Comparison of styrene and its metabolites styrene oxide and 4-vinylphenol on cytotoxicity and glutathione depletion in Clara cells of mice and rats
Comparison of styrene and its metabolites styrene oxide and 4-vinylphenol on cytotoxicity and glutathione depletion in Clara cells of mice and rats
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DOI：
10.1016/j.tox.2006.08.001
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发表时间：
2006-10-03
期刊：
影响因子：
4.5
通讯作者：
Carlson, Gary P.
中科院分区：
文献类型：
--
作者：
Harvilchuck, Jill A.;Carlson, Gary P.
苯乙烯是制造业中广泛使用的化合物。在小鼠和大鼠中，它具有肝毒性和肺毒性。它会导致小鼠肺肿瘤，但不会导致大鼠肺肿瘤。Clara细胞是苯乙烯及其代谢产物毒性作用的主要靶细胞，也是苯乙烯代谢活性最大的细胞。因此，从CD-1小鼠和Sprague-Dawley大鼠分离的Clara细胞用于比较苯乙烯及其代谢产物诱导的细胞毒性。苯乙烯的细胞毒性在体外大于其代谢产物氧化苯乙烯（外消旋，R-和S-）和4-乙烯基苯酚，与之前的肝毒性和肺毒性研究中观察到的体内细胞毒性相反。大鼠对苯乙烯及其代谢物的敏感性比小鼠低4倍。在体外加入化学品和体内处理CD-1小鼠后，还测量了小鼠中的谷氨酰胺水平。即使在未导致小鼠Clara细胞死亡的剂量下，也观察到谷胱甘肽浓度降低。谷胱甘肽显着减少，观察外消旋SO和R-SO治疗后3小时。在12小时时，所有化合物均观察到反弹效应，除R-SO外，所有化合物均反弹至对照组以上。这些研究表明，苯乙烯及其代谢产物的体外细胞毒性并不严格遵循体内效应，小鼠谷胱甘肽水平的降低可能与氧化应激有关。(c)2006爱思唯尔爱尔兰有限公司保留所有权利。
Styrene is a widely used compound in the manufacturing industry. In mice and rats, it is both hepatotoxic and pneumotoxic. It causes lung tumors in mice, but not in rats. The Clara cell is the main target for the toxicity of styrene and its metabolites, and it also has the greatest activity for styrene metabolism. Therefore, Clara cells isolated from CD-1 mice and Sprague-Dawley rats were used to compare the cytotoxicities induced by styrene and its metabolites. The cytotoxicity of styrene was greater in vitro than that of its metabolites styrene oxide (racemic, R- and S-) and 4-vinylphenol in contrast with what has been observed in vivo in previous studies on hepatotoxicity and pneumotoxicity. Susceptibility of rats to styrene and its metabolites are 4-fold less than that observed with mice. Glutathione levels were also measured in mice following addition of the chemicals in vitro and treatment of the CD-1 mice in vivo. Decreases in glutathione concentrations were seen even at doses which did not cause the death of mouse Clara cells. Significant decreases in glutathione were observed 3 h after treatment with racemic SO and R-SO. At 12 h, rebound effects were seen for all compounds, with all but R-SO rebounding above controls. These studies suggest that in vitro cytotoxicity of styrene and its metabolites does not strictly follow in vivo effects and that decreases in mouse glutathione levels may be related to oxidative stress. (c) 2006 Elsevier Ireland Ltd. All rights reserved.