Role Of Cytochrome P-450 Species For Cholesterol Homeostasis In The Brain

The blood-brain barrier is almost completely impermeable to cholesterol but allows passage of its side-chain oxidized metabolites. We and others have shown that about 2/3 of the de novo synthesis of cholesterol in this organ is balanced by excretion of 24S-hydroxycholesterol, an oxysterol generated by CYP46A1 in neuronal cells. Another side-chain oxidized cholesterol species, 27-hydroxycholesterol, is taken up by the human brain from the circulation. The latter oxysterol is generated by CYP27A1 in extracerebral tissues, and 27-hydroxycholesterol is thus a link between the extacerebral and intracerebral cholesterol pools. In the brain 27-hydroxycholesterol is rapidly metabolized into 7a-hydroxy-3-oxo-4-cholestenoic acid by the combined action of CYP27A1, CYP7B1 and 3 P-hydroxy steroid dehydrogenase. The C-27-steroid acid is efficiently excreted from the brain. The above conversions are critical for cholesterol homeostasis in the brain with the three cytochrome P-450 species as the most important factors. CYP46A1 and CYP7B1) are present in neuronal cells only and the mechanism for regulation of their activity will be discussed.