Pulmonary Inflammation Impacts on CYP1A1-Mediated Respiratory Tract DNA Damage Induced by the Carcinogenic Air Pollutant Benzo[a]pyrene.
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.
*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.
Volker M
VM
Arlt
*Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment & Health, King's College London, London SE1 9NH, United Kingdom.
Annette M
AM
Krais
Department of Toxicology, School for Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht University Medical Centre, 6200 MD Maastricht, The Netherlands.
Roger W
RW
Godschalk
Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London SE1 9NH, United Kingdom.
Yanira
Y
Riffo-Vasquez
Department of Biochemistry, Faculty of Science, Charles University, 12840 Prague 2, Czech Republic;
Iveta
I
Mrizova
Department of Histopathology, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London W12 0HS, United Kingdom, and.
Candice A
CA
Roufosse
*Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment & Health, King's College London, London SE1 9NH, United Kingdom.
Charmaine
C
Corbin
Department of Toxicology, School for Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht University Medical Centre, 6200 MD Maastricht, The Netherlands.
Quan
Q
Shi
Division of Preventive Oncology, National Center for Tumor Diseases, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Eva
E
Frei
Department of Biochemistry, Faculty of Science, Charles University, 12840 Prague 2, Czech Republic;
Marie
M
Stiborova
Department of Toxicology, School for Nutrition, Toxicology and Metabolism (NUTRIM), Maastricht University Medical Centre, 6200 MD Maastricht, The Netherlands.
Frederik-Jan
FJ
van Schooten
*Analytical and Environmental Sciences Division, MRC-PHE Centre for Environment & Health, King's College London, London SE1 9NH, United Kingdom.
David H
DH
Phillips
Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London SE1 9NH, United Kingdom.
Domenico
D
Spina
D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D001564:Benzo(a)pyrene / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D004249:DNA Damage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000201:enzymology*; D012137:Respiratory System / Q000378:metabolism / Q000473:pathology
D000393:Air Pollutants; D002273:Carcinogens; D001564:Benzo(a)pyrene; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1
DNA adducts; benzo[a]pyrene; bronchoalveolar lavage; carcinogen metabolism; cytochrome P450; pulmonary inflammation