Abstract
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.
Highlights
29 7% to 44 6% (P< 0.001) with no major change in total bile acid production
HepG2 cells were grown to confluence in T-75 flasks hanced chenodeoxycholic acid synthesis, indicating a selective
Defects in bile acid synthesis can occur in HepG2 cells, in regard to cholic acid synthesis [14],they appear to be related to cell culture conditions rather than to the deletion of a gene that is essential for the expression of the enzymes needed for bile acid synthesis
Summary
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 7a-hydroxycholesterol or 56-. In this study standard and the bile acids in the medium were extracted confluent cells were harvested from T-75 flasks at 10 days.
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