Respirable coal dust (CD) is a common cause of lung injury and pneumoconiosis in human and animals. Lung is an organ that is more susceptible to exposure to polycyclic aromatic hydrocarbons (PAHs), such as to tobacco products. The pulmonary toxicity and carcinogenicity of PAHs is dependent upon metabolic activation by cytochrome P4501A1 (CYP1A1), which is inducible by its own substrates and can activate the PAHs into reactive metabolites producing nucleotide adducts. Because preliminary results showed that the mixed exposure to both CD and PAHs reduced the metabolic activities of CYP1A1 in rats, we have examined the hypothesis that CD alters the localization and metabolic activity of CYP1A1 in the particle-exposed lung of ovine model. Therefore, the right apical lung lobes of lambs were instilled with 500 mg respirable CD (n=4) or saline (n=5) using a bronchoscope. The lambs were injected with
50 mg/kg of the model PAH, beta-naphthoflavone (BNF), on day 53 and 54 post- exposure and euthanized on day 56. CD exposure caused histiocytic inflammation extending from the terminal bronchioles into adjacent alveolar space and interstitium. In bronchoalveolar lavage (BAL) fluid of exposed lobes, 23 to 73% (mean 44.5%) of alveolar macrophages contained phagocytized CD. By immunofluorescence, the expression of CYP1A1 was significantly reduced within the alveolar septum. CYP1A1- dependent 7-ethoxyresorufin-O-dethylase (EROD) activity and CYP2B-dependent 7- pentoxyresorufin-O-deethylase (PROD) activity were both decreased in the pulmonary microsomes from CD-exposed lobes. These findings in a non-rodent model support the hypothesis that respirable CD modifies the induction and pulmonary localization of CYP1A1 protein.
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