Cyclosporin a and enterohepatic circulation of bile salts in rats: decreased cholate synthesis but increased intestinal reabsorption.
Cyclosporin A (CsA) has been shown to inhibit synthesis and hepatobiliary transport of bile salts. However, effects of CsA on the enterohepatic circulation of bile salts in vivo are largely unknown. We characterized the effects of CsA on the enterohepatic circulation of cholate, with respect to synthesis rate, pool size, cycling time, intestinal absorption, and the expression of relevant transporters in liver and intestine in rats. CsA (1 mg. 100 g(-1). day(-1) s.c.) or its solvent was administered daily to male rats for 10 days. Cholate synthesis rate and pool size were determined by a 2H4-cholate dilution technique. Bile and feces were collected for determination of cholate and total bile salts, respectively. Cycling time and intestinal absorption of cholate were calculated. The mRNA levels and corresponding transporter protein levels in liver and intestine were assessed by real-time polymerase chain reaction and Western analysis, respectively. CsA treatment decreased cholate synthesis rate by 71%, but did not affect pool size or cycling time. CsA reduced the amount of cholate lost per enterohepatic cycle by approximately 70%. Protein levels of the apical sodium-dependent bile salt transporter (Asbt) were 2-fold increased in distal ileum of CsA-treated rats, due to post-transcriptional events. In conclusion, chronic CsA treatment markedly reduces cholate synthesis rate in rats, but does not affect cholate pool size or cycling time. Our results strongly suggest that CsA enhances efficacy of intestinal cholate reabsorption through increased Asbt protein expression in the distal ileum, which contributes to maintenance of cholate pool size in CsA-treated rats.
Hulzebos
Christian V
CV
Groningen University Institute for Drug Exploration, Center for Liver, Digestive, and Metabolic Diseases, Laboratory of Pediatrics, University Hospital Groningen, Groningen, The Netherlands. c.hulzebos@bkk.azg.nl
Wolters
Henk
H
Plösch
Torsten
T
Kramer
Werner
W
Stengelin
Siegfried
S
Stellaard
Frans
F
Sauer
Pieter J J
PJ
Verkade
Henkjan J
HJ
Kuipers
Folkert
F
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000378:metabolism; D019826:Cholic Acid / Q000096:biosynthesis*; D002849:Chromatography, Gas; D016572:Cyclosporine / Q000494:pharmacology*; D004764:Enterohepatic Circulation / Q000187:drug effects*; D005243:Feces / Q000737:chemistry; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007700:Kinetics; D008111:Liver Function Tests; D008297:Male; D013058:Mass Spectrometry; D008566:Membranes / Q000737:chemistry / Q000378:metabolism; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger / Q000096:biosynthesis / Q000302:isolation & purification; D011865:Radioisotope Dilution Technique; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D027981:Symporters
D001647:Bile Acids and Salts; D002352:Carrier Proteins; D007166:Immunosuppressive Agents; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger; D027981:Symporters; C071908:sodium-bile acid cotransporter; D016572:Cyclosporine; D019826:Cholic Acid