Regulation of multidrug resistance protein 2 (Mrp2) by microsomal enzyme inducers and postnatal ontogeny

It is known that biliary elimination of organic anions can be increased in both young and mature rats by treatment with microsomal enzyme inducers, but the inducible efflux transporter responsible for this phenomenon has not yet been identified. Multidrug Resistance Protein 2 (Mrp2) is an ATP-dependent efflux transporter that transports organic anions into bile. Though well characterized in terms of substrates, the regulation of Mrp2 by microsomal enzyme inducers and age is not well understood. Thus, the main objective of this dissertation was to determine whether the increase in biliary excretion of endogenous and xenobiotic organic anions after microsomal enzyme induction is due to an increase of Mrp2.; The studies of this dissertation demonstrated that phenobarbital (PB) and preg-nenolone-16α-carbonitrile (PCN) increase bile flow and biliary excretion of endogenous and xenobiotic organic anions by increasing Mrp2 protein on canalicular membranes. In contrast, 3-methylcholanthrene and benzo(a)pyrene do not affect biliary organic anion excretion because they do not affect Mrp2 expression. Furthermore, the increase in Mrp2 is not the main cause of the enhanced plasma disappearance of dibromosulfophthalein after microsomal enzyme induction.; A comparison of Mrp2 expression after treatment with 18 microsomal enzyme inducers demonstrated that Mrp2 protein was significantly increased by pregnane-X-receptor (PXR) ligands and antioxidant/electrophile response element (ARE/EpRE) ligands. None of the 18 microsomal enzyme inducers significantly affected Mrp2 mRNA. Finally, Mrp2 expression was examined in male and female rats during normal and PCN-induced postnatal ontogeny. Mrp2 protein in male and female rats changed in an age-dependent manner, with both sexes reaching comparable adult levels by day 90. PCN increased Mrp2 protein, but not Mrp2 mRNA, in both sexes from 10 to 90 days of age.; In summary, these studies demonstrate that increases in Mrp2 protein after microsomal enzyme induction is responsible for drug-drug interactions involving endogenous and xenobiotic organic anions. In addition, Mrp2 protein expression in young male and female rats can be increased by microsomal enzyme induction, thus causing potential drug-drug interactions in young rats, as well. Furthermore, regulation of Mrp2 by microsomal enzyme inducers seems to occur in a non-classic manner (i.e., posttranscriptional mechanisms rather than increased transcription).