Holme, J. A., Gorria, M., Arlt, V. M., Ovrebo, S., Solhaug, A., Tekpli, X., Landvik, N. E., Huc, L., Fardel, O., Lagadic-Gossmann, D. (2007) Different mechanisms involved in apoptosis following exposure to benzo[a]pyrene in F258 and Hepa1c1c7 cells. CHEMICO-BIOLOGICAL INTERACTIONS, 167 (1). pp. 41-55. ISSN 0009-2797

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Abstract

The present study compares and elucidates possible mechanisms why B[a]P induces different cell signals and triggers apparently different apoptotic pathways in two rather similar cell lines (hepatic epithelial cells of rodents). The rate and maximal capacity of metabolic activation, as measured by the formation of B[a]P-tetrols and B[a]P-DNA adducts, was much higher in mouse hepatoma Hepa1c1c7 cells than in rat liver epithelial F258 cells due to a higher induced level of cyp1a1. B[a]P increased intracellular pH in both cell lines, but this change modulated the apoptotic process only in F258 cells. In Hepalclc7 cells reactive oxygen species (ROS) production appeared to be a consequence of toxicity, unlike F258 cells in which it was an initial event. The increased mitochondrial membrane potential found in F258 cells was not observed in Hepalclc7 cells. Surprisingly, F258 cells cultured at low cell density were somewhat more sensitive to low (50 nM) B[a]P concentrations than Hepa1c1c7 cells. This could be explained partly by metabolic differences at low B[a]P concentrations. In contrast to the Hepalclc7 model, no activation of cell survival signals including p-Akt, p-ERK1/2 and no clear inactivation of pro-apoptotic Bad was observed in the F258 model following exposure to B[a]P. Another important difference between the two cell lines was related to the role of Bax and cytochrome c. In Hepalclc7 cells, B[a]P exposure resulted in a "classical" translocation of Bax to the mitochondria and release of cytochrome c, whereas in F258 cells no intracellular translocation of these two proteins was seen. These results suggest that the rate of metabolism of B[a]P and type of reactive metabolites formed influence the resulting balance of pro-apoptotic and anti-apoptotic cell signaling, and hence the mechanisms involved in cell death and the chances of more permanent genetic damage. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

Item Type:	Article
Authors (ICR Faculty only):	Arlt, Volker
All Authors:	Holme, J. A., Gorria, M., Arlt, V. M., Ovrebo, S., Solhaug, A., Tekpli, X., Landvik, N. E., Huc, L., Fardel, O., Lagadic-Gossmann, D.
Uncontrolled Keywords:	benzo[a]pyrene; cell signaling; DNA adducts; metabolism; apoptosis POLYCYCLIC AROMATIC-HYDROCARBONS; DNA-DAMAGE; METABOLIC-ACTIVATION; EPITHELIAL-CELLS; PROTEIN-KINASE; P53; PHOSPHORYLATION; DEATH; BAD; BENZO<A>PYRENE
Research teams:	Closed research groups > Human Biomonitoring & Carcinogen Activation
Depositing User:	Users 10 not found.
Date Deposited:	20 May 2008 10:48
Last Modified:	25 Nov 2011 15:09
URI:	http://publications.icr.ac.uk/id/eprint/6117

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