title: Cytochrome P450-dependent toxicity of environmental polycyclic aromatic hydrocarbons towards human macrophages.
abstract: Polycyclic aromatic hydrocarbons (PAHs) such as benzo(a)pyrene (BP) are potent immunosuppressive environmental contaminants acting on lymphocytes and monocytes. To establish whether differentiated macrophages, which play a crucial role in innate and acquired immunity, can also constitute major cellular targets, we have characterized PAH effects towards primary human macrophages. BP-treatment was found to dramatically alter their functional capacities and to trigger a caspase- and mitochondrion-related apoptosis, associated with down-regulation of the survival factors c-FLIP(L) and Bcl-X(L) and up-regulation of the pro-apoptotic factor p53. Such deleterious effects were associated with BP metabolite production, whose inhibition by the cytochrome P-450 1A1 inhibitor alpha-naphthoflavone fully abolished BP toxicity. In contrast to BP, the related halogenated arylhydrocarbon 2,3,7,8-tetrachlorodibenzo-p-dioxin, known to be poorly metabolized if any, only minimally affected macrophages. Overall, these data provide evidence for a cytochrome P-450-dependent toxicity of PAHs towards human differentiated macrophages, which may contribute to their immunosuppressive effects.
authors.affiliation: INSERM U620, Faculté de Pharmacie, Rennes, France.
authors.forename: Julien
authors.initials: J
authors.lastname: van Grevenynghe
authors.forename: Lydie
authors.initials: L
authors.lastname: Sparfel
authors.forename: Marc
authors.initials: M
authors.lastname: Le Vee
authors.forename: David
authors.initials: D
authors.lastname: Gilot
authors.forename: Bernard
authors.initials: B
authors.lastname: Drenou
authors.forename: Renée
authors.initials: R
authors.lastname: Fauchet
authors.forename: Olivier
authors.initials: O
authors.lastname: Fardel
mesh_terms: D002454:Cell Differentiation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004785:Environmental Pollutants / Q000633:toxicity*; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects*; D011083:Polycyclic Compounds / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism
chemical_list: D004785:Environmental Pollutants; D011083:Polycyclic Compounds; D018336:Receptors, Aryl Hydrocarbon; D003577:Cytochrome P-450 Enzyme System