PPARalpha activation potentiates AhR-induced CYP1A1 expression.
CYP1A1 is an extrahepatic enzyme largely involved in the bioactivation of various procarcinogens such as polycyclic aromatic hydrocarbons (PAHs) and arylamines. CYP1A1 expression is mainly regulated by AhR. Our laboratory has recently shown a new CYP1A1 regulation pathway involving PPARalpha. The aim of this study was to evaluate, in a Caco-2 cell line, the effect of a coexposure to 3-methylcholanthrene (3MC, AhR ligand) and WY-14643 (WY, PPARalpha ligand) on CYP1A1 expression (enzymatic activity, mRNA level and promoter activity). An additive effect on CYP1A1 expression was shown in cells coexposed with 3MC (0.1 or 1 microM) and a low WY concentration (30 microM) whereas a potentiating effect was observed after coexposure with 3MC (0.1 or 1 microM) and a high WY concentration (200 microM). Furthermore, 200 microM WY, alone or with 3MC, was able to increase the AhR protein level (two-fold). In conclusion, coexposure with 3MC and the PPARalpha agonist WY leads to an additive or potentiating effect on CYP1A1 inducibility, depending on the WY concentration. Furthermore, at high concentration (200 microM), WY induced AhR expression, which could explain the potentiating effect on CYP1A1 inducibility observed after addition of an AhR ligand (3MC). This phenomenon should be taken into account for risk assessment involving CYP1A1 induction.
Fallone
Frédérique
F
FRE CNRS 2737, Université de la Méditerranée, UFR Pharmacie, 27 boulevard Jean Moulin, 13855 Marseille Cedex 5, France.
Villard
Pierre-Henri
PH
Decome
Laetitia
L
Sérée
Eric
E
Méo
Michel de
Md
Chacon
Christine
C
Durand
Alain
A
Barra
Yves
Y
Lacarelle
Bruno
B
D051792:Basic Helix-Loop-Helix Proteins; D015153:Blotting, Western; D018938:Caco-2 Cells; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004790:Enzyme Induction / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D008748:Methylcholanthrene / Q000494:pharmacology; D047493:PPAR alpha / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects; D018336:Receptors, Aryl Hydrocarbon / Q000737:chemistry / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D019363:Cytochrome P-450 CYP1A1; D008748:Methylcholanthrene; D047493:PPAR alpha; D011743:Pyrimidines; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; C111235:AHR protein, human; C006253:pirinixic acid