Cytochrome P450--physiological key factor against cholesterol accumulation and the atherosclerotic vascular process

Abstract

In the early 1960s liver cytochrome P450 (P450) was known as an enzyme in drug metabolism. By the late 1970s, P450 induction was associated with elevation of plasma high-density lipoprotein cholesterol and apolipoprotein AI indicating a reduced risk of atherosclerotic disease. Later on, 57 human P450 genes have been identified. One P450 enzyme participates in cholesterol synthesis, and several others catabolize it to oxysterols and other metabolites. Oxysterols are physiological ligands specific for liver X receptors (LXRs) in the activation of ATP-binding cassette (ABC) transporter and other cholesterol-lowering genes. Elevation of cholesterol leads to an endogenous induction of P450 and consequently to enhanced generation of oxysterols and activation of genes coding proteins which efflux cholesterol out of cells, transport it to the liver, catabolize and excrete cholesterol into bile, and prevent absorption of cholesterol in the intestine in the processes that maintain cellular cholesterol homeostasis and protect arteries from atherosclerosis. Peroxisome proliferator-activated receptors (PPARs) co-operate with LXRs and ABC transporters in cholesterol regulation. Secretion of oxysterol is a direct pathway for cellular cholesterol elimination. Several compounds induce P450 and other genes regulating cholesterol balance and prevent or regress atherosclerosis, whereas inhibition of P450 blocks oxidative reactions, promotes cholesterol accumulation, and enhances the atherosclerotic vascular process.