Effect of HMGCoA reductase inhibitors on cytochrome P450 expression in endothelial cell line.
Endothelial cells and smooth muscle cells are the major cells that constitute blood vessels, and endothelial cells line the lumen of blood vessels. These 2 types of cells also play an integral role in the regional specialization of vascular structure. On the basis of these observations, we designed our study to investigate the effect of various statins on CYP expression in endothelial cells. 3-hydroxymethyl coenzyme A reductase inhibitors play an important role in vascular function. The majority of the statins available on the market show extensive metabolism by cytochrome P450 (CYP) enzymes. Both cell types are involved in the bioconversion of arachidonic acid into vasoactive compounds. The aim of this study was to demonstrate the effect of statins on cytochrome P450 expression in endothelial cells. Our results show that endothelial cells expressed both CYPs involved in epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids (HETEs) production and the nuclear receptor implicated in cytochrome P450 regulation. Treatment of endothelial cells with lovastatin increased CYP2C9 expression. After 96 hours of treatment, fluvastatin and lovastatin clearly increased CYP2C9 protein level. CAR but not PXR was expressed in endothelial cells, indicating that the upregulating effect of statins on CYP2C9 in endothelial cells could be mediated through CAR only due to the lack of expression of PXR in these cells.
Bertrand-Thiebault
Céline
C
INSERM, U525, Equipe 4, Univ Henri Poincaré, Nancy I, Nancy, F-54000 France.
Masson
Christine
C
Siest
Gérard
G
Batt
Anne-Marie
AM
Visvikis-Siest
Sophie
S
D000704:Analysis of Variance; D001189:Aryl Hydrocarbon Hydroxylases / Q000187:drug effects / Q000378:metabolism; D000069059:Atorvastatin; D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000090702:Constitutive Androstane Receptor; D065729:Cytochrome P-450 CYP2C9; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology*; D004730:Endothelium, Vascular / Q000166:cytology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D000077340:Fluvastatin; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology; D017035:Pravastatin / Q000494:pharmacology; D000077297:Pregnane X Receptor; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis / Q000187:drug effects; D011987:Receptors, Steroid / Q000096:biosynthesis / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012501:Saphenous Vein / Q000166:cytology; D014157:Transcription Factors / Q000096:biosynthesis / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D000090702:Constitutive Androstane Receptor; D005229:Fatty Acids, Monounsaturated; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D000077297:Pregnane X Receptor; D011758:Pyrroles; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid; D014157:Transcription Factors; D000077340:Fluvastatin; D003577:Cytochrome P-450 Enzyme System; D008148:Lovastatin; D000069059:Atorvastatin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D017035:Pravastatin