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Journal of Lipid Research, Vol 35, 1524-1534, Copyright © 1994 by Lipid Research, Inc.

ARTICLES

The ansamycins: hypolipidemic agents stimulating cholesterol removal by nonclassical mechanisms

JC Gibson, WH Lee and JR Piccolo
Research Department, CIBA-GEIGY Corp., Summit, NJ 07901.

The ansamycins CGP 43371 and CGS 24565 are derivatives of the antibiotic rifamycin that reduce plasma cholesterol levels in both primate and nonprimate species. In vivo, a striking accumulation of macrophage cholesteryl ester was seen in ansamycin-treated rats and hamsters, but carbon clearance studies and reticuloendothelial system blockade by gadolinium chloride indicated that phagocytosis was not involved. Simple addition of an ansamycin to macrophages or monocytes in vitro failed to stimulate radiolabeled lipoprotein cholesteryl ester association or mass accumulation. In contrast to mononuclear cells, however, the ansamycins did enhance radiolabeled lipoprotein cholesteryl ester association by liver cells in vitro. Primary hepatocyte cultures prepared from rats treated with radiolabeled CGP 43371 secreted CGP 43371 over an 18-h period in a fraction floating at d < 1.02 g/ml after density gradient ultracentrifugation that was relatively enriched in apoA-I. The medium containing this secreted [14C]GP 43371-labeled lipoprotein was capable of enhancing the cholesteryl ester content of macrophages in vitro, suggesting that ansamycin-induced liver modification of lipoproteins might be involved. These drugs may serve as valuable tools for studying mechanisms of lipoprotein uptake.
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