Effect of acetaminophen on expression and activity of rat liver multidrug resistance-associated protein 2 and P-glicoprotein.

GHANEM CI; GOMEZ PC; ARANA MC; PERASSOLO M; RUIZ ML; VILLANUEVA SSM; OCHOA JE; CATANIA VA; BENGOCHEA LA; MOTTINO AD

BIOCHEMICAL PHARMACOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Año: 2004 vol. 68 p. 791 - 798

0006-2952

We evaluated the effect of acetaminophen (APAP), given as a single, 1 g/kg body weight dose, on expression and activity of rat livermultidrug resistance-associated protein 2 (Mrp2) and P-glycoprotein (P-gp), two major canalicular drug transporters. The studies wereperformed 24 h after administration of the drug. APAP induced an increase in plasma membrane content of Mrp2 detected by westernblotting, consistent with increased detection of the protein at the canalicular level by immunoflourescence microscopy. In vivo biliaryexcretion of dinitrophenyl-S-glutathione, a well known Mrp2 substrate, was slightly but significantly increased by APAP, agreeing wellwith upregulation of the transporter. Basal biliary excretion of oxidized glutathione, an endogenous Mrp2 substrate, was also increased byAPAP, likely indicating increased hepatic synthesis as a result of APAP-induced oxidative stress followed by accelerated canalicularsecretion mediated by Mrp2. APAP also increased the expression of P-gp detected by western blotting and immunofluorescencemicroscopy as well as the in vivo biliary secretory rate of digoxin, a model P-gp substrate. Because specific APAP-conjugated metabolitesare Mrp2 substrates, we postulate that induction of Mrp2 by APAP may represent an adaptive mechanism to accelerate liver disposition ofthe drug. In addition, increased Mrp2-mediated elimination of oxidized glutathione may be essential in maintaining the redox equilibriumin the hepatocyte under conditions of APAP-induced oxidative stress.# 2004 Elsevier Inc. All rights reserved.