Oxidative stress and apoptosis in fetal rat liver induced by maternal cholestasis. Protective effect of ursodeoxycholic acid.
OBJECTIVE
The sensitivity of fetal rat liver to maternal obstructive cholestasis during pregnancy (OCP), and the effect of ursodeoxycholic acid (UDCA) were investigated.


METHODS
UDCA was administered (i.g. 0.6 mg/kg b.wt./day) from day 14 to day 21 of pregnancy after maternal common bile duct ligation.


RESULTS
Impairment in the activity of antioxidant enzymes, levels of total glutathione and GSH/GSSG ratio and the degrees of lipid peroxidation and protein carbonylation were similar in livers of OCP mothers and fetuses at term, despite hypercholanemia was milder in fetuses. Treatment of OCP rats with UDCA reduced maternal and fetal liver oxidative stress. Although maternal hypercholanemia was not corrected, fetal serum concentrations of major bile acids (except UDCA and beta-muricholic acid) were reduced. Fetal liver expression of key enzyme in bile acid synthesis, Cyp7a1, Cyp27 and Cyp8b1 was not affected by OCP or UDCA treatment. In OCP fetal livers, the relative expression of Bax-alpha and Bcl-2 and the activity of caspase-3, but not caspase-8, were increased. These changes were markedly reduced in fetuses of OCP animals treated with UDCA.


CONCLUSIONS
OCP induced moderate fetal hypercholanemia but marked liver oxidative stress and apoptosis that were partly prevented by treatment of pregnant rats with UDCA.
Perez
Maria J
MJ
Laboratory of Experimental Hepatology and Drug Targeting, Research Unit, University Hospital, University of Salamanca, 37007 Salamanca, Spain.
Macias
Rocio I R
RI
Duran
Cristina
C
Monte
Maria J
MJ
Gonzalez-Buitrago
Jose M
JM
Marin
Jose J G
JJ
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001647:Bile Acids and Salts / Q000096:biosynthesis; D015415:Biomarkers / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002756:Cholagogues and Choleretics / Q000627:therapeutic use*; D002779:Cholestasis / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D004792:Enzyme Precursors / Q000378:metabolism; D005260:Female; D008099:Liver / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D008431:Maternal-Fetal Exchange / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011247:Pregnancy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D014580:Ursodeoxycholic Acid / Q000627:therapeutic use*; D051028:bcl-2-Associated X Protein
D048868:Adaptor Proteins, Signal Transducing; C494828:Bax protein, rat; D001647:Bile Acids and Salts; D015415:Biomarkers; C486656:Bmf protein, rat; D002756:Cholagogues and Choleretics; D004792:Enzyme Precursors; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D014580:Ursodeoxycholic Acid; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases