Cytochrome P450-dependent toxicity of environmental polycyclic aromatic hydrocarbons towards human macrophages

• Published in: Biochemical and biophysical research communications 2004-05, Vol.317 (3), p.708-716
• Main Authors: van Grevenynghe, Julien, Sparfel, Lydie, Vee, Marc Le, Gilot, David, Drenou, Bernard, Fauchet, Renée, Fardel, Olivier
• Format: Article
• Language: English
• Subjects: Apoptosis; Benzo( a)pyrene; Cell Differentiation; Cytochrome P-450; Cytochrome P-450 Enzyme System - metabolism; Environmental Pollutants - toxicity; Humans; Immunosuppression; Macrophages; Macrophages - cytology; Macrophages - drug effects; Polycyclic aromatic hydrocarbons; Polycyclic Compounds - toxicity; Receptors, Aryl Hydrocarbon - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2004.03.104

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 α-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.