INDUCTION OF MULTIDRUG-RESISTANCE GENE-EXPRESSION DURING CHOLESTASIS IN RATS AND NONHUMAN-PRIMATES

P-glycoprotein, an energy-dependent plasma membrane drug-efflux pump c apable of reducing the intracellular concentration of a variety of hyd rophobic xenobiotics, is encoded by mdr1, a member of the multidrug-re sistant (mdr) gene family. The physiological function of this protein is unknown. Because of its location on the bile canalicular domain of the hepatocyte, we and others have hypothesized that P-glycoprotein ma y have a physiological role as a biliary transporter of xenobiotics an d endobiotics and that its expression may therefore be altered in chol estasis. Both obstructive and alpha-naphthylisothiocyanate-induced cho lestasis increased mdr1a and 1b gene expression in rat liver. Hepatic P-glycoprotein levels were also increased, and the protein remained lo calized at the biliary hepatocyte domain. Induction of mdr1a and mdr1b gene expression in rat liver was accomplished by means of increased t ranscription. Alpha-naphthylisothiocyanate-induced cholestasis in cyno molgus monkeys increased hepatic expression of both the mdr1 and 2 gen es. To investigate the possible role of P-glycoprotein as a biliary ef flux transporter, biliary excretion of vinblastine, a representative s ubstrate of P-glycoprotein, was studied in rats. Increased hepatic mdr messenger RNA and P-glycoprotein levels, mediated by the xenobiotic i nducer 2-acetylaminofluorene, resulted in a significant increase in bi liary excretion of vinblastine, which was antagonized by the P-glycopr otein inhibitor verapamil. These findings suggest that P-glycoprotein functions as a biliary efflux pump for xenobiotics and, possibly, for unidentified physiological inducers that may mediate increased transcr iption of the mdr gene observed during cholestasis.