Effects of diesel exhaust particles (DEP) exposure on pulmonary cytochrome P-450 (P-450) metabolism.
Ma-JYC; Kane-E; Barger-MW; Castranova-V
Am J Respir Crit Care Med 2001 Apr; 163(5)(2)(Suppl):A172
Polycyclic aromatic hydrocarbons (PAHs) associated with DEP require bioactivation by P-450 to exert their toxic/carcinogenic effects. The objective of the present study was to determine the effects of exposure of rats to DEP on pulmonary P-450 metabolism. Rats were dosed with a single intratracheal instillation of either 5 or 35 mg/kg of DEP or carbon black (CB). CB was used as a particle control without absorbed organics. Rats were sacrificed 3 days after exposure, and pulmonary microsomes were isolated by differential centrifugation of lung homogenates. The protein level and activity of P-450 isozymes, CYP1A1 and CYP2B1, were monitored to assess the effects of DEP exposure on the P-450 enzyme system. CYP2B1 and CYP1A1 activities were measured by the Odealkylation of 7-pentoxyresorufin and 7-ethoxyresorufin, respectively. The protein levels were determined by Western blot analysis. At both exposure doses, DEP or CB significantly reduced CYP2B1 activity, while only high dose exposure lowered CYP2B1 protein level. At 5 mg/kg of DEP or CB, CYP1A1 activity was significantly lowered without affecting the protein level. At the 35 mg/kg exposure level, DEP significantly increased CYP1A1 activity and protein level, whereas CB reduced CP1A1 activity and had little effect on the protein level. These data suggest that the effects of DEP on pulmonary P-450 are two fold: an induction of CYP1A1 by PAHs, the organic components of DEP, and a reduction of CYP2B1 activity due for the most part to the carbonaceous core of the particles. Both effects may play important roles in DEP induced toxicity.
Diesel-exhausts; Exposure-levels; Pulmonary-system; Metabolism; Hydrocarbons; Carcinogens; Animal-studies; Laboratory-animals; Polycyclic-aromatic-hydrocarbons; Toxic-effects; Carcinogenesis; Carcinogenicity; Animals; Exposure-assessment; Pulmonary-system-disorders; Respiratory-system-disorders
American Journal of Respiratory and Critical Care Medicine. Abstracts of the American Thoracic Society 2001 International Conference, May 18-23, 2001, San Francisco, California