Department of Drug Metabolism and Pharmacokinetics, Archemix Corp., Cambridge, MA 02142, United States.
Toxicol Lett. 2012 May 5;210(3):353-9. doi: 10.1016/j.toxlet.2012.02.008. Epub 2012 Feb 16.
Styrene is one of the most important industrial intermediates consumed in the world and is mainly used as a monomer for reinforced plastics and rubber. Styrene has been found to be hepatotoxic and pneumotoxic in humans and experimental animals. The toxicity of styrene is suggested to be metabolism-dependent. Styrene-7,8-oxide has been considered as the major metabolite responsible for styrene-induced cytotoxicity. The objective of the study was to investigate the correlation between cytotoxicity of styrene and chemical and biochemical properties of the vinyl group of styrene by development of structure activity relationships (SAR). 4-Fluorostyrene, 4-chlorostyrene and 4-bromostyrene were selected for the SAR study. Cytotoxicity of styrene and the halogenated styrene derivatives with an order of 4-bromostyrene>4-chlorostyrene>4-fluorostyrene≈styrene was observed in CYP2E1 transgenic cells. Similar orders in the efficiency of the metabolism of styrene and the halogenated styrene analogues to their oxides and in the electrophilicity of the corresponding oxides were observed. Additionally, the order of the potency of cellular glutathione depletion and the degree of protein adduction induced by styrene and the halogenated styrenes were consistent with that of their cytotoxicities. The wild-type cells were less susceptible to the toxicity of the corresponding model compounds than CYP2E1 cells. The present study provided insight into the roles of the biochemical and chemical properties of styrene in its cytotoxicity.
苯乙烯是世界上最重要的工业中间体之一，主要用作增强塑料和橡胶的单体。苯乙烯已被发现对人类和实验动物具有肝毒性和肺毒性。苯乙烯的毒性被认为是代谢依赖性的。苯乙烯-7,8-氧化物已被认为是导致苯乙烯细胞毒性的主要代谢物。本研究的目的是通过发展构效关系（SAR）研究苯乙烯的细胞毒性与苯乙烯乙烯基的化学和生化性质之间的相关性。选择 4-氟苯乙烯、4-氯苯乙烯和 4-溴苯乙烯进行 SAR 研究。在 CYP2E1 转基因细胞中观察到苯乙烯和卤代苯乙烯衍生物的细胞毒性顺序为 4-溴苯乙烯>4-氯苯乙烯>4-氟苯乙烯≈苯乙烯。观察到苯乙烯和卤代苯乙烯类似物对其氧化物的代谢效率以及相应氧化物的亲电性的相似顺序。此外，细胞谷胱甘肽耗竭的效力和苯乙烯和卤代苯乙烯引起的蛋白质加合物程度的顺序与它们的细胞毒性一致。野生型细胞比 CYP2E1 细胞对相应模型化合物的毒性的敏感性较低。本研究深入了解了苯乙烯的生化和化学性质在其细胞毒性中的作用。
