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Mutagenesis Advance Access originally published online on January 20, 2007
Mutagenesis 2007 22(2):111-116; doi:10.1093/mutage/gel060
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© The Author 2007. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Growth kinetics in MCF-7 cells modulate benzo[a]pyrene-induced CYP1A1 up-regulation

Haiyan Jiao1,3, Sarah L. Allinson1, Michael J. Walsh1, Rebecca Hewitt1, Kathy J. Cole2, David H. Phillips2 and Francis L. Martin1,*

1Biomedical Sciences Unit, Department of Biological Sciences, Lancaster University, Lancaster LA1 4YQ, UK 2Institute of Cancer Research, Brookes Lawley Building, Cotswold Road, Sutton SM2 5NG, UK

Pro-carcinogens, such as benzo[a]pyrene (B[a]P), that are exogenous ligands of the aromatic hydrocarbon receptor may influence the susceptibility of target-cell populations through the up-regulation of cytochrome P450 (CYP) mixed function oxidases. We examined whether the growth kinetics of MCF-7 cells might determine the level of up-regulation of CYP1A1, CYP1A2 or CYP1B1 by B[a]P, and whether this could then influence subsequent levels of DNA damage. Cell cultures manipulated to be G0/G1-phase concentrated, S-phase concentrated or G2/M-phase concentrated were treated with B[a]P and the expression levels of CYP1A1, CYP1A2, CYP1B1, cyclin-dependent kinase inhibitor 1A [CDKN1A (P21WAF1/CIP1)], B-cell leukaemia/lymphoma-2 (BCL-2), and Bcl-2-associated X levels were determined. Levels of DNA damage were measured as DNA single-strand breaks (SSBs) by the alkaline single-cell gel electrophoresis (comet) assay or as DNA adducts by 32P-postlabelling analysis. B[a]P-induced up-regulation of CYP1A1 was >100-fold in S-phase-concentrated cells, but in G0/G1-phase- or G2/M-phase-concentrated cultures up-regulation occurred to a significantly lower extent. Consistent with this, B[a]P-treated S-phase-concentrated cultures exhibited markedly up-regulated P21WAF1/CIP1, higher levels of dose-related increases in DNA SSBs, and increased DNA adduct levels presumably as a result of CYP1A1-mediated activation of B[a]P to B[a]P-diol-epoxide compared with the cultures enriched for the other cell cycle phases. Growth kinetics in vitro may be an important predeterminant of susceptibility to an exogenous pro-carcinogen in short-term test systems and these findings have important implications when extrapolating such results to a particular target-cell population in vivo.

* To whom correspondence should be addressed. Tel: +44 1524 594505; Fax: +44 1524 593192; Email: f.martin{at}lancaster.ac.uk

3 Present address: Department of Medical Genetics and Cell Biology, Ningxia Medical College, 692 Shengli Street, Yinchuan, Ningxia 750004, People's Republic of China

Received on July 29, 2006; revised on October 27, 2006; accepted on October 31, 2006.


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