Structure-toxicity relationship study of para-halogenated styrene analogues in CYP2E1 transgenic cells

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.

► We investigated the structure-toxicity relationship of halogenated styrenes.
► Cytotoxicity order: 4-bromostyrene > 4-chlorostyrene > 4-fluorostyrene ≈ styrene.
► Bioactivation of the styrenes follows the same order of their toxicities.
► GSH depletion and protein covalent binding are consistent with their toxicities.
► The results indicate bioactivation of styrene is correlated with its cytotoxicity.