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.
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April 1991
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Research Article|
April 15 1991
Cyclosporin A blocks bile acid synthesis in cultured hepatocytes by specific inhibition of chenodeoxycholic acid synthesis
H M Princen
;
H M Princen
*Gaubius Institute TNO, P.O. Box 612, 2300 AP Leide, University of Groningen, Bloemsingel 10, 9712 KZ Groningen, The Netherlands.
‡Department of Pediatrics, University of Groningen, Bloemsingel 10, 9712 KZ Groningen, The Netherlands.
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P Meijer
;
P Meijer
*Gaubius Institute TNO, P.O. Box 612, 2300 AP Leide, University of Groningen, Bloemsingel 10, 9712 KZ Groningen, The Netherlands.
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B G Wolthers
;
B G Wolthers
†Central Laboratory for Clinical Chemistry, University Hospital, Oostersingel 59, 9713 EZ Groninge, University of Groningen, Bloemsingel 10, 9712 KZ Groningen, The Netherlands.
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R J Vonk
;
R J Vonk
‡Department of Pediatrics, University of Groningen, Bloemsingel 10, 9712 KZ Groningen, The Netherlands.
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F Kuipers
F Kuipers
‡Department of Pediatrics, University of Groningen, Bloemsingel 10, 9712 KZ Groningen, The Netherlands.
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Biochem J (1991) 275 (2): 501–505.
Citation
H M Princen, P Meijer, B G Wolthers, R J Vonk, F Kuipers; Cyclosporin A blocks bile acid synthesis in cultured hepatocytes by specific inhibition of chenodeoxycholic acid synthesis. Biochem J 15 April 1991; 275 (2): 501–505. doi: https://doi.org/10.1042/bj2750501
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