Zonation of multidrug resistance‐associated protein 2 in rat liver after induction with dexamethasone

Abstract

The present study was aimed to evaluate the hepatic zonation of multidrug resistance-associated protein 2 (mrp2), an important drug transporter, and its potential changes during the induction of its expression by known inducer, dexamethasone (DEX). The hepatic expression of mrp2 was studied by immunohistochemistry with consequent quantification by measurement of integral optical densities of mrp2 staining in the periportal and perivenous areas of the liver acinus in control and DEX-pretreated rats (1 mg/kg daily per os for 4 days). Overall changes in mrp2 expression and function produced by DEX were monitored using Western blotting and an in vivo clearance study of endogenous-conjugated bilirubin, a mrp2 substrate. In the control animals, a quantitative image analysis revealed the primary periportal localization of mrp2 within the liver acinus with the expression of mrp2 being 16.7-fold of that in the perivenous area. After DEX pretreatment, the expression of mrp2 increased, especially in the perivenous hepatocytes. The overall expression of mrp2 increased 3.2-fold in comparison with the control group. This observation was confirmed by Western blotting, which showed a 1.3-fold increase in the mrp2 protein after DEX pretreatment. The functional consequences of the induced mrp2 protein in the livers of the DEX-pretreated rats were demonstrated by the increased biliary excretion of conjugated bilirubin. In conclusion, these results indicate the zonation of mrp2 protein expression primarily to periportal hepatocytes. The induction by DEX produced spatially disproportional changes with an increase in the mrp2 protein being most prominent in the perivenous hepatocytes.