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HERO ID
5019271
Reference Type
Journal Article
Subtype
Abstract
Title
Demonstration of the contributions of pulmonary CYPs to naphthalene-induced airway toxicity using lung-Cpr-null mice
Author(s)
Kovalchuk, N; Zhang, QYu; Van Winkle, L; Ding, X
Year
2018
Is Peer Reviewed?
Yes
Journal
FASEB Journal
ISSN:
0892-6638
EISSN:
1530-6860
Volume
32
Issue
1
Page Numbers
529.3
Language
English
Web of Science Id
WOS:000436985002041
URL
https://www.fasebj.org/doi/10.1096/fasebj.2018.32.1_supplement.529.3
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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.
Conference Name
Experimental Biology Meeting
Conference Location
Amer Assoc Anatomists, San Diego, CA
Conference Dates
April 21-25, 2018
Tags
IRIS
•
Naphthalene
Database Searches
WOS
Combined data set
Data set for title/abstract screening
Data set for full text review
Excluded – PECO criteria not met (full-text)
Supplemental material
Mechanistic
Mechanisms of cancer
Feb 2019 Update
WOS
Other
•
Naphthalene (2021 Evidence mapping publication)
Database Searches
WOS
Combined data set
Data set for title/abstract screening
Data set for full text review
Excluded – PECO criteria not met (full-text)
Supplemental material
Mechanistic
Mechanisms of cancer
Feb 2019 Update
WOS
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