Bile acid synthesis in HepG2 cells: effect of cyclosporin.
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.
Division of Hepatic Diseases, New York University Medical Center, NY 10016.
J
J
Levy
K
K
Budai
N B
NB
Javitt
D001647:Bile Acids and Salts / Q000096:biosynthesis*; D002635:Chenodeoxycholic Acid / Q000096:biosynthesis; D019826:Cholic Acid; D002793:Cholic Acids / Q000096:biosynthesis; D016572:Cyclosporine / Q000494:pharmacology*; D006801:Humans; D013261:Sterols / Q000378:metabolism; D014407:Tumor Cells, Cultured
D001647:Bile Acids and Salts; D002793:Cholic Acids; D013261:Sterols; D002635:Chenodeoxycholic Acid; D016572:Cyclosporine; D019826:Cholic Acid