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1 Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, Zurich, Switzerland
2 Department of Pathology, University Hospital, Zurich, Switzerland
3 Institute of Clinical Pharmacology, Inselspital, University of Berne, Berne, Switzerland
4 Department of Biochemistry and Molecular Biology, University of Salamanca, Salamanca, Spain
5 Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain
6 Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan
* To whom correspondence should be addressed. E-mail: stpierre{at}kpt.unizh.ch.
Physiologic cholestasis linked to immature hepatobiliary transport systems for organic anions occurs in rat and human neonates. In utero, the placenta facilitates vectorial transfer of certain fetal-derived solutes to the maternal circulation for elimination. We compared the ontogenesis of organic anion transporters in the placenta and the fetal liver of the rat to assess their relative abundance throughout gestation and to determine whether the placenta compensates for the late maturation of transporters in the developing liver. The mRNA of members of the organic anion transporting polypeptide (Oatp) superfamily, the multidrug resistance protein (Mrp) family, one organic anion transporter (OAT), and the bile acid carriers, Na+-taurocholate co-transporting polypeptide (Ntcp) and bile salt export pump (Bsep) was quantified by real-time PCR. The most abundant placental transporters were Oatp4a1, whose mRNA increased 10-fold during gestation, and Mrp1. Mrp1 immunolocalized predominantly to epithelial cells of the endoplacental yolk sac, suggesting an excretory role that could sequester fetal-derived solutes in the yolk sac cavity, and faintly to the basal syncytiotrophoblast surface. The mRNA levels of Oatp2b1, Mrp3 and Bsep in the placenta exceeded those in the fetal liver until day 20 of gestation, suggesting that the fetus relies on placental clearance of substrates when expression in the developing liver is low. Mrp3 immunolocalized to the epithelium of the endoplacental yolk sac and less abundantly in the labyrinth zone and endothelium of the maternal arteries. The placental expression of Oatp1a1, Oatp1a4, Oatp1a5, Oatp1b2, Oat, Ntcp, Mrp2, and Mrp6 was low.
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