Lanosterol 14-demethylase activity expressed in rat brain microsomes.

The occurrence of sterol 14-demethylase in rat brain microsomes was confirmed. The brain microsomes from adult rats converted lanosterol into its 14-demethylated products, 4,4-dimethylcholesta-8, 24-dienol, and 4,4-dimethylcholesta-8,14,24-trienol, in the presence of NADPH and molecular 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 lanosterol 14-demethylation in rat brain microsomes and its dependency on P45014DM. A representative value of the lanosterol demethylase activity 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 corresponding value observed with liver microsomes from the same rats, while the latter was 4-times higher than the corresponding value obtained with the liver microsomes. This fact suggested that the ratio of P45014DM to other P450 species was higher in brain than in liver. Lanosterol 14-demethylation is situated at the root of the sterol-biosynthetic branch of the mevalonic acid pathway. Therefore, the present finding enzymologically supports the existence of the sterol biosynthetic pathway in brain.