CYCLOSPORINE-A BLOCKS BILE-ACID SYNTHESIS IN CULTURED-HEPATOCYTES BY SPECIFIC-INHIBITION OF CHENODEOXYCHOLIC ACID SYNTHESIS

Bile acid synthesis, determined by conversion of [4-C-14]cholesterol into bile acids in rat and human hepatocytes and by measurement of mass production of bile acids in rat hepatocytes, was dose-dependently decreased by cyclosporin A, with 52% (rat) and 45% (human) inhibition at 10-mu-M. The decreased bile acid production in rat hepatocytes was due only to a fall in the synthesis of beta-muricholic and chenodeoxycholic acids (-64% at 10-mu-M-cyclosporin A), with no change in the formation of cholic acid. In isolated rat liver mitochondria, 26-hydroxylation of cholesterol was potently inhibited by the drug (concn. giving half-maximal inhibition = 4-mu-M). These results suggest that cyclosporin A blocks the alternative pathway in bile acid synthesis, which leads preferentially to the formation of chenodeoxycholic acid.