Inhibition of cholesterol synthesis and cell growth by 24(R,S),25-iminolanosterol and triparanol in cultured rat hepatoma cells

G. Popjak, A. Meenan, E. J. Parish, W. D. Nes

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39 Scopus citations

Abstract

24(R,S)-25-Iminolanosterol (IL) and triparanol added to cultures of rat hepatoma cells, H4-II-C3 (H4) interrupt the conversion of lanosterol to cholesterol and, depending on their concentrations, cause the accumulation in the cells of intermediates in the lanosterol to cholesterol conversion. At 45 μM, both substances cause the accumulation of 5α-cholesta-8(9),24-dien-3β-ol (zymosterol), and at the low concentration of 4.5 μM, they cause the accumulation of cholesta-5,24-dien-3β-ol (desmosterol). The efffect of intermediate concentrations of 9 or 22.5 μM of either substance is to cause the accumulation in the three sterols: cholesta-5,7,24-trien-3β-ol, zymosterol, and desmosterol. The synthesis of these intermediary sterols, not found normally in H4 cells, is particularly pronounced in cultures kept in lipid-depleted media that contain the inhibitors and proceeds by the use of endogenous substrates at the expense of cholesterol. The synthesis of cholesterol from [14C]acetate or [2-14C]mevalonate is completely blocked by either inhibitor even at 4.5 μM. IL or triparanol inhibits the growth of H4 cells. Cells seeded into either full growth or lipid depleted medium containing 22.5 μM IL will not grow unless the media are supplemented with low density lipoproteins (60 μg/ml). Supplementation of the media with 4.6 mM mevalonate does not counteract the inhibitory effect of IL on cell growth.

Original languageEnglish
Pages (from-to)6230-6238
Number of pages9
JournalJournal of Biological Chemistry
Volume264
Issue number11
StatePublished - 1989

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