Cytochromes P450 et tonus vasculaire

Abstract : The cytochromes P450 (CYP) are enzymes whose mainly known role is detoxification. However, their activity can lead to the formation of metabolites having pharmacological, toxicological or physiological effects. For a few years, the role of the P450 cytochromes in the metabolism of the acid arachidonic has been well described. Among the metabolites produced at the time of this biotransformation, the epoxyeicosatrinoïc acids (EETs) and the hydroxyeicosatetraenoïc acids (HETEs) occupy an important place in the regulation of vascular tone. Thus EETs have vasodilatator properties while HETEs have maily vasoconstrictor properties. During this work, we studied the expression of various P450 cytochromes in the human saphenous veins and we characterized the expression profile of these enzymes in various cellular types contained in the vascular walls. We showed that the expression of the majority of the cytochromes P450, in particular CYP1B, CYP2C, CYP2E1, CYP2J2 and CYP3A, was increased in the samples of human varicose veins. We have studied the regulation of various cytochromes P450, namely CYP2C, occupying an important place in the regulation of vascular homeostasis, by some statins in human endothelial cells (EV304) and human hepatoblastoma cell line (HepG2). The statins are molecules used in the treatment of the hypercholesterolemia, presenting pleiotropic effects, in particular on the vascular function. We observed that atorvastatin was the molecule having the most effect on the expression of the cytochromes P450 2C8, 2C9, 2J2, 3A5 and 3A7. Indeed, this molecule decreases the expression of the various cytochromes P450in ECV304 cells whereas it increases their expression in the HepG2 cells. The statines also influence the expression of two types of nuclear receptor implied in the regulation of the cytochromes P450. Thus, fluvastatin, increases the expression of the nuclear receptors CAR and PXR. Lastly, we studied the effect of the polymorphism of a cytochrome P450 of the 2C family on the blood pressure and the inflammatory markers of cardiovascular pathologies. We observed that the values of blood pressures did not vary according to the polymorphism of CYP2C19. On the other hand, the plasma levels of interleukine-6 are higher at the carriers of the allele CYP2C19*2. In the same way, the plasma concentrations of the lipidic parameters such as triglycerides are higher at the same subjects. Thus, a modification of the expression of the cytochromes P450can play a part in varicose pathology and vascular pathology with inflammatory component. This expression can be modulated by the statins. Lastly, polymorphism CYP2C19*2 is correlated with the inflammatory component of vascular pathologies probably via the metabolites of the acid arachidonic. These results then raise the question of the modulation of the production of the vaso-active molecules resulting from the arachidonic acid in vascular pathologies and from possible treatments by the statins or by inhibitors of P450 cytochromes.
Document type :
Médicaments. Université Henri Poincaré - Nancy I, 2004. Français
Contributor : Céline Thiebault <>
Submitted on : Thursday, December 14, 2006 - 10:19:04 AM
Last modification on : Thursday, December 14, 2006 - 3:15:46 PM
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  • HAL Id : tel-00120305, version 1



Céline Thiebault. Cytochromes P450 et tonus vasculaire. Médicaments. Université Henri Poincaré - Nancy I, 2004. Français. <tel-00120305>




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