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Carcinogenesis Advance Access originally published online on October 29, 2005
Carcinogenesis 2006 27(3):656-663; doi:10.1093/carcin/bgi256
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Carcinogenesis vol.27 no.3 © Oxford University Press 2005; all rights reserved.

Potent inhibition of carcinogen-bioactivating cytochrome P450 1B1 by the p53 inhibitor pifithrin {alpha}

Lydie Sparfel *, Julien Van Grevenynghe, Marc Le Vee, Caroline Aninat and Olivier Fardel

INSERM U620, IFR 140, Université de Rennes I, 2 Avenue du Pr Léon Bernard, 35043 Rennes, France

* To whom correspondence should be addressed. Tel: +33 2 23 23 48 68; Fax: +33 2 23 23 47 94; Email: lydie.sparfel{at}rennes.inserm.fr

Pifithrin {alpha} (PFT{alpha}) is a chemical compound that inhibits p53-mediated gene activation and apoptosis. It has also been recently shown to alter metabolism of carcinogenic polycyclic aromatic hydrocarbons (PAHs). This has led us to examine the effect of PFT{alpha} on the activity of cytochrome P-450 (CYP) 1 isoforms, known to metabolize PAHs, such as benzo(a)pyrene (BP), into mutagenic metabolites. We report that PFT{alpha} caused a potent inhibition of CYP1-related activity as measured by ethoxyresorufin O-deethylase activity in CYP1-containing MCF-7 cells and liver microsomes. It also directly affected the catalytic activity of human recombinant CYP1A1, CYP1A2 and CYP1B1 isoforms, with a potent inhibitory effect towards CYP1B1. The nature of this CYP1B1 inhibition by PFT{alpha} was mixed-type with an apparent Ki of 4.38 nM. Blockage of CYP1 activity by PFT{alpha} was associated with a decreased metabolism of BP, a reduced formation of BP-derived adducts and a diminished BP-induced apoptosis in human cultured cells targets for PAHs like primary human macrophages and p53-negative KG1a leukaemia cells. These data further substantiate an unexpected and p53-independent action of PFT{alpha} for preventing toxicity of chemical carcinogens such as PAHs, through inhibition of CYP1 enzyme activities, especially that of CYP1B1.


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