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Pulmonary Inflammation Impacts on CYP1A1-Mediated Respiratory Tract DNA Damage Induced by the Carcinogenic Air Pollutant Benzo[a]pyrene

Arlt, Volker M; Krais, Annette M LU ; Godschalk, Roger W.; Riffo-Vasquez, Yanira; Mrizova, Iveta; Roufosse, Candice A; Corbin, Charmaine; Shi, Quan; Frei, Eva and Stiborova, Marie, et al. (2015) In Toxicological Sciences 146(2). p.25-213
Abstract

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... (More)

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.

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keywords
Air Pollutants, Animals, Benzo(a)pyrene, Carcinogens, Cytochrome P-450 CYP1A1, DNA Damage, Male, Mice, Mice, Inbred C57BL, Pneumonia, Respiratory System, Journal Article, Research Support, Non-U.S. Gov't
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Toxicological Sciences
volume
146
issue
2
pages
13 pages
publisher
Oxford University Press
external identifiers
  • scopus:84939614563
ISSN
1096-0929
DOI
10.1093/toxsci/kfv086
language
English
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no
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861d6c42-e77f-4e53-ba5b-aa9792a6807e
date added to LUP
2017-10-17 15:30:47
date last changed
2017-10-29 05:07:33
@article{861d6c42-e77f-4e53-ba5b-aa9792a6807e,
  abstract     = {<p>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.</p>},
  author       = {Arlt, Volker M and Krais, Annette M and Godschalk, Roger W. and Riffo-Vasquez, Yanira and Mrizova, Iveta and Roufosse, Candice A and Corbin, Charmaine and Shi, Quan and Frei, Eva and Stiborova, Marie and van Schooten, Frederik-Jan and Phillips, David H. and Spina, Domenico},
  issn         = {1096-0929},
  keyword      = {Air Pollutants,Animals,Benzo(a)pyrene,Carcinogens,Cytochrome P-450 CYP1A1,DNA Damage,Male,Mice,Mice, Inbred C57BL,Pneumonia,Respiratory System,Journal Article,Research Support, Non-U.S. Gov't},
  language     = {eng},
  number       = {2},
  pages        = {25--213},
  publisher    = {Oxford University Press},
  series       = {Toxicological Sciences},
  title        = {Pulmonary Inflammation Impacts on CYP1A1-Mediated Respiratory Tract DNA Damage Induced by the Carcinogenic Air Pollutant Benzo[a]pyrene},
  url          = {http://dx.doi.org/10.1093/toxsci/kfv086},
  volume       = {146},
  year         = {2015},
}