The effects of various inducers and inhibitors of hepatic microsomal mixed-function oxidase (MFO) system and diethylmaleate treatment on styrene-induced acute nephrotoxicity in male Fischer-344 rats were studied. Groups of rats were pretreated with either 3-methylcholanthrene (15 mg/kg, i.p., 3 days), or phenobarbital (80 mg/kg, i.p., 3 days), or SKF525-A (50 mg/kg, i.p., 1 h), or piperonyl butoxide (300 mg/kg, i.p., 2 h), or diethylmaleate (400 mg/kg, i.p., 90 min) prior to an i.p. administration of styrene (0, 0.6 and 0.9 g/kg) in corn oil. The uptake of p-aminohippurate (PAH) by renal cortical slices, the morphology of renal cortices, as well as urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) and gamma-glutamyl transpeptidase (gamma-GT) of control and pretreated rats were examined 24 h after styrene. The inducers and inhibitors of MFO system failed to modify further the acute nephrotoxicity of styrene. On the other hand, diethylmaleate pretreatment not only reduced further the uptake of PAH, but also produced further significant increase in the urinary excretion of NAG and gamma-GT observed at the higher dose of styrene. Similarly, ultrastructural studies showed a moderate increase in the severity of kidney damage induced at the higher dose of styrene due to pretreatment with diethylmaleate. These data suggest that tissue glutathione concentrations and hence, corresponding conjugating activity might be important determinants of styrene nephrotoxicity. The results further indicate that a metabolic activation system not involving certain cytochrome P-450 might be responsible in styrene-induced nephrotoxicity.