| Polycyclic aromatic hydrocarbons induce both apoptotic and anti-apoptotic signals in Hepa1c1c7 cells. | |
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MedLine Citation:
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PMID: 14729587 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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In this study we show that benzo[a]pyrene (B[a]P) and the cyclopenta polycyclic aromatic hydrocarbons (CP-PAH) cyclopenta[c,d]pyrene (CPP), benz[j]aceanthrylene (B[j]A) and benz[l]aceanthrylene (B[l]A) induce apoptosis in Hepa1c1c7 cells, as measured by fluorescence microscopy and flow cytometry. The compounds induced formation of the active form of caspase-3, cleavage of its intracellular substrate, poly(ADP-ribose)polymerase (PARP), and DNA fragmentation. B[j]A was found to be the most potent in inducing apoptosis, followed by B[a]P, CPP and B[l]A. All compounds increased expression of CYP1A1 with relative potencies B[j]A > B[a]P >> CPP > B[l]A, corresponding well with their relative apoptotic responses. alpha-Naphthoflavone (alphaNF), an inhibitor of CYP1A1, reduced the induced apoptosis. B[a]P and CP-PAH exposure also resulted in an accumulation of the tumour suppressor protein p53. No changes were observed in the protein levels of Bax and Bcl-2, whereas the anti-apoptotic Bcl-xl protein was down-regulated, as judged by western blot analysis. Fluorescence microscopic analysis revealed a translocation of p53 to the nucleus and of Bax to the mitochondria. Furthermore, caspase-8 was activated and Bid cleaved. Interestingly, the levels of anti-apoptotic phospho-Bad (Ser155 and Ser112) had a biphasic increase after B[a]P or CPP treatment. Whereas alphaNF markedly reduced the activation of B[a]P to reactive metabolites, as measured by covalent binding to macromolecules, it did not inhibit the up-regulation of phospho-Bad. Neither of the compounds triggered apoptosis in primary cultures of rat lung cells (Clara cells, type 2 cells and lung alveolar macrophages), possibly due to a lack of CYP1A1 induction. In conclusion, B[a]P and the CP-PAH induced apoptotic as well as anti-apoptotic signals in Hepa1c1c7 cells. |
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Authors:
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Anita Solhaug; Magne Refsnes; Marit Låg; Per E Schwarze; Trine Husøy; Jørn A Holme |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2004-01-16 |
Journal Detail:
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Title: Carcinogenesis Volume: 25 ISSN: 0143-3334 ISO Abbreviation: Carcinogenesis Publication Date: 2004 May |
Date Detail:
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Created Date: 2004-04-22 Completed Date: 2004-06-14 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 8008055 Medline TA: Carcinogenesis Country: England |
Other Details:
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Languages: eng Pagination: 809-19 Citation Subset: IM |
Affiliation:
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Division of Environmental Medicine, Norwegian Institute of Public Health, PO Box 4404 Nydalen, N-0403 Oslo, Norway. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / drug effects* Carrier Proteins / metabolism Caspase 3 Caspases / metabolism Cells, Cultured Cytochrome P-450 CYP1A1 / metabolism Flow Cytometry Liver Neoplasms / metabolism, pathology* Lung / drug effects, metabolism Male Mice Microscopy, Fluorescence Poly(ADP-ribose) Polymerases / metabolism Polycyclic Hydrocarbons, Aromatic / pharmacology* Proto-Oncogene Proteins / metabolism Proto-Oncogene Proteins c-bcl-2 / metabolism Rats Tumor Suppressor Protein p53 / metabolism bcl-2-Associated X Protein bcl-Associated Death Protein bcl-X Protein |
| Chemical | |
Reg. No./Substance:
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0/Bad protein, mouse; 0/Bad protein, rat; 0/Bax protein, mouse; 0/Bax protein, rat; 0/Bcl2l1 protein, mouse; 0/Bcl2l1 protein, rat; 0/Carrier Proteins; 0/Polycyclic Hydrocarbons, Aromatic; 0/Proto-Oncogene Proteins; 0/Proto-Oncogene Proteins c-bcl-2; 0/Tumor Suppressor Protein p53; 0/bcl-2-Associated X Protein; 0/bcl-Associated Death Protein; 0/bcl-X Protein; EC 1.14.14.1/Cytochrome P-450 CYP1A1; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 3.4.22.-/Casp3 protein, mouse; EC 3.4.22.-/Casp3 protein, rat; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases |
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