Effect of Ursodeoxycholic Acid on the Impairment Induced by Maternal Cholestasis in the Rat Placenta-Maternal Liver Tandem Excretory Pathway
- M. A. Serrano1,
- R. I. R. Macias2,
- M. Vallejo1,
- O. Briz2,
- A. Bravo3,
- M. J. Pascual1,
- M. V. St-Pierre4,
- B. Stieger4,
- P. J. Meier4 and
- J. J. G. Marin2
- Departments of 1Biochemistry and Molecular Biology (M.A.S., M.V., M.J.P.) and 2Physiology and Pharmacology (R.I.R.M, O.B., J.J.G.M.), University of Salamanca, Salamanca, Spain; 3Veterinary School of Lugo (A.B.), University of Santiago de Compostela, Spain; and 4Division of Clinical Pharmacology and Toxicology (M.V.S.-P., B.S., P.J.M.), University Hospital, Zurich, Switzerland
- Jose J. G. Marin, Department of Physiology and Pharmacology, University of Salamanca, 37007-Salamanca, Spain. E-mail: jjgmarin{at}usal.es
Abstract
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.
Footnotes
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This work was supported in part by Grants PB98-259 from the Direccion General de Educacion Superior e Investigacion Cientifica, Ministerio de Educacion y Cultura, Spain, and SA023/02 from the Junta de Castilla y Leon, Spain, and the Swiss National Science Foundation. The group is a member of the Spanish Network for Cooperative Research on Hepatitis, Instituto de Salud Carlos III, Spain (Grant G03/015).
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DOI: 10.1124/jpet.102.047977
- Abbreviations:
- BA
- bile acid
- OCP
- obstructive cholestasis during pregnancy
- ICP
- intrahepatic cholestasis of pregnancy
- UDCA
- ursodeoxycholic acid
- GC
- glycocholate
- mTPM
- maternal-facing trophoblast plasma membrane
- PCR
- polymerase chain reaction
- BDL
- bile duct ligation
- Mrp
- multidrug resistance-associated protein
- Oatp
- organic anion-transporting polypeptide
- bLPM
- basolateral liver plasma membrane
- cLPM
- canalicular liver plasma membrane
- rPLII
- rat placental lactogen type II
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- Received December 10, 2002.
- Accepted December 30, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
