Effect of Ursodeoxycholic Acid on the Impairment Induced by Maternal Cholestasis in the Rat Placenta-Maternal Liver Tandem Excretory Pathway

Abstract

We investigated the effects of ursodeoxycholic acid (UDCA; 60 g/day/100 g b.wt.) on the impairment induced by maternal obstructive cholestasis during pregnancy (OCP) in the rat placentamaternal liver tandem excretory pathway. A blunted catheter was implanted in the common bile duct on day 14 of pregnancy, and the tip was cut on day 21. [ 14 C]Glycocholate (GC) was then administered through the umbilical artery of "in situ" perfused placenta (placental transfer test) or through the maternal jugular vein (biliary secretion test), and GC bile output was measured. OCP impaired both GC placental transfer and maternal biliary secretion. UDCA moderately improved the latter but had a more marked beneficial effect on GC placental transfer. Histological examination revealed trophoblast atrophy and structural alterations, e.g., loss of apical membrane microvilli in OCP placentas. Gene expression level was investigated by real-time quantitative reverse transcription-polymerase chain reaction and Western blot analysis. OCP reduced both placental lactogen II (a trophoblastspecific gene) mRNA and the functional amount of epithelial tissue, determined by transplacental diffusion of antipyrin. Using a rapid filtration technique, impairment in the ATP-dependent GC transport across trophoblast apical plasma membranes obtained from OCP placentas was found. UDCA partially prevented all these changes. The expression level of organic anion transporters Oatp1, Oatp2, and Oatp4, and multidrug resistance-associated proteins Mrp1, Mrp2, and Mrp3 in whole placenta were not affected or were moderately affected by OCP but greatly enhanced by UDCA. In summary, UDCA partially prevents deleterious effects of OCP on the rat placenta-maternal liver tandem excretory pathway, mainly by preserving trophoblast structure and function.

Excretion of biliary compounds during intrauterine life

“…The available data for the rat orthologues Mrp1, Mrp2, Mrp3 and Mrp4 suggest that they have similar expression patterns as those described for human isoforms [68] . Moreover, it has been observed that, at least in rats, there is a strong up-regulation of these transporters during maternal cholestasis, which can contribute to the protection of the fetus against the high concentrations of bile acids and biliary pigments existing on the maternal side of the placenta under these circumstances [68] .…”

“…Under normal physiological circumstances, mRNA expression levels at term were low for Oatp1a1, Oatp1b4 and Oatp1b2, but high for Oatp4a1 [42] . However, maternal cholestasis induces an up-regulation of these transporters, which is further enhanced when pregnant rats are treated with UDCA [68] . In addition, Oatp2b1 is also present in rat placenta and its ability to transport taurocholate has been described [69] .…”

“…Functional studies have suggested that bilirubin might be exported across the apical pole of the trophoblast via an ATP-dependent mechanism [103] . Whether one or several isoforms of MRPs expressed in human [71] and rat [42,68] placenta are involved in this process is not known.…”

“…Moreover, it has been observed that, at least in rats, there is a strong up-regulation of these transporters during maternal cholestasis, which can contribute to the protection of the fetus against the high concentrations of bile acids and biliary pigments existing on the maternal side of the placenta under these circumstances [68] .…”

Effect of ursodeoxycholic acid treatment on the altered progesterone and bile acid homeostasis in the mother‐placenta‐foetus trio during cholestasis of pregnancy

“…Previous studies using experimental models of maternal cholestasis in rats [17] have reported an impairment in the placental transfer of bile acids due to trophoblast atrophy and a lack of apical membrane microvilli. This damage was partially prevented by UDCA administration [18].…”