LANOSTEROL 14-DEMETHYLASE ACTIVITY EXPRESSED IN RAT-BRAIN MICROSOMES

The occurrence of sterol 14-demethylase in rat brain microsomes was co nfirmed, The brain microsomes from adult rats converted lanosterol int o its 14-demethylated products, 4,4-dimethylcholesta- 8,24-dienol, and 4,4-dimethylcholesta-8,14,24-trienol, in the presence of NADPH and mo lecular oxygen, This metabolism of lanosterol was inhibited by carbon monoxide and ketoconazole, a potent inhibitor of sterol 14-demethylase P450 (P45014DM or CYP51), These facts indicated the occurrence of lan osterol 14-demethylation in rat brain microsomes and its dependency on P45014DM, A representative value of the lanosterol demethylase activi ty of the brain microsomes was 8.4 pmol/min/mg protein or 640 pmol/min /nmol of total P450, The former was about one-thirteenth of the corres ponding value observed with liver microsomes from the same rats, while the latter was 4-times higher than the corresponding value obtained w ith the liver microsomes. This fact suggested that the ratio of P45014 DM to other P450 species was higher in brain than in liver, Lanosterol 14-demethylation is situated at the root of the sterol-biosynthetic b ranch of the mevalonic acid pathway, Therefore, the present finding en zymologically supports the existence of the sterol biosynthetic pathwa y in brain.