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

Abstract

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 (hPl) 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, hPl 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 ≫ OATP-A, whereas in hPl and hTCs this was OATP-8 ≫ OATP-A ≫ OATP-C. Expression levels for these OATPs were hL ≫ hTCs > hPl. Injection of mRNA of OATP-A, OATP-C or OATP-8 or RNA from hL, hPl or hTCs into Xenopus laevis oocytes conferred on them the ability to take up [3H]17β-d-glucuronosyl oestradiol ([3H]E217βG) and [3H]UCB, although in the case of OATP-A mRNA, the induced uptake of [3H]UCB was very low. Cis-inhibition of [3H]E217βG and [3H]UCB uptake by both unlabelled E217βG and UCB was found in all cases. The affinity and efficiency of [3H]UCB transport was OATP-C > OATP-8. Kinetic parameters for [3H]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.