EFFECTS OF 19-OXYGENATED LANOSTEROL DERIVATIVES ON 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A REDUCTASE-ACTIVITY AND LANOSTEROL DEMETHYLASE ACTIVITY

The effects of 19-oxygenated lanosterol derivatives on lanosterol 14 a lpha-demethylase (P-450(14DM) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity were studied. 3 beta-Hydroxglanost-9(11 )-en-19-oic acid (6) was found to be an effective inhibitor (IC50:0.5 mu M) of P-450(14DM) in the reconstituted system using purified pig li ver P-450(14DM) and was most active in inhibiting HMG-CoA reductase ac tivity IC50:1.0 mu M) in mouse L cells. In [2-C-14]acetate incorporati on studies using mouse L cells, 6 was found to reduce the incorporatio n of acetate into C-27-sterol (desmosterol) with a concomitant increas e in radiolabeled C-30-sterols. These results demonstrate that 6 is a dual-action inhibitor of cholesterol biosynthesis.