title: Benzo[a]pyrene diones are produced by photochemical and enzymatic oxidation and induce concentration-dependent decreases in the proliferative state of human pulmonary epithelial cells.
abstract: Organic components within mixtures of combustion-derived materials may play an important role in the correlation between air pollution and adverse cardio/respiratory health. One class of these organic components, polycyclic aromatic hydrocarbons (PAHs), has been shown to produce a wide variety of adverse health effects. An air toxic and a model PAH, benzo[a]pyrene (BaP), is a component of combustion-derived particulate matter (PM). Although most biological effects associated with BaP have been attributed to the cytochrome P-450 derived BaP 7,8-diol 9,10-epoxide, many other BaP oxidation products are formed in atmospheric and biological reactions and may contribute to PAH-induced adverse health effects. In an ambient environment, BaP and other PAHs undergo oxidation in the presence of ultraviolet light, O(2), O(3), NO(2), or OH(*). Biological peroxidase- and P-450 mediated conversion of BaP produces an extensive metabolic profile of BaP oxidation products that significantly outnumber the 7,8-diol/diol epoxide. The data herein show that in addition to near-ultraviolet light and P-450 isozymes, lactoperoxidase (airway peroxidase) converted BaP into a mixture of three diones, the 1,6-, 3,6-, and 6,12-BaP dione (BPD). In addition, it was found that low concentrations of BPDs induced a concentration-dependent decrease in the proliferation state of human pulmonary epithelial cells in vitro. Nanomolar concentrations of BPDs mediated cell growth inhibition, which was partially reversed by co-incubation with N-acetyl-L-cysteine and ascorbate. BPDs induced the formation of reactive oxygen species as measured by the fluorophore 2,7-dichloro-fluorescein. Together, these results may indicate a role for PAH oxidation products (PAH diones) in the adverse health effects associated with combustion-derived PM and semivolatile organic compounds.
authors.affiliation: Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108, USA. mreed@lrri.org
authors.forename: Matthew
authors.initials: M
authors.lastname: Reed
authors.forename: Michael
authors.initials: M
authors.lastname: Monske
authors.forename: Fredine
authors.initials: F
authors.lastname: Lauer
authors.forename: Stephen
authors.initials: S
authors.lastname: Meserole
authors.forename: Jerry
authors.initials: J
authors.lastname: Born
authors.forename: Scott
authors.initials: S
authors.lastname: Burchiel
mesh_terms: D001564:Benzo(a)pyrene / Q000009:adverse effects / Q000737:chemistry*; D018929:Cell Culture Techniques; D003577:Cytochrome P-450 Enzyme System / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008168:Lung / Q000166:cytology / Q000473:pathology*; D010084:Oxidation-Reduction; D010777:Photochemistry; D014835:Volatilization
chemical_list: D001564:Benzo(a)pyrene; D003577:Cytochrome P-450 Enzyme System