Luoma Pauli V
Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland.
Eur J Clin Pharmacol. 2008 Sep;64(9):841-50. doi: 10.1007/s00228-008-0515-5. Epub 2008 Jul 17.
Lipoproteins are closely associated with the atherosclerotic vascular process. Elevated levels of high-density 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 lipoprotein-cholesterol (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.
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.
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.
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.
脂蛋白与动脉粥样硬化血管病变密切相关。血浆中高密度脂蛋白胆固醇（HDL-C）和载脂蛋白AI（apo AI）水平升高表明冠心病（CHD）发生概率较低且寿命延长，而低密度脂蛋白胆固醇（LDL-C）和apo B水平升高则表明CHD和死亡风险增加。有关基因激活以及细胞色素P450的诱导与血浆apo AI和HDL-C水平升高以及LDL-C水平降低之间关系的研究，为预防和治疗动脉粥样硬化疾病提供了一种新的潜在方法。
这是一篇综述，旨在阐明P450酶和基因激活对胆固醇稳态、动脉粥样硬化血管病变、动脉粥样硬化的预防和逆转以及动脉粥样硬化疾病（尤其是CHD，全球主要死因）表现的影响。
P450酶维持细胞胆固醇稳态。它们通过增强羟基胆固醇（氧化甾醇）的生成并激活胆固醇消除机制来应对胆固醇积累。CYP7A1、CYP27A1、CYP46A1和CYP3A4酶产生进入循环的主要氧化甾醇。这些氧化甾醇通过核受体激活ATP结合盒（ABC）A1和其他基因，导致多余胆固醇的消除并保护动脉免受动脉粥样硬化影响。几种药物和非药物化合物是肝脏X受体、孕烷X受体和其他受体的配体，可激活参与胆固醇消除的P450和其他基因，预防或逆转动脉粥样硬化并减少心血管事件。
P450酶在胆固醇平衡的生理维持中至关重要。它们激活消除多余胆固醇并对抗动脉粥样硬化进程的机制。几种药物和非药物化合物可诱导P450和其他基因，预防或逆转动脉粥样硬化并减少非致命性和致命性CHD及其他动脉粥样硬化疾病的发生。
