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Cytochrome P450 et activation génétique — de la pharmacologie à l’élimination du cholestérol et à la régression de l’athérosclérose

Cytochrome P450 and gene activation — from pharmacology to cholesterol elimination and regression of atherosclerosis

  • Nutrigénomique
  • Published:
Bio tribune magazine

Résumé

Historique

Les lipoprotéines sont étroitement associées au processus vasculaire athéroscléreux. Des taux élevés de cholestérol lié à des lipoprotéines de haute densité (HDL-C) et d’apolipoprotéines AI (apo AI) dans le plasma indiquent une faible probabilité de maladie coronarienne (MC) de même qu’une longévité accrue, alors que des taux élevés en cholestérol lié à des lipoprotéines de basse densité (LDL-C) et en apo B indiquent un risque accru de MC et de décès. Des études associant l’activation génique et l’induction du cytochrome P450 à des taux plasmatiques élevés en apo AI et HDL-C et des taux plasmatiques diminués en LDL-C ont présenté une nouvelle approche potentielle pour prévenir et traiter la maladie athéroscléreuse.

Objectif et méthodes

Cette revue a pour but de clarifier le röle des enzymes P450 et de l’activation génique sur l’homéostasie du cholestérol, le processus vasculaire athéroscléreux, la prévention et la régression de l’athérosclérose ainsi que l’expression de la maladie athéroscléreuse, en particulier la MC, la plus importante cause de décès dans le monde.

Résultats

Les enzymes P450 maintiennent l’homéostasie du cholestérol cellulaire. Elles répondent à l’accumulation de cholestérol en augmentant la production d’hydroxycholestérols (oxystérols) et en activant les mécanismes d’élimination du cholestérol. Les enzymes CYP7A1, CYP27A1, CYP46A1 et CYP3A4 génèrent d’importants oxystérols qui passent dans la circulation. Les oxystérols activent — via des récepteurs nucléaires — l’ATP binding cassette (ABC) A1 et d’autres gènes, entrainant l’élimination de l’excédant de cholestérol et protégeant les artères de l’athérosclérose. Plusieurs médicaments et composés non pharmacologiques sont des ligands pour le récepteur X du foie (liver X receptor), le récepteur de pregnane X (pregnane X receptor) et d’autres récepteurs, ils activent les P450 et d’autres gènes impliqués dans l’élimination du cholestérol, préviennent ou font régresser l’athérosclérose et réduisent les accidents cardiovasculaires.

Conclusions

Les enzymes P450 sont essentielles au maintien physiologique de l’équilibre du cholestérol. Elles activent les mécanismes qui éliminent l’excès de cholestérol et neutralisent le processus athéroscléreux. Plusieurs médicaments et composés non pharmacologiques activent les P450 et d’autres gènes, empêchent ou font régresser l’athérosclérose et réduisent l’apparition de MC fatales ou non fatales ainsi que l’apparition d’autres maladies athéroscléreuses.

Abstract

Background

Lipoproteins are closely associated with the atherosclerotic vascular process. Elevated levels of highdensity lipoprotein cholesterol (HDL-C) and apolipoprotein AI (apo AI) in plasma indicate a low probability of coronary heart disease (CHD) together with enhanced longevity, and elevated levels of low-density lipoproteincholesterol (LDL-C) and apo B indicate an increased risk of CHD and death. Studies linking gene activation and the induction of cytochrome P450 with elevated plasma levels of apo AI and HDL-C and lowered plasma levels of LDL-C presented a new potential approach to prevent and treat atherosclerotic disease.

Objective and methods

This is a review aimed at clarifying the effects of P450-enzymes and gene activation on cholesterol homeostasis, the atherosclerotic vascular process, prevention and regression of atherosclerosis and the manifestation of atherosclerotic disease, particularly CHD, the leading cause of death in the world.

Results

P450-enzymes maintain cellular cholesterol homeostasis. They respond to cholesterol accumulation by enhancing the generation of hydroxycholesterols (oxysterols) and activating cholesterol-eliminating mechanisms. The CYP7A1, CYP27A1, CYP46A1 and CYP3A4 enzymes generate major oxysterols that enter the circulation. The oxysterols activate — via nuclear receptors — ATP-binding cassette (ABC) A1 and other genes, leading to the elimination of excess cholesterol and protecting arteries from atherosclerosis. Several drugs and nonpharmacologic compounds are ligands for the liver X receptor, pregnane X receptor and other receptors, activate P450 and other genes involved in cholesterol elimination, prevent or regress atherosclerosis and reduce cardiovascular events.

Conclusions

P450-enzymes are essential in the physiological maintenance of cholesterol balance. They activate mechanisms which eliminate excess cholesterol and counteract the atherosclerotic process. Several drugs and nonpharmacologic compounds induce P450 and other genes, prevent or regress atherosclerosis and reduce the occurrence of non-fatal and fatal CHD and other atherosclerotic diseases.

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Lunoma, P.V. Cytochrome P450 et activation génétique — de la pharmacologie à l’élimination du cholestérol et à la régression de l’athérosclérose. Bio trib. mag. 30, 15–24 (2009). https://doi.org/10.1007/s11834-009-0109-2

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