Published ahead of print on April 8, 2004, doi:10.1165/rcmb.2003-0425OC Am. J. Respir. Cell Mol. Biol., Volume 31, Number 2, August 2004, 171-183 A more recent version of this article appeared on August 1, 2004
Submitted on November 24, 2003 RESPIRABLE COAL DUST PARTICLES MODIFY CYTOCHROME P4501A1 (CYP1A1) EXPRESSION IN RAT ALVEOLAR CELLSMohamed M Ghanem1,1 Health Effects Laboratory Division, NIOSH, CDC, Morgantown, WV, USA; Genetics and Developmental Biology Program, West Virginia University, Morgantown, WV, USA, 2 Health Effects Laboratory Division, NIOSH, CDC, Morgantown, WV, USA, 3 Genetics and Developmental Biology Program, West Virginia University, Morgantown, WV, USA * To whom correspondence should be addressed. E-mail: AHubbs{at}cdc.gov.
Cytochrome P4501A1 (CYP1A1) metabolizes polycyclic aromatic hydrocarbons in cigarette smoke to DNA-binding reactive intermediates associated with carcinogenesis. Epidemiological 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, 40mg CD/rat or vehicle (saline) and eleven days later, pulmonary CYP1A1 was induced by intraperitoneal injection of
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-naphthoflavone (BNF; 50mg/kg). Fourteen days after CD exposure, CYP1A1 protein and activity were measured by Western blot and 7-ethoxyresorufin-O-deethylase (EROD) 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 40mg CD compared with BNF alone. CD exposure significantly inhibited BNF-induced EROD activity in a dose-responsive manner. By Western blot, induction of CYP1A1 protein by BNF was significantly reduced by 40mg CD compared with BNF alone. These findings indicate that CD decreases BNF-induced CYP1A1 protein expression and activity in the lung.
