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Toxicol Sci. 2015 Aug;146(2):213-25. doi: 10.1093/toxsci/kfv086. Epub 2015 Apr 23.

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

Author information

1
*Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment & Health, King's College London, London SE1 9NH, United Kingdom, volker.arlt@kcl.ac.uk.
2
*Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment & Health, King's College London, London SE1 9NH, United Kingdom.
3
Department of Toxicology, School for Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht University Medical Centre, 6200 MD Maastricht, The Netherlands.
4
Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London SE1 9NH, United Kingdom.
5
Department of Biochemistry, Faculty of Science, Charles University, 12840 Prague 2, Czech Republic;
6
Department of Histopathology, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London W12 0HS, United Kingdom, and.
7
Division of Preventive Oncology, National Center for Tumor Diseases, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.

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 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.

KEYWORDS:

DNA adducts; benzo[a]pyrene; bronchoalveolar lavage; carcinogen metabolism; cytochrome P450; pulmonary inflammation

PMID:
25911668
PMCID:
PMC4517052
DOI:
10.1093/toxsci/kfv086
[Indexed for MEDLINE]
Free PMC Article

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