BACKGROUND: Many constituents of tobacco smoke (TS) require bioactivation to exert toxic effects; however, few studies have examined the role of bioactivation enzymes in the adverse effects of TS exposure. This knowledge gap is a major source of uncertainty for risk assessment and chemoprevention efforts.
OBJECTIVES: Our aim is to test the hypothesis that cytochrome P450 (P450) enzyme mediated bioactivation is essential to the development of TS exposure-induced lung toxicity, by determining the contributions of P450 enzymes in the mouse Cyp2abfgs gene subfamilies to environmental tobacco smoke (ETS)-induced lung inflammation.
METHODS: Adult female wildtype (WT) and Cyp2abfgs-null mice (both on C57BL/6J background) were exposed to filtered air or ETS, intermittently, for 1 or 2 weeks. Lung inflammation was assessed by quantification of inflammatory cells, cytokines, chemokines, proteins in bronchoalveolar lavage fluid (BALF), and histopathological analysis. Glutathione (GSH) conjugates of two ETS constituents, naphthalene (NA) and 3-methylindole (3MI), were measured in mice exposed to ETS for four hours.
RESULTS: Persistent macrophagic and neutrophilic lung inflammation was observed in ETS-exposed WT mice; the extent of which was significantly reduced in ETS-exposed Cyp2abfgs-null mice. Levels of proinflammatory cytokines and chemokines, along with the total protein concentration, were increased in cell-free BALF from ETS-exposed WT mice, but not Cyp2abfgs-null mice. Additionally, GSH-conjugates of NA and 3MI were detected in the lungs of WT, but not Cyp2abfgs-null, mice following ETS exposure.
CONCLUSIONS: These results provide the first in vivo evidence that the mouse Cyp2abfgs gene cluster plays an important role in ETS-induced lung inflammation.