Cyclosporin A blocks bile acid synthesis in cultured hepatocytes by specific inhibition of chenodeoxycholic acid synthesis.
Bile acid synthesis, determined by conversion of [4-14C]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 of 10 microM. 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 microM-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 microM). These results suggest that cyclosporin A blocks the alternative pathway in bile acid synthesis, which leads preferentially to the formation of chenodeoxycholic acid.
Princen
H M
HM
Gaubius Institute TNO, Leiden, The Netherlands.
Meijer
P
P
Wolthers
B G
BG
Vonk
R J
RJ
Kuipers
F
F
D000818:Animals; D001647:Bile Acids and Salts / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000302:isolation & purification; D002478:Cells, Cultured; D002635:Chenodeoxycholic Acid / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D002784:Cholesterol / Q000378:metabolism*; D003524:Cyclosporins / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051381:Rats
D001647:Bile Acids and Salts; D003524:Cyclosporins; D002635:Chenodeoxycholic Acid; D002784:Cholesterol