Excretion of fetal biliverdin by the rat placenta-maternal liver tandem

Abstract

Fetal liver immaturity is accompanied by active heme catabolism. Thus fetal biliary pigments must be excreted toward the mother by the placenta. To investigate biliverdin handling by the placenta-maternal liver tandem, biliverdin-IXalpha was administered to 21-day pregnant rats through the jugular vein or the umbilical artery of an in situ perfused placenta. Jugular administration resulted in the secretion into maternal bile of both bilirubin and biliverdin (3:1). However, when biliverdin was administered to the placenta, most of it was transformed into bilirubin before being transferred to the maternal blood. Injecting Xenopus laevis oocytes with mRNA from rat liver or placenta enhanced their ability to take up biliverdin, which was inhibited by estradiol 17beta-d-glucuronide. The expression of three OATP isoforms in this system revealed that they have a varying degrees of ability to transport biliverdin (Oatp1/1a1 > Oatp2/1a4 > Oatp4/1b2). The abundance of their mRNA in rat trophoblast was Oatp1/1a1 >> Oatp4/1b2 > Oatp2/1a4. The expression of biliverdin-IXalpha reductase in rat placenta was detected by RT-PCR/sequencing and Western blot analysis. The relative abundance of biliverdin-IXalpha reductase mRNA (determined by real-time quantitative RT-PCR) was fetal liver > placenta > maternal liver. Common bile duct ligation in the last week of pregnancy induced an upregulation of biliverdin-IXalpha reductase in maternal liver but had no effect on fetal liver and placenta. In conclusion, several members of the OATP family may contribute to the uptake of fetal biliverdin by the rat placenta. Before being transferred to the mother, biliverdin is extensively converted into bilirubin by biliverdin-IXalpha reductase, whose expression is maintained even though bilirubin excretion into maternal bile is impaired.

Excretion of biliary compounds during intrauterine life

“…However, biliverdin is able to inhibit bilirubin transfer in rat placenta when co-administered through the umbilical artery of in situ perfused rat placentas [106] . The transport of biliverdin from the trophoblast toward the mother is very poor and/or that placental biotransformation of biliverdin into bilirubin is very efficient.…”

“…Hepatobiliary role of the fetal-placental unit 821 MRP2, and probably MRP1, are also able to perform ATP-dependent transport of bilirubin glucuronides [5] . However, owing to the low UDP-glucuronosyl transferase activity of the fetal liver and the absence of placental biotransformation of unconjugated bilirubin during transplacental transfer [106] , MRP2 and MRP1 are not expected to play an important role in bilirubin transfer across the placenta.…”

“…It has been shown that biliverdin itself is poorly transferred-without prior reduction to bilirubin -across the guinea pig [26] and rat [106] placenta. However, biliverdin is able to inhibit bilirubin transfer in rat placenta when co-administered through the umbilical artery of in situ perfused rat placentas [106] .…”

“…Among the transporters involved in fetal biliverdin uptake by rat placenta, several OATPs, in particular Oatp1a1, may be involved [106] . Once in the placenta, and prior to being transferred to the mother, biliverdin is extensively converted into bilirubin by BVRα, which is highly expressed in this organ [106] .…”

“…Once in the placenta, and prior to being transferred to the mother, biliverdin is extensively converted into bilirubin by BVRα, which is highly expressed in this organ [106] . The small amount of biliverdin that reaches the maternal blood is efficiently taken up, probably in part by Oatp1a1, Oatp1a4 and Oatp1b2, and biotransformed into bilirubin, which joins the fetal bilirubin transferred by the placenta, to be eliminated mainly through secretion into the bile by the maternal liver [106] .…”