Up-regulation of basolateral multidrug resistance protein 3 (Mrp3) in cholestatic rat liver.

Abstract

Cholestasis induces down-regulation of multidrug resistance protein 2 (Mrp2, symbol Abcc2), which is localized to the canalicular membrane. Given the overlapping substrate specificities of Mrp2 and multidrug resistance protein 3 (Mrp3, symbol Abcc3), we examined the hypothesis of a different subcellular and lobular localization of these members of the Mrp family in rat liver after bile duct ligation. We raised a polyclonal antibody against rat Mrp3 and detected this protein in the basolateral plasma membrane of hepatocytes surrounding the central veins and of cholangiocytes. The Mrp3 protein level was less than 2% of the expression observed after 72 hours of obstructive cholestasis. After 48 hours of bile duct ligation, the Mrp3 protein was increased and was further enhanced after 72 hours. In 72-hour-cholestatic rat liver Mrp3 was expressed, in addition, in periportal hepatocytes. However, there was a preponderance of Mrp3 in the pericentral area of the liver lobule. In Mrp2-deficient mutant rat liver, the Mrp3 protein expression was most enhanced and its zonation was lost. The Mrp3 immunostaining of cholangiocytes was preserved in cholestatic and in Mrp2-deficient mutant liver. Canalicular Mrp2 decreased and amounted to 34% of normal after bile duct ligation for 72 hours. We conclude that the hepatocellular up-regulation of Mrp3 in cholestasis together with cholangiocellular Mrp3 may compensate for the biliary obstruction and impaired canalicular Mrp2 function by clearing cholephilic anionic substances into the blood.

• Authors: M G Donner, D Keppler
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 34 Issue 2 Pg. 351-9 (Aug 2001) ISSN: 0270-9139 [Print] United States
• PMID: 11481620 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B
• ATP-Binding Cassette Transporters
• Abcc2 protein, rat
• Carrier Proteins
• multidrug resistance protein 3

Topics

• ATP Binding Cassette Transporter, Subfamily B (metabolism)
• ATP-Binding Cassette Transporters (metabolism)
• Animals
• Carrier Proteins (metabolism)
• Cholestasis (metabolism)
• Fluorescent Antibody Technique, Indirect
• Immunoblotting
• Intracellular Membranes (metabolism)
• Liver (metabolism)
• Male
• Rats
• Rats, Sprague-Dawley
• Up-Regulation