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3011553 
Journal Article 
Pulmonary Inflammation Impacts on CYP1A1-Mediated Respiratory Tract DNA Damage Induced by the Carcinogenic Air Pollutant Benzo[a]pyrene 
Arlt, VM; Krais, AM; Godschalk, RW; Riffo-Vasquez, Y; Mrizova, I; Roufosse, CA; Corbin, C; Shi, Q; Frei, E; Stiborova, M; van Schooten, FJ; Phillips, DH; Spina, D 
2015 
1 
Toxicological Sciences
ISSN: 1096-6080
EISSN: 1096-0929 
OXFORD UNIV PRESS 
OXFORD 
146 
2 
213-225 
English 
25911668 
WOS:000359630300002 
Pulmonary inflammation can contribute to the development of lung cancer in humans. We investigated whether pulmonary inflammation alters the genotoxicity of polycyclic aromatic hydrocarbons (PAHs) in the lungs of mice and what mechanisms are involved. To model nonallergic acute inflammation, mice were exposed intranasally to lipopolysaccharide (LPS; 20 µg/mouse) and then instilled intratracheally with benzo[a]pyrene (BaP; 0.5 mg/mouse). BaP-DNA adduct levels, measured by (32)P-postlabeling analysis, were approximately 3-fold higher in the lungs of LPS/BaP-treated mice than in mice treated with BaP alone. Pulmonary Cyp1a1 enzyme activity was decreased in LPS/BaP-treated mice relative to BaP-treated mice suggesting that pulmonary inflammation impacted on BaP-induced Cyp1a1 activity in the lung. Our results showed that Cyp1a1 appears to be important for BaP detoxification in vivo and that the decrease of pulmonary Cyp1a1 activity in LPS/BaP-treated mice results in a decrease of pulmonary BaP detoxification, thereby enhancing BaP genotoxicity (ie, DNA adduct formation) in the lung. Because less BaP was detoxified by Cyp1a1 in the lungs of LPS/BaP-treated mice, more BaP circulated via the blood to extrapulmonary tissues relative to mice treated with BaP only. Indeed, we observed higher BaP-DNA adduct levels in livers of LPS/BaP-treated mice compared with BaP-treated mice. Our results indicate that pulmonary inflammation could be a critical determinant in the induction of genotoxicity in the lung by PAHs like BaP. Cyp1a1 appears to be involved in both BaP bioactivation and detoxification although the contribution of other enzymes to BaP-DNA adduct formation in lung and liver under inflammatory conditions remains to be explored. 
benzo[a]pyrene; pulmonary inflammation; cytochrome P450; carcinogen metabolism; DNA adducts; bronchoalveolar lavage 
IRIS
• Ammonia, Oral - Problem Formulation
NAAQS
• ISA-PM (2019)
     Considered
     In Scope
          Mode of action