title: P-glycoprotein function and expression during obstructive cholestasis in rats.
abstract: OBJECTIVE
  The present study was aimed at evaluation of in vivo biliary and renal excretion of rhodamine 123 (Rho123), a P-glycoprotein (P-gp) substrate, in rats during either acute or chronic cholestasis induced by bile duct obstruction (BDO).
  
  
  METHODS
  The Rho123 clearance study was performed either one (BDO1) or seven (BDO7) days after BDO. Bile flow was reconstituted, and bile and urine were collected after steady-state plasma concentration of Rho123 was attained. Tissue expression of P-gp was evaluated by quantitative immunohistochemistry, and immunoblotting.
  
  
  RESULTS
  Significant up-regulation of the liver P-gp protein was observed in acute and chronic cholestasis. Primary periportal location of P-gp was enlarged also to pericentral areas. In the kidneys, immunohistochemistry showed pancellular increase in P-gp after 1 day of BDO, which subsided after 7 days of BDO. Nevertheless, biliary and renal clearances (CL(Bile) and CL(R)) of Rho123 did not reflect the induction of P-gp expression. While CL(Bile) was reduced one day after cholestasis and restored on the seventh day, the CL(R) was preserved in BDO1 group and reduced in BDO7 group without change in glomerular filtration rate. In parallel, biliary and renal clearances of conjugated bilirubin were significantly reduced in both cholestatic groups compared with controls.
  
  
  CONCLUSIONS
  These findings suggest that extrahepatic cholestasis causes time-dependent changes in elimination of Rho123 which do not exactly reflect alteration of P-gp expression in the rat liver and kidney. These data may help to explain impaired elimination of P-gp substrates after short-term cholestasis that may commonly occur in clinical practice.
authors.affiliation: Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University in Prague, Hradec Kralove, The Czech Republic. micuda@lfhk.cuni.cz
authors.forename: Stanislav
authors.initials: S
authors.lastname: Micuda
authors.forename: Eva
authors.initials: E
authors.lastname: Brcakova
authors.forename: Leos
authors.initials: L
authors.lastname: Fuksa
authors.forename: Jolana
authors.initials: J
authors.lastname: Cermanova
authors.forename: Jan
authors.initials: J
authors.lastname: Osterreicher
authors.forename: Milos
authors.initials: M
authors.lastname: Hroch
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Mokry
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Pejchal
authors.forename: Jirina
authors.initials: J
authors.lastname: Martinkova
authors.forename: Frantisek
authors.initials: F
authors.lastname: Staud
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism / Q000502:physiology*; D000208:Acute Disease; D000818:Animals; D001646:Bile / Q000378:metabolism; D001663:Bilirubin / Q000378:metabolism; D015153:Blotting, Western; D001651:Cholestasis, Extrahepatic / Q000209:etiology / Q000378:metabolism*; D002908:Chronic Disease; D004195:Disease Models, Animal; D005456:Fluorescent Dyes; D007668:Kidney / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D020112:Rhodamine 123
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005456:Fluorescent Dyes; D020112:Rhodamine 123; D001663:Bilirubin