オキシステロール-存在,構造,生体内作用-

Oxygenated derivatives of cholesterol (oxysterols) exist in the human body as intermediates in the biosynthetic pathways of bile acids, steroid hormone and vitamin D. 7α-Hydroxycholesterol and 27-hydroxycholesterol are identified as intermediates in the conversion of cholesterol to bile acids in the liver. Steroid hormones are formed from cholesterol via pregnenolone through a series of sequential hydroxylations at carbon-22 (C-22) and C-20. The first step in the biosynthesis of vitamin D occurs in the skin and uses 7-dehydrocholesterol. The enzymatic production of 24-hydroxycholesterol was demonstrated in the developing brain. In addition to these specific enzymatic reactions, nonspecific peroxidation in vivo and non-enzymatic autoxidation of cholesterol may occur, because of the susceptibility of cholesterol to the attack by oxygen molecules. In the 1970's, Kandutsch and colleagues demonstrated that oxysterols were potent inhibitors of HMG-CoA reductase activity. Many oxysterols such as 7-ketocholesterol and 25-hydroxycholesterol may play a role as the intracellular regulator of cholesterol synthesis. Oxysterols repress enzymes of sterol biosynthesis (HMG-CoA reductase and HMG-CoA synthase), and activate enzymes of catabolism (7α-hydroxycholesterol) and sterol storage (acyl CoA: cholesterol acyltransferase). These actions prevent the accumulation of unesterified cholesterol within cells. However, the molecular mechanism(s) of action of oxysterols are not well understood in all instances. The similarity in the actions by LDL-cholesterol and oxysterols bring a hypothesis that the action of LDL-cholesterol may be mediated by oxysterols in the cell. Then, oxysterols have been demonstrated to possess a variety of biological properties, including cytotoxicity, atherogenicity, mutagenicity and carcinogenicity. In this paper, recent studies on oxysterols, especially monooxygenated cholesterol derivatives, were reviewed with regard to the analysis, biological significance and specific diseases which are closely related with metabolic disorders of oxysterols including atherosclerosis and cerebrotendinous xanthomatosis and so on.