Styrene is a widely used chemical. In mice it is both hepatotoxic and pneumotoxic, and this toxicity is thought to be associated with its metabolism to styrene oxide. In vitro studies by several investigators suggest that this bioactivation in mice is primarily due to CYP2E1 and CYP2F2. However, in vivo studies demonstrate that CYP2E1 knockout mice can metabolize styrene to a similar extent as the wild-type mice. The current studies compared the in vitro metabolism of styrene by hepatic and pulmonary microsomes from CYP2E1 knockout and wild-type mice. There was no difference in the hepatic microsomal metabolism of styrene to styrene oxide between the two strains. The metabolism of styrene was lower in the lungs of the knockout mice than in the wild-type. Chemical inhibitors were used to ascertain the contributions made by various cytochromes P-450: imipramine for CYP2C, alpha -methylbenzylaminobenzotriazole for CYP2B, alpha -naphthoflavone for CYP1A, 5-phenyl-1-pentyne for CYP2F2, and diethyldithiocar-bamate for CYP2E1. The data indicate that CYP2E1 and CYP2F2 may be important in wild-type mice, but they do not clearly indicate what cytochromes P-450 are responsible for the metab-olism in the knockout mice. Inhibition of styrene metabolism in the knockout mice by diethyl-dithiocarbamate indicates this inhibitor is not completely selective for CYP2E1. These in vitro data support the in vivo finding of styrene metabolism in CYP2E1 knockout mice and indicate that other enzymes are contributing to styrene metabolism in these mice.