Long-term exposure to ozone increases acute pulmonary centriacinar injury by 1-nitronaphthalene: I. Region-specific enzyme activity.

To test whether exposure to ozone alters pulmonary cytochrome P450 monooxygenase-mediated metabolism of xenobiotics, rates of 1-nitronaphthalene (1-NN) metabolism were measured in microsomes prepared from trachea, intrapulmonary airways, and distal lung of rats exposed to filtered air (FA) or ozone (O(3)) (0.8 ppm 8 h/day for 90 days). Regioisomeric glutathione conjugates derived from intermediate epoxides were measured by HPLC. Compared with FA, rates of glutathione conjugate formation in distal lung (including the central acinus) were elevated 2-fold in O(3)-exposed rats. Activity for cytochrome P450 2B, the isozyme thought to be responsible for the metabolic activation of 1-NN, was increased 3-fold in the distal lung of O(3)- compared with FA-exposed rats. There was a 2 +/- 0. 5-fold increase in immunodetectable CYP 2B protein in microsomes from the same lung subcompartment (P <.05). Immunodetectable protein was expressed in nonciliated epithelial (or "Clara") cells and not associated with ciliated epithelial cells. No differences between O(3)- and FA-exposed rats were noted in 1-NN metabolism or CYP 2B activity in trachea or intrapulmonary airways. This study emphasizes that cellular and biochemical alterations associated with long-term O(3) exposure vary considerably by location within the lung. Long-term exposure to O(3) elevates both CYP 2B activity and 1-NN metabolism in an airway-specific manner.