Demonstration of the contributions of pulmonary CYPs to naphthalene‐induced airway toxicity using lung‐Cpr‐null mice

Abstract

Naphthalene (NA) is an omnipresent air pollutant and respiratory toxicant. NA induces cytotoxicity in airways following bioactivation by CYP (P450) enzymes. Previous studies suggested that liver and lung are both capable of bioactivating NA in vitro and in vivo. However, direct evidence for a specific role of pulmonary P450 enzymes in mediating NA‐induced airway toxicity, particularly upon exposure to NA via the systemic route, is still lacking.The aim of this study was to examine the specific contribution of pulmonary CYPs to airway toxicity of NA using a lung‐Cpr‐null mouse. We predicted that lung epithelial cells that lack Cpr expression, which would have little microsomal P450 activity, would be resistant to NA‐induced cytotoxicity. Cre‐mediated deletion of Cpr in the lung‐Cpr‐null mouse occurred in a substantial proportion of the Club cells, which, before undergoing Cpr deletion, had high ability to bioactivate NA. Under the conditions used, doxycycline‐induced deletion of Cpr occurred in 66% of Club cells in proximal airways and 86% of Club cells in distal airways, based on the results of a dual immunofluorescence study. Levels of NA and NA‐GSH (a biomarker of NA bioactivation) were similar in the plasma of lung‐Cpr‐null mice and their control littermates after administration of a single bolus dose of NA (200 mg/kg). Histological examination of airways revealed that NA‐induced damage of epithelial cells is focal and mild in lung‐Cpr‐null mice compared to severe exfoliation of epithelial cells in most airways in NA‐treated control mice. Moreover, the number of proliferating (BrdU‐positive) airway epithelial cells was 4‐fold lower in NA‐treated lung‐Cpr‐null mice than in NA‐treated control littermates.These results confirm that CYPs in the lung can mediate NA‐induced airway epithelial damage in vivo.Support or Funding Informationsupported in part by NIH grant ES020867This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.