Cytochrome P450-dependent toxicity of environmental polycyclic aromatic hydrocarbons towards human macrophages.
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.
van Grevenynghe
Julien
J
INSERM U620, Faculté de Pharmacie, Rennes, France.
Sparfel
Lydie
L
Le Vee
Marc
M
Gilot
David
D
Drenou
Bernard
B
Fauchet
Renée
R
Fardel
Olivier
O
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
D004785:Environmental Pollutants; D011083:Polycyclic Compounds; D018336:Receptors, Aryl Hydrocarbon; D003577:Cytochrome P-450 Enzyme System