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    Keywords: APOPTOSIS ; CELLS ; CELL ; PATHWAY ; PATHWAYS ; TOXICITY ; SYSTEM ; DEATH ; NF-KAPPA-B ; ACTIVATION ; DNA ; 3-aminobenzanthrone ; 3-nitrobenzanthrone ; CARCINOGENESIS ; DIESEL EXHAUST ; ENVIRONMENTAL CONTAMINANT 3-NITROBENZANTHRONE ; PHOSPHORYLATION ; cytokines ; MOUSE ; CELL-DEATH ; genetics ; DAMAGE ; HUMAN ACETYLTRANSFERASES ; METABOLIC-ACTIVATION ; POLYCYCLIC AROMATIC-HYDROCARBONS ; DNA-DAMAGE ; NETHERLANDS ; TRANSLOCATION ; FLOW-CYTOMETRY ; AKT ; CYTOKINE ; MAPK ; SCIENCE ; ADDUCT FORMATION ; cell death ; DNA damage ; DNA ADDUCT ; ERK ; CARCINOGEN 3-NITROBENZANTHRONE ; AIR-POLLUTANT 3-NITROBENZANTHRONE ; Genetic ; IMMUNE ; 3-Ammobenzanthrone ; LUNG EPITHELIAL-CELLS
    Abstract: 3-Nitrobenzanthrone (3-NBA) is a mutagenic and carcinogenic environmental pollutant found in diesel exhaust and urban air pollution. In the present work we have characterised the effects of 3-NBA and its metabolite 3-aminobenzanthrone (3-ABA) on cell death and cytokine release in mouse hepatoma Hepa1c1c7 cells. These effects were related to induced DNA damage and changes in cell signalling pathways. 3-NBA resulted in cell death and caused most DNA damage as judged by the amount of DNA adducts (P-32-postlabelling assay), single strand (ss)DNA breaks and oxidative DNA lesions (comet assay) detected. An increased phosphorylation of H2AX, chk1, chk2 and partly ATM was observed using flow cytometry and/or Western blotting. Both compounds increased phosphorylation of p53 and MAPKs (ERK, p38 and JNK). However, only 3-NBA caused an accumulation of p53 in the nucleus and a translocation of Bax to the mitochondria. The p53 inhibitor pifithrin-alpha inhibited 3-NBA-induced apoptosis, indicating that cell death was a result of the triggering of DNA signalling pathways. The highest phosphorylation of Akt and degradation of I kappa B-alpha (suggesting activation of NF-kappa B) were also seen after treatment with 3-NBA. In contrast 3-ABA increased IL-6 release, but caused little or no toxicity. Cytokine release was inhibited by PD98059 and curcumin, suggesting that ERK and NF-kappa B play a role in this process. in conclusion, 3-NBA seems to have a higher potency to induce DNA damage compatible with its cytotoxic effects, while 3-ABA seems to have a greater effect on the immune system. (C) 2009 Elsevier B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 19941874
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