US EPA

2858890 

Journal Article 

Mechanistic Investigation On Cytotoxicity Of Styrene 

Zheng, J; Chung, J; Yuan, W 

2004 

1 

Toxicologist
ISSN: 0731-9193 

TOX/4000932 

78 

1-S 

English 

Styrene (ST) is one of the most important industrial chemicals widely used in the production of many commercial polymers. Human exposures occur from such diverse sources as automobile exhaust, cigarette smoke, carpets, heating systems, painting and even food packaging. ST has been found to be toxic to respiratory system. Formation of styrene epoxide has been suggested to be initial step for cytotoxicity of ST, and CYP2E1 has been speculated as one of possible cytochrome P450 enzymes responsible for bioactivation of ST. To probe the role of CYP2E1, we exposed transgenic cell line expressing CYP2E1 and cHo1 cell line (wild-type and lt;2E1- /- and gt;) to ST and found CYP2E1 cells were more susceptible to ST than wild-type cells, indicating participation of CYP2E1 in ST cytotoxicity. To investigate the structure-activity relationships of ST, CYP2E1 cells were exposed to ST analogs ethyl benzene (EB), vinylcyclohexane (VH), and ethylcyclohexane (EH). EB and VH were found as toxic as ST, but EH showed no toxicity to the cells. This indicates that unsaturation (i.e. olefins) of ST analogs is required for their toxicity. Epoxides are known to be derived from olefins. We propose that EB and VH are metabolized to corresponding epoxides, and the resulting epoxide metabolites cause cell injury. To probe the role of epoxide metabolites in their cytotoxicity, we used glutathione derivatives and epoxide hydrolaes inhibitors as modulators. Ethyl glutathione ester was found to decrease cytotoxicity of ST, EB and VH, while soluble epoxide hydrolase inhibitors as well as microsomal epoxide hydrolase inhibitors dramatically increased cytotoxic effect of ST and the derivatives. In conclusion, CYP2E1 is an enzyme responsible for bioactivation of ST. Unsaturation is a critical structure required for ST cytotoxicity, and epoxide metabolites may play an important role in ST-induced cytotoxicity.