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

Abstract

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.