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Research ArticleENDOCRINE AND REPRODUCTIVE

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
Journal of Pharmacology and Experimental Therapeutics May 2003, 305 (2) 515-524; DOI: https://doi.org/10.1124/jpet.102.047977
M. A. Serrano
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R. I. R. Macias
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M. Vallejo
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O. Briz
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A. Bravo
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M. J. Pascual
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M. V. St-Pierre
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B. Stieger
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P. J. Meier
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J. J. G. Marin
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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

  • 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).

  • 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
    • Received December 10, 2002.
    • Accepted December 30, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 305 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 305, Issue 2
1 May 2003
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Research ArticleENDOCRINE AND REPRODUCTIVE

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
Journal of Pharmacology and Experimental Therapeutics May 1, 2003, 305 (2) 515-524; DOI: https://doi.org/10.1124/jpet.102.047977

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Research ArticleENDOCRINE AND REPRODUCTIVE

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
Journal of Pharmacology and Experimental Therapeutics May 1, 2003, 305 (2) 515-524; DOI: https://doi.org/10.1124/jpet.102.047977
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