Department of Natural Sciences, University of Michigan-Dearborn, Dearborn, Michigan 48128, USA.
Chem Res Toxicol. 2012 Mar 19;25(3):747-54. doi: 10.1021/tx200553p. Epub 2012 Mar 7.
Azaspiracids (AZA) are polyether marine toxins of dinoflagellate origin that accumulate in shellfish and represent an emerging human health risk. Although monitored and regulated in many European and Asian countries, there are no monitoring programs or regulatory requirements in the United States for this toxin group. This did not prove to be a problem until June 2009 when AZAs were identified in US seafood for the first time resulting in human intoxications and further expanding their global distribution. Efforts are now underway in several laboratories to better define the effects and mechanism(s) of action for the AZAs. Our investigations have employed Jurkat T lymphocyte cells as an in vitro model to characterize the toxicological effects of AZA1, AZA2, and AZA3. Cytotoxicity experiments employing a metabolically based dye (i.e., MTS) indicated that AZA1, AZA2, and AZA3 each elicited a lethal response that was both concentration- and time-dependent, with EC(50) values in the sub- to low nanomolar range. On the basis of EC(50) comparisons, the order of potency was as follows: AZA2 > AZA3 > AZA1, with toxic equivalence factors (TEFs) relative to AZA1 of 8.3-fold and 4.5-fold greater for AZA2 and AZA3, respectively. Image analysis of exposed cells using Nomarski differential interference contrast (DIC) imaging and fluorescent imaging of cellular actin indicated that the morphological effects of AZA1 on this cell type are unique relative to the effects of AZA2 and AZA3. Collectively, our data support the growing body of evidence suggesting that natural analogues of AZA are highly potent and that they may have multiple molecular targets.
azaspiracids (aza) 是由甲藻产生的聚醚海洋毒素，在贝类中积累，对人类健康构成新的风险。尽管在许多欧洲和亚洲国家进行了监测和监管，但美国没有针对该毒素组的监测计划或监管要求。直到 2009 年 6 月，aza 首次在美国海鲜中被发现导致人类中毒，并进一步扩大了其在全球的分布，这种情况才被证明是一个问题。目前，几个实验室正在努力更好地定义 aza 的作用效果和作用机制。我们的研究采用 jurkat t 淋巴细胞作为体外模型，来描述 aza1、aza2 和 aza3 的毒性作用。基于代谢的染料（即 mts）的细胞毒性实验表明，aza1、aza2 和 aza3 各自引起了一种致命的反应，这种反应既依赖于浓度又依赖于时间，ec50 值在亚纳摩尔到低纳摩尔范围内。基于 ec50 比较，效力顺序如下：aza2 > aza3 > aza1，aza2 和 aza3 的毒性等效因子（tef）相对于 aza1 分别增加了 8.3 倍和 4.5 倍。用诺马斯基微分干涉对比（dic）成像对暴露细胞进行图像分析和细胞肌动蛋白的荧光成像表明，aza1 对这种细胞类型的形态效应是独特的，与 aza2 和 aza3 的效应不同。总之，我们的数据支持越来越多的证据表明，aza 的天然类似物具有很高的效力，并且它们可能具有多个分子靶点。
