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 alpha-demethylase (P-450(14DM)) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity were studied. 3 beta-Hydroxylanost-9(11)-en-19-oic acid (6) was found to be an effective inhibitor (IC50:0.5 microM) 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 (IC50:1.0 microM) 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.
Sonoda
Y
Y
Kyoritsu College of Pharmacy, Tokyo, Japan.
Suzuki
S
S
Udagawa
K
K
Ota
K
K
Tasaka
R
R
Fukamachi
Y
Y
Sato
Y
Y
D000085:Acetates / Q000378:metabolism; D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D007739:L Cells; D007810:Lanosterol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D050356:Lipid Metabolism; D051379:Mice; D010088:Oxidoreductases / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D058886:Sterol 14-Demethylase; D013552:Swine
D000085:Acetates; D007810:Lanosterol; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D010088:Oxidoreductases; D006903:Hydroxymethylglutaryl CoA Reductases; C548415:Cyp51 protein, mouse; D058886:Sterol 14-Demethylase