title: Effects of exposure to diesel exhaust particles (DEP) on pulmonary metabolic activation of mutagenic agents.
abstract: Exposure of rats to diesel exhaust particles (DEP) or carbon black (CB) has been shown to induce time-dependent changes in CYP1A1and CYP2B1 in the lung. The present study evaluated the role of these metabolic enzymes on the pulmonary bioactivation of mutagens. Male Sprague-Dawley rats were intratracheally instilled with saline (control), DEP or CB (35 mg/kg body weight) and sacrificed at 1, 3, or 7 days post-exposure. Both control and exposed lung S9 increased the mutagenic activity of 2-aminoanthracene (2-AA), 2-aminofluorene (2-AF), 1-nitropyrene (1-NP), and the organic extract of DEP (DEPE) in Ames tests with Salmonella typhimurium YG1024 in a dose-dependent manner. Lung microsomes prepared form control or particle-exposed S9, but not cytosolic protein, activated 2-AA mutagenicity. Compared to saline controls, CB-exposed S9 was a less potent inducer of 2-AA mutagenicity at all time points, whereas DEP-exposed S9 was less potent than control saline at 3 and 7 days but not 1 day post-exposure. At 3 days post-exposure, DEP- or CB-exposed lung S9 did not significantly affect the mutagenicity of DEPE or 1-NP, when compared to the controls. The mutgenicity of 2-AA, 2-AF, 1-NP, and DEPE were significantly decreased in the presence of inhibitors for CYP1A1 (alpha-naphthoflavone) or CYP2B (metyrapone), but markedly enhanced by CYP1A1 or CYP2B1 supersomes with all the cofactors, suggesting that both CYP1A1 and CYP2B1 were responsible for mutagen activation. These results demonstrated that exposure of rats to DEP or CB altered metabolic activity of lung S9 and S9 metabolic activity dependent mutagen activation. The bioactivation of mutagens are metabolic enzyme- and substrate-specific, and both CYP1A1 and CYP2B1 play important roles in pulmonary mutagen activation.
authors.affiliation: Health Effects Laboratory Division, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown, WV 26505-2888, USA.
authors.forename: H W
authors.initials: HW
authors.lastname: Zhao
authors.forename: M W
authors.initials: MW
authors.lastname: Barger
authors.forename: J K H
authors.initials: JK
authors.lastname: Ma
authors.forename: V
authors.initials: V
authors.lastname: Castranova
authors.forename: J Y C
authors.initials: JY
authors.lastname: Ma
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000378:metabolism; D002244:Carbon / Q000633:toxicity; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005449:Fluorenes / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism*; D011721:Pyrenes / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012486:Salmonella typhimurium / Q000187:drug effects; D001335:Vehicle Emissions / Q000633:toxicity*
chemical_list: D000873:Anthracenes; D005449:Fluorenes; D009153:Mutagens; D011721:Pyrenes; D001335:Vehicle Emissions; C012177:2-aminofluorene; D002244:Carbon; C006593:2-anthramine; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; C032668:1-nitropyrene