Respirable Coal Dust Particles Modify Cytochrome P4501A1 (CYP1A1) Expression in Rat Alveolar Cells

Abstract

Cytochrome P4501A1 (CYP1A1) metabolizes polycyclic aromatic hydrocarbons in cigarette smoke to DNA-binding reactive intermediates associated with carcinogenesis. Epidemiologic studies indicate that the majority of coal miners are smokers but have a lower risk of lung cancer than other smokers. We hypothesized that coal dust (CD) exposure modifies pulmonary carcinogenesis by altering CYP1A1 induction. Therefore, male Sprague Dawley rats were intratracheally instilled with 2.5, 10, 20, or 40 mg CD/rat or vehicle (saline); and 11 d later, pulmonary CYP1A1 was induced by intraperitoneal injection of beta-naphthoflavone (BNF; 50 mg/kg). Fourteen days after CD exposure, CYP1A1 protein and activity were measured by Western blot and 7-ethoxyresorufin-O-deethylase activity, respectively. CYP1A1 and the alveolar type II markers, cytokeratins 8/18, were localized and quantified in lung sections by dual immunofluorescence with morphometry. The area of CYP1A1 expression in alveolar septa and alveolar type II cells in response to BNF was reduced by exposure to 20 or 40 mg CD compared with BNF alone. CD exposure significantly inhibited BNF-induced 7-ethoxyresorufin-O-deethylase activity in a dose-responsive manner. By Western blot, induction of CYP1A1 protein by BNF was significantly reduced by 40 mg CD compared with BNF alone. These findings indicate that CD decreases BNF-induced CYP1A1 protein expression and activity in the lung.

Endothelial responses of the alveolar barrier in vitro in a dose-controlled exposure to diesel exhaust particulate matter

“…In addition also other investigators reported about the potential of DEPM to interfere with the expression level of Cyp1a1 in rat alveolar cells [53]. Others speculated that such a downregulation after exposure to exhaust components could represent a cytoprotective response [54], preventing the cells from toxic metabolites.…”

Transcriptional Regulation of Human CYP2A13 Expression in the Respiratory Tract by CCAAT/Enhancer Binding Protein and Epigenetic Modulation

“…On the other hand, only scant information is available on the effects of inflammation on extrahepatic P450 expression. One study showed that downregulation of CYP1A1 in the lung is associated with inflammation (Ghanem et al, 2004). In another study, lipopolysaccharide was found to induce CYP2E1 in astrocytes via C/EBP ␤ and ␦ binding sites in the CYP2E1 promoter (Kelicen and Tindberg, 2004).…”

Unusual inflammatory and fibrogenic pulmonary responses to single-walled carbon nanotubes in mice

“…Paraffin-embedded sections of the left lung lobe were used for immunofluorescent detection of cytokeratin-8/18. After xylene deparaffinizating, cytokeratin-8/18 staining was done by the procedure described by Ghanem et al (11). A polyclonal guinea pig anticytokeratin-8/18 was used as the primary antibody (Research Diagnostics, Flanders, NJ), and an FITC-labeled donkey anti-guinea pig IgG (Research Diagnostics) was used as the secondary antibody to detect cytokeratin.…”