Pulmonary toxicity of
styrene is initiated by
cytochromes P450-dependent metabolic activation. P450 2E1 and P450 2F2 are considered to be two main
cytochrome P450 enzymes responsible for
styrene metabolism in mice. The objective of the current study was to determine the correlation between the formation of
styrene metabolites (i.e.,
styrene oxide and 4-vinylphenol) and pulmonary toxicity of
styrene, using Cyp2e1- and Cyp2f2-null mouse models. A dramatic decrease in the formation of
styrene glycol and
4-vinylphenol was found in Cyp2f2-null mouse lung microsomes relative to that in the wild-type mouse lung microsomes; however, no significant difference in the production of the
styrene metabolites was observed between lung microsomes obtained from Cyp2e1-null and the wild-type mice. The knockout and wild-type mice were treated with
styrene (6.0 mmol/kg, ip), and cell counts and LDH activity in bronchoalveolar lavage fluids were monitored to evaluate the pulmonary toxicity induced by
styrene. Cyp2e1-null mice displayed a susceptibility to lung toxicity of
styrene similar to that of the wild-type animals; however, Cyp2f2-null mice were resistant to
styrene-induced pulmonary toxicity. In conclusion, both P450 2E1 and P450 2F2 are responsible for the metabolic activation of
styrene. The latter
enzyme plays an important role in
styrene-induced pulmonary toxicity. Both
styrene oxide and
4-vinylphenol are suggested to participate in the development of
lung injury induced by
styrene.