Vol. 305, Issue 2, 515-524, May 2003

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

M. A. Serrano, R. I. R. Macias, M. Vallejo, O. Briz, A. Bravo, M. J. Pascual, M. V. St-Pierre, B. Stieger, P. J. Meier and J. J. G. Marin

Departments of Biochemistry and Molecular Biology (M.A.S., M.V., M.J.P.) and Physiology and Pharmacology (R.I.R.M, O.B., J.J.G.M.), University of Salamanca, Salamanca, Spain; Veterinary School of Lugo (A.B.), University of Santiago de Compostela, Spain; and Division of Clinical Pharmacology and Toxicology (M.V.S.-P., B.S., P.J.M.), University Hospital, Zurich, Switzerland

We investigated the effects of ursodeoxycholic acid (UDCA; 60 µg/day/100 g b.wt.) on the impairment induced by maternal obstructive cholestasis during pregnancy (OCP) in the rat placenta-maternal 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. [¹⁴C]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 trophoblast-specific 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.