Effect of tamoxifen on cholesterol synthesis in HepG2 cells and cultured rat hepatocytes

The objective of this study was to investigate the mechanisms by which tamo xifen modifies cholesterol metabolism in cellular models of liver metabolis m, HepG2 cells and rat hepatocytes. The effect of tamoxifen on cholesterol and triglyceride-palmitate synthesis was measured using isotopomer spectral analysis (ISA) and gas chromatography-mass spectrometry (GC-MS) and compar ed with the effects of progesterone, estradiol, the antiestrogen ICI 182,78 0, and an oxysterol, 25-hydroxycholesterol (250HC). Cholesterol synthesis i n cells incubated in the presence of either [1-C-13]acetate, [U-C-13]glucos e, or [4,5-C-13]mevalonate for 48 hours was reduced in the presence of 10 m u mol/L tamoxifen and 12.4 mu mol/L 250HC in both HepG2 cells and rat hepat ocytes. The ISA methodology allowed a clear distinction between effects on synthesis and effects on precursor enrichment, and indicated that these com pounds did not affect enrichment of the precursors of squalene. Progesteron e was effective in both cell;types at 30 mu mol/L and only in HepG2 cells a t 10 mu mol/L. Estradiol and ICI 182,780 at 10 mu mol/L did not inhibit cho lesterol synthesis. None of the compounds altered the synthesis of triglyce ride-palmitate in either cell type, Treatment of cells with tamoxifen produ ced accumulation of three sterol precursors of cholesterol, zymosterol, des mosterol, and Delta(8) cholesterol. This pattern of precursors indicates in hibition of Delta(24,25) reduction in addition to the previously described inhibition of Delta(8) isomerase. We conclude that tamoxifen is an effectiv e inhibitor of the conversion of lanosterol to cholesterol in cellular mode ls at concentrations comparable to those present in the plasma of tamoxifen -treated individuals. Our findings indicate that this mechanism may contrib ute to the effect of tamoxifen in reducing plasma cholesterol in humans. Co pyright (C) 1998 by W.B. Saunders Company.