Dr. Vore's laboratory is focused on understanding the transport of organic anions, such as bile salts and the glucuronide and glutathione conjugates of xenobiotics across the hepatocyte. We characterized the expression of the bile salt transporters Ntcp and Bsep (Abcb11), and the non-bile acid organic anion transporters Oatp1/2 and Mrp2 (Abcc2) in pregnancy and the postpartum period. Expression of Mrp2 is decreased markedly in pregnancy, consistent with decreased biliary excretion of glutathione and glucuronide conjugates during this period. Decreased expression of Mrp2 is due to a decrease in the rate of translation of Mrp2 mRNA in pregnancy. In contrast, expression of Ntcp mRNA and protein is stable in pregnancy, but increases postpartum in response to prolactin secretion. We have shown that prolactin acts via prolactin receptors and the Jak2-Stat5 signaling pathway to increase expression of Ntcp. We are also investigating the mechanisms by which estradiol-17-glucuronide, a naturally occurring estrogen metabolite, inhibits bile flow. This metabolite is a substrate of two ABC-transporters, Mrp2 and MDR1 P-glycoprotein (Abcb1), in canalicular membranes and that while MDR1 substrates protect against the cholestasis, Mrp2 is essential for the cholestatic response. We showed that estradiol-17-glucuronide decreases bile flow by causing the endocytic retrieval of Mrp2 and Bsep from the canalicular membrane, a process mediated by protein kinase C and the phosphoinositide 3-kinase/protein kinase B signaling pathways.

Recent studies have focused on the regulation of translation of Mrp2, and demonstrated that upstream open reading frames (uORF) in the 5'-untranslated region of rat Mrp2 decrease the rate of translation of the Mrp2 coding frame. In human MRP2, an uORF at -105 has an optimal consensus motif for translation, and decreases the rate of translation of the MRP2 coding frame.

We also study the impact of single nucleotide polymorphisms (SNPs) in human MRP2 and MRP1 (ABCC1) on transport function. MRP1 is expressed in the basolateral domain of numerous tissues, including the heart, and has a similar substrate specificity as MRP2. An MRP1 SNP, Gly671Val, is linked to doxorubicin induced cardiac injury; we have shown that this SNP markedly inhibits the ATP-dependent transport of the glutathione conjugate of 4-hydroxy-2-trans-nonenal, a product of lipid peroxidation.