Cytochrome P450-dependent toxicity of environmental polycyclic aromatic hydrocarbons towards human macrophages |
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Authors: | van Grevenynghe Julien Sparfel Lydie Le Vee Marc Gilot David Drenou Bernard Fauchet Renée Fardel Olivier |
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Affiliation: | INSERM U620, Faculté de Pharmacie, Rennes, France. |
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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. |
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Keywords: | Polycyclic aromatic hydrocarbons Macrophages Apoptosis Cytochrome P-450 Benzo(a)pyrene Immunosuppression |
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