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

The multidrug resistance protein 2 (Mrp2) also called canalicular multidrug resistance protein (cMrp) or canalicular multispecific organic anion trans porter (cMoat) is a transmembrane export pump located at the canalicular do main of hepatocytes. Mrp2 transports a broad spectrum of organic anions inc luding glucuronides, glutathione conjugates, and organic sulphates into bil e. Based on previous observations in rat hepatocytes, the inducibility of m rp2 gene expression in primate liver was investigated in rhesus monkeys tre ated with tamoxifen or rifampicin. It was found that treatment with tamoxif en (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 th e protein level, tamoxifen also was a highly effective inducer, while rifam picin showed some inducing effect in a female and was inactive in a male mo nkey. In sections of paraffin-embedded liver tissue, immunofluorescence sta ining confirmed the results of Western blot analysis. Induced Mrp2 was loca lized to the canalicular domain of the hepatocytes. In conclusion, our data show inducibility of mrp2 gene expression in the liver of primates which m ay represent an adaptive response aimed at the enhanced biliary elimination of the inducing drugs and/or their metabolites.