Induction of hepatic mrp2 (cmrp/cmoat) gene expression in nonhuman primates treated with rifampicin or tamoxifen.

Abstract

The multidrug resistance protein 2 (Mrp2) also called canalicular multidrug resistance protein (cMrp) or canalicular multispecific organic anion transporter (cMoat) is a transmembrane export pump located at the canalicular domain of hepatocytes. Mrp2 transports a broad spectrum of organic anions including glucuronides, glutathione conjugates, and organic sulphates into bile. Based on previous observations in rat hepatocytes, the inducibility of mrp2 gene expression in primate liver was investigated in rhesus monkeys treated with tamoxifen or rifampicin. It was found that treatment with tamoxifen (25 mg/kg per day; over 7 days) or rifampicin (15 mg/kg per day; over 7 days) leading to an induction of cytochrome P450 3A4, resulted in a strong increase in mrp2 mRNA in the liver of male and female rhesus monkeys. On the protein level, tamoxifen also was a highly effective inducer, while rifampicin showed some inducing effect in a female and was inactive in a male monkey. In sections of paraffin-embedded liver tissue, immunofluorescence staining confirmed the results of Western blot analysis. Induced Mrp2 was localized to the canalicular domain of the hepatocytes. In conclusion, our data show inducibility of mrp2 gene expression in the liver of primates which may represent an adaptive response aimed at the enhanced biliary elimination of the inducing drugs and/or their metabolites.