Journal Article

Polycyclic aromatic hydrocarbons induce both apoptotic and anti-apoptotic signals in Hepa1c1c7 cells

Anita Solhaug, Magne Refsnes, Marit Låg, Per E. Schwarze, Trine Husøy and Jørn A. Holme

in Carcinogenesis

Volume 25, issue 5, pages 809-819
Published in print May 2004 | ISSN: 0143-3334
Published online May 2004 | e-ISSN: 1460-2180 | DOI:
Polycyclic aromatic hydrocarbons induce both apoptotic and anti-apoptotic signals in Hepa1c1c7 cells

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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. α-Naphthoflavone (αNF), 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 αNF 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.

Keywords: AhR, aryl hydrocarbon receptor; B[j]A, benz[j]aceanthrylene; B[l]A, benz[l]aceanthrylene; B[a]P, benzo[a]pyrene; BPDE, benzo[a]pyrene 7,8-diol-9,10-epoxide; CPP, cyclopenta[c,d]pyrene; CP-PAH, cyclopenta polycyclic aromatic hydrocarbons; DMSO, dimethyl sulphoxide; EGF, epidermal growth factor; FBS, foetal bovine serum; 3-MC, 3-methylcholanthrene; αNF, α-naphthoflavone; PAH, polycyclic aromatic hydrocarbons; PARP, poly(ADP-ribose) polymerase; PBS, phosphate-buffered saline; PI, propidium iodide; PMSF, phenylmethylsulfonyl fluoride

Journal Article.  7416 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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