부산대학교 도서관

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.tox.2006.12.009 Byline: Nina E. Landvik (a), Morgane Gorria (b), Volker M. Arlt (c), Nana Asare (a), Anita Solhaug (a), Dominique Lagadic-Gossmann (b), JA[cedilla]rn A. Holme (a) Keywords: Nitro-polycyclic aromatic hydrocarbons; Cell signaling; DNA damage; p53; Metabolism; Apoptosis Abbreviations: [alpha]-NF, [alpha]-Naphthoflavone; AhR, Aryl hydrocarbon receptor; B[a]P, Benzo[a]pyrene; CP-PAHs, Cyclopenta-polycyclic aromatic hydrocarbons; CYP, Cytochrome P450; cyt c, Cytochrome c; DEP, Diesel exhaust particles; DEPE, Diesel exhaust particle extracts; DMSO, Dimethyl sulfoxide; DNP, Dinitropyrene; ERK, Extracellular signal-related kinase; JNK, c-jun N-terminal kinase; MAPK, Mitogen activated protein kinases; 1-NP, 1-Nitropyrene; nitro-PAHs, Nitrated-polycyclic aromatic hydrocarbons; NOS, Nitric oxide synthase; NR, Nitroreductases; PAHs, Polycyclic aromatic hydrocarbons; PI, Propidium iodide; PKA, Protein kinase A; ROS, Reactive oxygen species; TLC, Thin-layer chromatography Abstract: Nitrated-polycyclic aromatic hydrocarbons (nitro-PAHs) and diesel exhaust particle extracts (DEPE) induced apoptosis in Hepa1c1c7 cells with the following potency: 1,3-dinitropyrene (1,3-DNP)>1-nitropyrene (1-NP)a'DEPEa'1,8-dinitropyrene (1,8-DNP). The compounds induced cyp1a1, and activated various intracellular signalling pathways related to apoptosis. The CYP inhibitor [alpha]-naphthoflavone strongly reduced 1,3-DNP-induced cell death, whereas cell death induced by 1-NP was rather increased. Toxic 1,3-DNP and 1-NP were found to induce a concentration-dependent lipid peroxidation. 1,3-DNP caused pro-apoptotic events, including increased phosphorylation and accumulation of p53 in the nucleus, cleavage of bid and of caspases 8 and 3, down-regulation of bcl-x.sub.L and phosphorylation of p38 and JNK MAPK. Furthermore, 1,3-DNP increased the activation of survival signals including phosphorylation of Akt and inactivation (phosphorylation) of pro-apoptotic bad. Although less potent, rather similar effects were observed following exposure to DEPE, compared to 1-NP. The most important finding was that the most mutagenic and carcinogenic compound tested, 1,8-DNP, induced little (if any) cell death, despite the fact that this compound seemed to give the most DNA damage as judged by DNA adduct formation, increased phosphorylation of p53 and accumulation of cells in S-phase. Immunocytochemical studies revealed that the p53 protein did not accumulate into the nucleus suggesting that 1,8-DNP inactivated the pro-apoptotic function of the p53 protein by a non-mutagenic event. These results suggest that after exposure to 1,8-DNP more cells may survive with DNA damage, thereby increasing its mutagenic and carcinogenic potential. Author Affiliation: (a) Division of Environmental Medicine, Norwegian Institute of Public Health, P.O. Box 4404 Nydalen, N-0403 Oslo, Norway (b) Inserm U620, Universite Rennes 1, 2 av Pr Leon Bernard, 35043 Rennes Cedex, France (c) Section of Molecular Carcinogenesis, Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom Article History: Received 20 September 2006; Revised 14 November 2006; Accepted 1 December 2006