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Journal of Lipid Research, Vol 35, 1795-1800, Copyright © 1994 by Lipid Research, Inc.

ARTICLES

Bile acid synthesis in HepG2 cells: effect of cyclosporin

J Levy, K Budai and NB Javitt
Division of Hepatic Diseases, New York University Medical Center, NY 10016.

The hypothesis that cyclosporin specifically affects the pathway of bile acid synthesis that begins with 27-hydroxylation of cholesterol was evaluated in HepG2 cells, which synthesize chenodeoxycholic acid and cholic acid from endogenous 7 alpha-hydroxycholesterol. At a concentration in the medium of 8.3 microM cyclosporin, the proportion of cholic acid increased from 29 +/- 7% to 44 +/- 6% (P < 0.001) with no major change in total bile acid production. Chenodeoxycholic acid synthesis was enhanced by the addition of either 7 alpha- hydroxycholesterol or 5 beta-cholestane-3 alpha,7 alpha-diol to the medium and cholic acid synthesis was enhanced by the addition of 5 beta- cholestane-3 alpha,7 alpha,12 alpha-triol to the medium. Cyclosporin significantly inhibited only enhanced chenodeoxycholic acid synthesis, indicating a selective interference in mitochondrial side chain oxidation of less polar intermediates in bile acid synthesis derived from either initial 7 alpha- or initial 27-hydroxylation of cholesterol. The increase in the proportion of cholic acid that occurs in the presence of cyclosporin mimics that occurring in genetically determined sterol 27-hydroxylase deficiency (cerebrotendinous xanthomatosis). Cyclosporin is useful for dissecting the subcellular pathways of bile acid synthesis.
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