Pregnane X receptor-dependent and -independent effects of 2-acetylaminofluorene on cytochrome P450 3A23 expression and liver cell proliferation.
The arylamide 2-acetylaminofluorene (AAF) is a powerful carcinogen displaying a marked promoting activity, also known to regulate expression of liver detoxifying proteins. In this study we identified CYP3A23, a major inducible cytochrome P-450 (CYP) isoform, as an AAF target in hepatocytes. Indeed, exposure to AAF of primary rat hepatocytes resulted in a marked up-regulation of CYP3A23 expression at both mRNA and protein levels. Using CYP3A23 reporter gene constructs, we further demonstrated that AAF activated the CYP3A23 Direct Repeat 3 (DR3) promoter element interacting with the nuclear pregnane X receptor (PXR). Moreover, the PXR antagonist ecteinascidin-743 fully suppressed AAF-related CYP3A23 induction. Low doses of AAF inhibiting DNA synthesis in hepatocytes however failed to trigger PXR-related CYP3A23 induction and PXR-negative epithelial liver cells remained sensitive to the mito-inhibitory effects of AAF. Such data indicate that AAF up-regulates CYP3A23 through PXR activation but does not require PXR for exerting its carcinogenic promoting properties based on inhibition of cell growth.
Sparfel
Lydie
L
INSERM U456, Faculté de Pharmacie, 2 Avenue du Pr Leon Bernard, Rennes 35043, France.
Payen
Léa
L
Gilot
David
D
Sidaway
James
J
Morel
Fabrice
F
Guillouzo
André
A
Fardel
Olivier
O
D015073:2-Acetylaminofluorene / Q000494:pharmacology*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics*; D002273:Carcinogens / Q000494:pharmacology*; D002455:Cell Division; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A; D004247:DNA / Q000096:biosynthesis; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000166:cytology; D008297:Male; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D011987:Receptors, Steroid / Q000502:physiology*; D015533:Transcriptional Activation; D015854:Up-Regulation
D002273:Carcinogens; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D004247:DNA; D015073:2-Acetylaminofluorene; D001189:Aryl Hydrocarbon Hydroxylases; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A