EFFECTS OF VARIOUS PRETREATMENTS ON THE HEPATOTOXICITY OF INHALED STYRENE IN THE B6C3F1 MOUSE

1. The roles of cytochrome P450 monooxygenases (P450) and glutathione (GSH) in styrene hepatotoxicity were investigated in mice by pretreati ng with either phenobarbital (PB; P450 inducer), SKF 525A (P450 inhibi tor), N-acetylcysteine (NAG; GSH precursor), or saline (vehicle contro l) prior to a 6-h exposure to either 500 ppm styrene on air. 2. Styren e caused hepatocellular degeneration or necrosis in all groups; these changes were more extensive and severe in mice pretreated with PB. Sty rene significantly increased relative liver weights and serum ALT and SDH levels only in mice pretreated with PB. NAC did not prevent GSH de pletion or hepatotoxicity. 3. In the fat of SKF 525A-pretreated mice a slight but statistically significant increase in styrene levels was o bserved, suggesting that metabolism was decreased; the SO/styrene rati o in the fat of PB-pretreated mice showed a slight, but statistically significant, increase indicating a slight increase in styrene metaboli sm. Neither SKF 525A nor PB caused changes in microsomal enzyme activi ty in vitro. 4. These results suggest that styrene may be activated by a pathway not totally dependent upon P450 enzyme activity, or more li kely that PB and SKF 525A are not specific for the P450 enzymes involv ed in activation and detoxification of styrene.