Diodovich Cristina, Urani Chiara, Maurici Daniela, Malerba Ilaria, Melchioretto Pasquale, Orlandi Marco, Zoia Luca, Campi Valentina, Carfi' Maria, Pellizzer Cristian, Gribaldo Laura
ECVAM, Institute for Health and Consumer Protection, JRC, Ispra, Italy.
J Appl Toxicol. 2006 Jul-Aug;26(4):317-25. doi: 10.1002/jat.1142.
Styrene is one of the most important monomers produced worldwide. IARC classified styrene as a possible carcinogen to humans (group 2B). Styrene-7,8-oxide (SO) is the main reactive metabolite of styrene, and it is found to be genotoxic in several in vitro test systems. Styrene and styrene-7,8-oxide (SO) toxicity to HepG2 cells was investigated by evaluating end-points such as heat shock proteins (Hsps), metallothioneins (MT), apoptosis-related proteins, accumulation of styrene within the cells and expression of two isoforms of cytochrome P450. The potential activity of styrene and styrene-7,8-oxide in modulating gene expression was also investigated. The results showed induction of Hsp70, metallothioneins, BclX(S/L) and c-myc expression and a decrease in Bax expression in HepG2 after treatments, confirming that these compounds activated protective mechanisms. Moreover, up-regulation of TGFbeta2 and TGFbetaRIII in HepG2 cells was found after exposure to styrene, while in human primary hepatocytes these genes were down-regulated after both treatments. Finally, it was found that styrene and SO treatments did not induce CYP1A2 and CYP2E1 protein expression. In conclusion, both compounds caused toxic stress in HepG2 cells, with SO being more toxic; in the meantime, a different effect of the two compounds in HepG2 cells and primary human hepatocytes was observed regarding their activity in gene modulation.
苯乙烯是全球生产的最重要单体之一。国际癌症研究机构将苯乙烯归类为对人类可能的致癌物（2B组）。苯乙烯-7,8-氧化物（SO）是苯乙烯的主要活性代谢产物，并且在多个体外测试系统中被发现具有遗传毒性。通过评估热休克蛋白（Hsps）、金属硫蛋白（MT）、凋亡相关蛋白、细胞内苯乙烯的积累以及细胞色素P450两种同工型的表达等终点指标，研究了苯乙烯和苯乙烯-7,8-氧化物（SO）对HepG2细胞的毒性。还研究了苯乙烯和苯乙烯-7,8-氧化物在调节基因表达方面的潜在活性。结果显示，处理后HepG2细胞中Hsp70、金属硫蛋白、BclX(S/L)和c-myc的表达被诱导，而Bax表达下降，证实这些化合物激活了保护机制。此外，暴露于苯乙烯后，HepG2细胞中TGFbeta2和TGFbetaRIII上调，而在人原代肝细胞中，两种处理后这些基因均下调。最后，发现苯乙烯和SO处理未诱导CYP1A2和CYP2E1蛋白表达。总之，两种化合物均在HepG2细胞中引起毒性应激，其中SO毒性更强；同时，观察到两种化合物在HepG2细胞和人原代肝细胞中对基因调节的活性存在不同影响。
