Evidence that the major oxysterols in human circulation originate from distinct pools of cholesterol: a stable isotope study

The major oxysterols in human circulation are 7 alpha-, 27-, and (24S)-hydr oxycholesterol. Two unique experiments were performed to elucidate their or igin and kinetics. A volunteer was exposed to O-18(2)-enriched air. A rapid incorporation of O-18 in both 7 alpha- and 27-hydroxycholesterol and disap pearance of label after exposure were observed. The half-life was estimated to be less than 1 h, Incorporation of O-18 in (24S)-hydroxycholesterol was not significant. In the second experiment a volunteer was infused with lip osomes containing 10 g of [H-2(6)]cholesterol, This resulted in an enrichme nt of plasma cholesterol with H-2 Of UP to 13%, and less than 0.5% in cereb rospinal fluid cholesterol, The content of H-2 in circulating 7 alpha -hydr oxycholesterol remained approximately equal to that of plasma cholesterol a nd decreased with a half-life of about 13 days. The 2H content of circulati ng 27-hydroxycholesterol was initially lower than that of cholesterol but i n the last phase of the experiment it exceeded that of cholesterol, No sign ificant incorporation of H-2 in (24S)-hydroxycholesterol was observed. It i s evident that 7 alpha -hydroxycholesterol must originate from a rapidly mi scible pool, about 80% of 27-hydroxycholesterol from a more slowly exchange able pool, and more than 90% of (24S)-hydroxycholesterol from a nonexchange able pool, presumably the brain, The results are discussed in relation to t he role of oxysterols in cholesterol homeostasis and their use as markers f or pathological conditions.