Effects of 19-Oxygenated Lanosterol Derivatives on 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Activity and Lanosterol Demethylase Activity

抄録

The effects of 19-oxygenated lanosterol derivatives on lanosterol 14α-demethylase (P-450_14DM) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity were studied. 3β-Hydroxylanost-9 (11)-en-19-oic acid (6) was found to be an effective inhibitor (IC₅₀ : 0.5 μM) of P-450_14DM in the reconstituted system using purified pig liver P-450_14DM and was most active in inhibiting HMG-CoA reductase activity (IC₅₀ : 1.0μM) in mouse L cells. In [2-¹⁴C] acetate incorporation studies using mouse L cells, 6 was found to reduce the incorporation of acetate into C₂₇-sterol (desmosterol) with a concomitant increase in radiolabeled C₃₀-sterols. These results demonstrate that 6 is a dual-action inhibitor of cholesterol biosynthesis.