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DEVELOPMENTAL PHYSIOLOGY AND PREGNANCY

Temporal expression profiles of organic anion transport proteins in placenta and fetal liver of the rat

¹Division of Clinical Pharmacology and Toxicology, Department of Medicine, and ²Department of Pathology, University Hospital, Zürich 8091, Switzerland; ³Institute of Clinical Pharmacology, Inselspital, University of Berne, 3010 Berne, Switzerland; ⁴Department of Biochemistry and Molecular Biology and ⁵Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain; and ⁶Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan

Submitted 21 May 2003 ; accepted in final form 19 July 2004

Physiological 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 cotransporting 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 sequesters 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.

organic anion transporting polypeptides; multidrug resistance proteins; bile salt export pump; ontogenesis; endoplacental yolk sac; placenta

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