Evaluation of the genotoxic potential of the natural neurotoxin Tetrodotoxin (TTX) in a battery of in vitro and in vivo genotoxicity assays
Evaluation of the genotoxic potential of the natural neurotoxin Tetrodotoxin (TTX) in a battery of in vitro and in vivo genotoxicity assays
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DOI：
10.1016/j.mrgentox.2007.05.016
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发表时间：
2007-12-01
影响因子：
1.9
通讯作者：
Pritchard, Lincoln
中科院分区：
文献类型：
--
作者：
Guzman, Antonio;de Henestrosa, Antonio R. Fernandez;Pritchard, Lincoln
在一组体外和体内遗传毒性试验中评价了天然神经毒素河豚毒素（TTX）的遗传毒性潜力。这些试验包括细菌回复突变试验（艾姆斯试验）、体外人淋巴细胞染色体畸变试验、体内小鼠骨髓微核试验和体内大鼠肝脏UDS试验。体外试验中的最大试验浓度由制剂溶媒（0.02%乙酸溶液）中TTX的溶解度限度确定。在艾姆斯试验中，TTX浓度高达200 μ g/板。在染色体畸变试验中，人淋巴细胞在不存在S9的情况下暴露于浓度高达50 μ g/ml的TTX 3和20 h，在存在S9的情况下暴露于TTX 3 h。对于体内试验，通过皮下给药后TTX的急性致死毒性确定最大试验剂量水平。在小鼠微核试验中，对雄性和雌性动物给予2、4和8 μ g/kg剂量水平的TTX，并在给药后24和48 h（仅高剂量动物）采集骨髓样品。在UDS试验中，雄性大鼠给予TTX两次，间隔14小时，剂量水平为2.4和8 μ g/kg，最后一次剂量在肝脏灌注和肝细胞培养前2小时给药。所有试验均包括相关溶剂和阳性对照培养物和动物。在本研究中进行的试验中，明确显示TTX缺乏体外或体内遗传毒性活性。结果表明，TTX作为治疗性镇痛剂给药不会对患者造成遗传毒性风险。(c)2007 Elsevier B. V.保留所有权利。
The genotoxic potential of the natural neurotoxin Tetrodotoxin (TTX) was evaluated in a battery of in vitro and in vivo genotoxicity assays. These comprised a bacterial reverse-mutation assay (Ames test), an in vitro human lymphocyte chromosome-aberration assay, an in vivo mouse bone-marrow micronucleus assay and an in vivo rat-liver UDS assay.Maximum test concentrations in in vitro assays were determined by the TTX limit of solubility in the formulation vehicle (0.02% acetic acid solution). In he Ames test, TTX was tested at concentrations of up to 200 mu g/plate, In he chromosome-aberration assay human lymphocytes were exposed to TTX at concentrations of up to 50 mu g/ml for 3 and 20 h in the absence of S9, and for 3 h in the presence of S9. For the in vivo assays, maximum tested dose levels were determined by the acute lethal toxicity of TTX after subcutaneous administration. In the mouse micronucleus assay TTX dose levels of 2, 4 and 8 mu g/kg were administered to male and female animals, and bone-marrow samples taken 24 and 48 h (high-dose animals only) after administration. In the UDS assay, male rats were given TTX on two occasions with a 14-h interval at dose levels of 2.4 and 8 mu g/kg, the last dose being administered 2 h before liver perfusion and hepatocyte culturing. Relevant vehicle and positive control cultures and animals were included in all assays.TTX was clearly shown to lack in vitro or in vivo genotoxic activity in the assays conducted in this study. The results suggest that administration of TTX as a therapeutic analgesic agent would not pose a genotoxic risk to patients. (c) 2007 Elsevier B.V. All rights reserved.