PMID- 12059062
OWN - NLM
STAT- MEDLINE
DCOM- 20021206
LR  - 20190814
IS  - 0036-5521 (Print)
IS  - 0036-5521 (Linking)
VI  - 37
IP  - 5
DP  - 2002 May
TI  - Cholestatic effect of large bilirubin loads and cholestasis protection conferred 
      by cholic acid co-infusion: a molecular and ultrastructural study.
PG  - 585-96
AB  - BACKGROUND: Large intravenous bilirubin loads block biliary phospholipid 
      secretion, produce canalicular membrane lesions and cause canalicular 
      cholestasis. Cholic acid co-infusion forestalls these untoward effects. The aim 
      of this study was first to determine whether bilirubin overload causes 
      cholestasis through reducing the activity or the hepatic expression of the bile 
      salt export pump (bsep) or Na-taurocholate co-transporting polypeptide (ntcp) 
      and, secondly, whether cholic acid co-infusion forestalls cholestasis by 
      upregulating bsep, ntcp or phosphoglycoprotein 3 (pgp3) expressions or 
      activities. A further aim was to determine whether large bilirubin infusions also 
      produce ultrastructural changes inside hepatocytes. METHODS: The effects of 
      intravenous infusion of 2 g bilirubin over 150 min on hepatic expression of bsep, 
      ntcp and pgp3 were studied in bile acid-depleted and cholic acid co-infused pigs, 
      and related to canalicular bile acid transport and bile secretion. Effects on 
      hepatocyte ultrastructural morphology were analysed by electron microscopy. 
      RESULTS: Bilirubin-induced cholestasis reflected marked diminution of bsep and 
      pgp3 transport activities and not reduced hepatic expression of these 
      transporters. Hepatocyte ultrastructural abnormalities were predominantly 
      confined to the hepatocyte canalicular membrane in cholestatic livers. Cholic 
      acid co-infusion with bilirubin conferred complete cholestasis protection through 
      enhancing pgp3 and bsep transporter activities and not through upregulating their 
      expression. Bilirubin infusion did not change ntcp expression. CONCLUSION: 
      Bilirubin-induced cholestasis is due to markedly impaired activity of the 
      membrane-embedded bsep transporter consequent upon ultrastructural injury to the 
      canalicular membrane. Cholic acid co-infusion with bilirubin enhances bsep and 
      pgp3 activities and confers protection against canalicular membrane injury and 
      bilirubin-induced cholestasis.
FAU - Labori, K J
AU  - Labori KJ
AD  - Institute for Experimental Medical Research, Ullevaal University Hospital, Oslo, 
      Norway.
FAU - Arnkvaern, K
AU  - Arnkvaern K
FAU - Bjornbeth, B A
AU  - Bjornbeth BA
FAU - Press, C McL
AU  - Press CM
FAU - Raeder, M G
AU  - Raeder MG
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Scand J Gastroenterol
JT  - Scandinavian journal of gastroenterology
JID - 0060105
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B)
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 11)
RN  - 0 (ATP-Binding Cassette Transporters)
RN  - 0 (Abcb11 protein, rat)
RN  - 0 (Carrier Proteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (Membrane Transport Proteins)
RN  - 0 (Organic Anion Transporters, Sodium-Dependent)
RN  - 0 (Pgp3 protein, Sus scrofa)
RN  - 0 (Symporters)
RN  - 145420-23-1 (sodium-bile acid cotransporter)
RN  - G1JO7801AE (Cholic Acid)
RN  - RFM9X3LJ49 (Bilirubin)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B/drug effects/metabolism
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 11
MH  - ATP-Binding Cassette Transporters/drug effects/metabolism
MH  - Animals
MH  - Bile Ducts, Intrahepatic/*drug effects/*metabolism/ultrastructure
MH  - Bilirubin/administration & dosage/*pharmacology
MH  - Carrier Proteins/drug effects/metabolism
MH  - Cholestasis/chemically induced/metabolism/*pathology
MH  - Cholic Acid/*pharmacology
MH  - Drug Interactions
MH  - Feedback, Physiological
MH  - Hepatocytes/*drug effects/*metabolism/ultrastructure
MH  - Infusions, Intravenous
MH  - *Membrane Proteins
MH  - *Membrane Transport Proteins
MH  - Microscopy, Electron
MH  - Organic Anion Transporters, Sodium-Dependent
MH  - Swine
MH  - Symporters
EDAT- 2002/06/13 10:00
MHDA- 2002/12/07 04:00
CRDT- 2002/06/13 10:00
PHST- 2002/06/13 10:00 [pubmed]
PHST- 2002/12/07 04:00 [medline]
PHST- 2002/06/13 10:00 [entrez]
AID - 10.1080/00365520252903152 [doi]
PST - ppublish
SO  - Scand J Gastroenterol. 2002 May;37(5):585-96. doi: 10.1080/00365520252903152.