Role of organic anion-transporting polypeptides, OATP-A, OATP-C and OATP-8, in the human placenta-maternal liver tandem excretory pathway for foetal bilirubin

Recent functional studies have suggested that, in addition to simple diffusion, carrier-mediated transport may play an important role in foetal unconjugated bilirubin (UCB) uptake by the placenta. We have investigated the role of organic anion-transporting polypeptides (OATPs) in UCB transport by the placenta-maternal liver tandem. RNA was obtained from human liver (hL), human placenta (hP1) at term, and purified (> 80%) cytokeratin-7-positive mononucleated human trophoblast cells (hTCs). By analytical reverse transcription (RT)-PCR, agarose gel electrophoresis separation and sequencing, the mRNA of OATP-A (SLC21A3) and OATP-8 (SLC21A8) was identified in hL, hP1 and hTCs, whereas that of OATP-C (SLC21A6) was detectable only in hL. Real-time quantitative RT-PCR revealed that in hL the abundance of mRNA was OATP-8 > OATP-C much greater than OATP-A, whereas in hP1 and hTCs this was OATP-8 much greater than OATP-A much greater than OATP-C. Expression levels for these OATPs were hL much greater than hTCs > hP1. Injection of mRNA of OATP-A, OATP-C or OATP-8 or RNA from hL, hP1 or hTCs into Xenopus laevis oocytes conferred on them the ability to take up [H-3]17beta-D-glucuronosyl oestradiol ([H-3]E(2)17betaG) and [H-3]UCB, although in the case of OATP-A mRNA, the induced uptake of [H-3]UCB was very low. Cis-inhibition of [H-3]E(2)17betaG and [H-3]UCB uptake by both unlabelled E(2)17betaG and UCB was found in all cases. The affinity and efficiency of [H-3]UCB transport was OATP-C > OATP-8. Kinetic parameters for [H-3]UCB uptake induced by RNA from hTCs resembled most closely those of OATP-8. In conclusion, our results suggest that OATP-8 may play a major role in the carrier-mediated uptake of foetal UCB by the placental trophoblast, whereas both OATP-8 and OATP-C may substantially contribute to UCB uptake by adult hepatocytes.