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

`Cholestasis induces down-regulation of multidrug resistance protein 2 (Mrp 2, symbol Abcc2), which is localized to the canalicular membrane. Given the overlapping substrate specificities of Mrp2 and multidrug resistance prote in 3 (Mrp3, symbol Abcc3), we examined the hypothesis of a different subcel lular and lobular localization of these members of the Mrp family in rat li ver after bile duct ligation. We raised a polyclonal antibody against rat M rp3 and detected this protein in the basolateral plasma membrane of hepatoc ytes surrounding the central veins and of cholangiocytes. The Mrp3 protein level was less than 2% of the expression observed after 72 hours of obstruc tive cholestasis. After 48 hours of bile duct ligation, the Mrp3 protein wa s increased and was further enhanced after 72 hours. In 72-hour-cholestatic rat liver Mrp3 was expressed, in addition, in periportal hepatocytes, Howe ver, there was a preponderance of Mrp3 in the pericentral area of the liver lobule. In Mrp2-deficient mutant rat liver, the Mrp3 protein expression wa s most enhanced and its zonation was lost. The Mrp3 immuno-staining of chol angiocytes was preserved in cholestatic and in Mrp2-deficient mutant liver. Canalicular Mrp2 decreased and amounted to 34% of normal after bile duct l igation 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.