Potent inhibition of carcinogen-bioactivating cytochrome P450 1B1 by the p53 inhibitor pifithrin alpha.
Pifithrin alpha (PFTalpha) 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 PFTalpha 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 PFTalpha 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 PFTalpha was mixed-type with an apparent K(i) of 4.38 nM. Blockage of CYP1 activity by PFTalpha 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 PFTalpha for preventing toxicity of chemical carcinogens such as PAHs, through inhibition of CYP1 enzyme activities, especially that of CYP1B1.
Sparfel
Lydie
L
INSERM U620, IFR 140, Université de Rennes I, 2 Avenue du Pr Léon Bernard, 35043 Rennes, France. lydie.sparfel@rennes.inserm.fr
Van Grevenynghe
Julien
J
Le Vee
Marc
M
Aninat
Caroline
C
Fardel
Olivier
O
D017209:Apoptosis; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001564:Benzo(a)pyrene / Q000494:pharmacology / Q000633:toxicity*; D052160:Benzothiazoles; D001943:Breast Neoplasms / Q000473:pathology; D002273:Carcinogens / Q000494:pharmacology / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D006801:Humans; D007938:Leukemia / Q000473:pathology; D008264:Macrophages; D008862:Microsomes, Liver; D020033:Protein Isoforms; D013844:Thiazoles / Q000494:pharmacology*; D014050:Toluene / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects*
D052160:Benzothiazoles; D002273:Carcinogens; D020033:Protein Isoforms; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D001564:Benzo(a)pyrene; D014050:Toluene; C121565:pifithrin; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1