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首页> 外文期刊>Life sciences >Comparative study of toxicological and cell cycle effects of okadaic acid and dinophysistoxin-2 in primary rat hepatocytes
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Comparative study of toxicological and cell cycle effects of okadaic acid and dinophysistoxin-2 in primary rat hepatocytes

机译：冈田酸和dinophysistoxin-2在原代大鼠肝细胞中的毒理学和细胞周期效应的比较研究

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Aims: To determine the relative toxicity and effects on the cell cycle of okadaic acid and dinophysistoxin-2 in primary hepatocyte cultures. Main methods: Cytotoxicity was determined by the MTT method, caspase-3 activity and lactate dehydrogenase release to the medium. The cell cycle analysis was performed by imaging flow cytometry and the effect of the toxins on cell proliferation was studied by quantitative PCR and confocal microscopy. Key findings: We show that dinophysistoxin-2 is less toxic than okadaic acid for primary hepatocytes with a similar difference in potency as that observed in vivo in mice after intraperitoneal injection. Both toxins induced apoptosis with caspase-3 increase. They also inhibited the hepatocytes cell cycle in G1 affecting diploid cells and diploid bi-nucleated cells. In proliferating hepatocytes exposed to the toxins, a decrease of p53 gene expression as well as a lower protein level was detected. Studies of the tubulin cytoskeleton in toxin treated cells, showed nuclear localization of this molecule and a granulated tubulin pattern in the cytoplasm. Significance: The results presented in this work show that the difference in toxicity between dinophysistoxin-2 and okadaic acid in cultured primary hepatocytes is the same as that observed in vivo after intraperitoneal injection. Okadaic acid and dinophysistoxin-2 arrest the cell cycle of hepatocytes at G1 even in diploid bi-nucleated cells. p53 and tubulin could be involved in the cell cycle inhibitory effect.
机译：目的：确定冈田酸和dinophysistoxin-2在原代肝细胞培养物中的相对毒性及其对细胞周期的影响。主要方法：用MTT法测定细胞毒性，caspase-3活性和乳酸脱氢酶释放到培养基中。通过成像流式细胞仪进行细胞周期分析，并通过定量PCR和共聚焦显微镜研究了毒素对细胞增殖的影响。关键发现：我们显示，对于腹腔注射后的小鼠，原发性肝细胞中的dinophysistoxin-2的毒性低于冈田酸，其功效与体内相似。两种毒素均诱导凋亡，caspase-3增加。他们还抑制了G1中的肝细胞周期，从而影响二倍体细胞和二倍体双核细胞。在暴露于毒素的增殖肝细胞中，检测到p53基因表达下降以及蛋白质水平降低。对毒素处理过的细胞中微管蛋白细胞骨架的研究表明，该分子的核定位和细胞质中颗粒状的微管蛋白模式。启示：这项工作的结果表明，在培养的原代肝细胞中，狄诺氏菌毒素2和冈田酸之间的毒性差异与腹膜内注射后体内观察到的相同。冈田酸和dinophysistoxin-2甚至在二倍体双核细胞中也阻止了肝细胞在G1的细胞周期。 p53和微管蛋白可能参与细胞周期抑制作用。

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