models, zebrafish () excluded. Transgenic zebrafish models have been developed for tissue-specific cell ablation, which use nitroreductase to ablate specific tissues or cell types following exposure to the non-toxic pro-drug metronidazole (MTZ). When metabolized by nitroreductase, MTZ produces a potent cytotoxin, which specifically ablates the tissue in which metabolism occurs. Uses, beyond tissue-specific cell ablation, are possible for the hepatocyte-specific zebrafish line, including investigations of the role of nitroreductase in the toxicity of nitrated compounds. The hepatic ablation characteristics of this transgenic line were explored, in order to expand its potential uses. Embryos were exposed at 48, 72, or 96 hours post fertilization (hpf) to a range of MTZ concentrations, and the ablation profiles were compared. Ablation occurred at a 10-fold lower concentration than previously reported. Embryos were exposed to a selection of other compounds, with and without MTZ, in order to investigate alternative uses for this transgenic line. Test compounds were selected based on: their ability to undergo nitroreduction, known importance of hepatic metabolism to toxicity, and known pharmaceutical hepatotoxins. Selected compounds included nitrated polycyclic aromatic hydrocarbons (nitro-PAHs), the PAHs retene and benzo[a]pyrene, and the pharmaceuticals acetaminophen and flutamide. The results suggest a range of potential roles of the liver in the toxicity of these compounds, and highlight the additional uses of this transgenic model in toxicity testing.
硝基还原酶负责将硝基官能团还原为氨基官能团，在一系列动物模型中都有发现，斑马鱼除外。已经开发出用于组织特异性细胞消融的转基因斑马鱼模型，该模型利用硝基还原酶在暴露于无毒前体药物甲硝唑（MTZ）后消融特定组织或细胞类型。当被硝基还原酶代谢时，MTZ会产生一种强效细胞毒素，该毒素会特异性地消融发生代谢的组织。对于肝细胞特异性斑马鱼品系而言，除了组织特异性细胞消融之外，还有其他用途，包括研究硝基还原酶在硝化化合物毒性中的作用。为了扩大其潜在用途，对该转基因品系的肝脏消融特性进行了探索。在受精后48、72或96小时（hpf）将胚胎暴露于一系列MTZ浓度下，并比较消融情况。消融发生时的浓度比之前报道的低10倍。为了研究该转基因品系的其他用途，将胚胎暴露于一系列其他化合物中，有MTZ和无MTZ的情况都有。选择测试化合物的依据是：它们进行硝基还原的能力、已知的肝脏代谢对毒性的重要性以及已知的药物性肝毒素。所选化合物包括硝化多环芳烃（nitro-PAHs）、多环芳烃惹烯和苯并[a]芘，以及药物对乙酰氨基酚和氟他胺。结果表明肝脏在这些化合物毒性中具有一系列潜在作用，并突出了该转基因模型在毒性测试中的其他用途。
