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The Toxicological Mechanism Of Styrene In CYP2E1 Transgenic Cells
Chung, J; Yuan, W; Zheng, J
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Styrene has been found to be toxic to the respiratory system, and the toxicity of styrene is metabolism-dependent. CYP2E1 is suggested to be one of the cytochrome P450 enzymes responsible for the bioactivation of styrene. As an initial step to understand the mechanism of cytotoxicity of styrene, we investigated the role of CYP2E1 and styrene oxide metabolite in the cytotoxicity induced by styrene as following. Styrene was found to be more toxic to CYP2E1 cells than to the wildtype, while there was no difference observed in cytotoxicity to the two cell lines after exposure to styrene oxide. Both soluble and microsomal epoxide hydrolase inhibitors dramatically enhanced styrene toxicity. Glutathione and glutathione ethyl ester showed protection against styrene cytotoxicity. We also developed a GST (hGSTP isozyme) transgenic cell line from the CYP2E1 cells. The GST transgenic cells (CYP2E1-GST+) was found to be less susceptible to styrene than the corresponding wild-type cells. In addition, we developed structure-activity (toxicity) relationships of styrene. The cytotoxicity of a selection of styrene analogues, including ethylbenzene, vinylcyclohexane, and ethylcyclohexane, was assessed to determine if unsaturation is required for styrene toxicity. Both ethylbenzene and vinylcyclohexane were found to be as toxic as styrene to CYP2E1 cells, whereas little toxicity of ethylcyclohexane to CYP2E1 cells observed. This indicates that the double bonds (? system) are essential for styrene cytotoxicity. An N-acetylcysteine conjugate derived from styrene oxide was identified by LC/MS/MS in the sample obtained from the incubation of CYP2E1 cell lysate with styrene in the presence of N-acetylcysteine. The formation of the N-acetylcysteine conjugate was also found to be NADPH-dependent. Our studies clearly demonstrated the toxicological role of CYP2E1 and styrene oxide metabolite in cell injury induced by styrene.
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