Effect of maternal cholestasis on bile acid transfer across the rat placenta–maternal liver tandem

Macias, Rocio I.R.; Pascual, María José; Bravo, Ana; Alcalde, Maria P.; Larena, Monica G.; Pierre, Marie V. St.; Serrano, María A.; Marin, José J.G.

doi:10.1053/he.2000.5921

Cited by 52 publications

(48 citation statements)

References 35 publications

(50 reference statements)

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“…Moreover, at least in rodents, bilirubin does not undergo any major biotransformation during its residence in the placenta [104] . The existence of vectorial properties for transplacental bilirubin transfer are consistent with the moderate increases in serum bilirubin concentrations observed in the fetuses of pregnant rats with marked hyperbilirubinemia due to common bile duct ligation [47] . The mechanism for the placental uptake of fetal biliary pigments is not completely understood.…”

Section: Excretion Of Biliary Pigmentssupporting

confidence: 74%

“…The accumulation of bile acids in fetal serum can have serious consequences, depending on the magnitude of the hypercholanemia [45] ; in the most severe cases there is an increased risk of stillbirth and perinatal mortality [46] , while in less severe conditions, maternal hypercholanemia can affect normal fetal development, the liver being one of the tissues most affected [47] . In fact, in a laboratory animal model of maternal hypercholanemia, the repercussions on fetal hepatobiliary function, although reversible, are maintained in young animals [20] , and are characterized by a partial impairment in the ability of the liver to secrete organic anions, whereas the bile acidinduced biliary secretion of phospholipids, but not cholesterol, is increased [20,48] .…”

Section: The Hepatobiliary Excretory Function During Intrauterine Lifementioning

confidence: 99%

“…In fact, ATP-dependent mechanisms account for the vectorial transfer of these compounds in the fetus-to-mother direction [54] . This has important implications, because in situations of maternal hypercholanemia there is only a moderate increase in bile acid concentrations in fetal serum [47] .…”

Section: Excretion Of Bile Acidsmentioning

confidence: 99%

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Excretion of biliary compounds during intrauterine life

Macı́as¹,

Marin²,

Serrano³

2009

WJG

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In adults, the hepatobiliary system, together with the kidney, constitute the main routes for the elimination of several endogenous and xenobiotic compounds into bile and urine, respectively. However, during intrauterine life the biliary route of excretion for cholephilic compounds, such as bile acids and biliary pigments, is very poor. Although very early in pregnancy the fetal liver produces bile acids, bilirubin and biliverdin, these compounds cannot be efficiently eliminated by the fetal hepatobiliary system, owing to the immaturity of the excretory machinery in the fetal liver. Therefore, the potentially harmful accumulation of cholephilic compounds in the fetus is prevented by their elimination across the placenta. Owing to the presence of detoxifying enzymes and specific transport systems at different locations of the placental barrier, such as the endothelial cells of chorionic vessels and trophoblast cells, this organ plays an important role in the hepatobiliary-like function during intrauterine life. The relevance of this excretory function in normal fetal physiology is evident in situations where high concentrations of biliary compounds are accumulated in the mother. This may result in oxidative stress and apoptosis, mainly in the placenta and fetal liver, which might affect normal fetal development and challenge the fate of the pregnancy. The present article reviews current knowledge of the mechanisms underlying the hepatobiliary function of the fetal-placental unit and the repercussions of several pathological conditions on this tandem.

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Section: Excretion Of Biliary Pigmentssupporting

confidence: 74%

Section: The Hepatobiliary Excretory Function During Intrauterine Lifementioning

confidence: 99%

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Excretion of biliary compounds during intrauterine life

Macı́as¹,

Marin²,

Serrano³

2009

WJG

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“…Among transporters involved, ABCG2, also known as breast cancer resistance protein (BCRP), plays a key role [16]. 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].…”

Section: Introductionmentioning

confidence: 99%

“…Although a few studies have already addressed the issue of the effect of maternal cholestasis on foetal bile acid homeostasis in humans [19] or in animal models [17,18], the whole picture is incomplete, which has prompted us to investigate further the impairment in bile acid homeostasis in the mother-placenta-foetus trio during ICP. We have also addressed the question of whether removal of PMS is included among the mechanisms of action accounting for the beneficial effect of UDCA in ICP.…”

Section: Introductionmentioning

confidence: 99%

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

Estiú¹,

Monte

Rivas

et al. 2015

Brit J Clinical Pharma

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AIMIntrahepatic cholestasis of pregnancy (ICP) is characterized by pruritus and elevated bile acid concentrations in maternal serum. This is accompanied by an enhanced risk of intra-uterine and perinatal complications. High concentrations of sulphated progesterone metabolites (PMS) have been suggested to be involved in the multifactorial aetiopathogenesis of ICP. The aim of this study was to investigate further the mechanism accounting for the beneficial effect of oral administration of ursodeoxycholic acid (UDCA), which is the standard treatment, regarding bile acid and PMS homeostasis in the mother-placenta-foetus trio. METHODUsing HPLC-MS/MS bile acids and PMS were determined in maternal and foetal serum and placenta. The expression of ABC proteins in placenta was determined by real time quantitative PCR (RT-QPCR) and immunofluorescence. RESULTSIn ICP, markedly increased concentrations of bile acids (tauroconjugates > glycoconjugates >> unconjugated), progesterone and PMS in placenta and maternal serum were accompanied by enhanced concentrations in foetal serum of bile acids, but not of PMS. UDCA treatment reduced bile acid accumulation in the mother-placenta-foetus trio, but had no significant effect on progesterone and PMS concentrations. ABCG2 mRNA abundance was increased in placentas from ICP patients vs. controls and remained stable following UDCA treatment, despite an apparent further increase in ABCG2. CONCLUSIONUDCA administration partially reduces ICP-induced bile acid accumulation in mothers and foetuses despite the lack of effect on concentrations of progesterone and PMS in maternal serum. Up-regulation of placental ABCG2 may play an important role in protecting the foetus from high concentrations of bile acids and PMS during ICP. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Intrahepatic cholestasis of pregnancy (ICP) is characterized by an increase in maternal serum concentrations of bile acids and sulphated progesterone metabolites. WHAT THIS STUDY ADDS• The accumulation of sulphated progesterone metabolites in the serum of ICP patients is associated with enhanced concentrations of progesterone. Although these compounds may be involved in the aetiopathogenesis of ICP, the magnitude of this accumulation does not correlate with the degree of hypercholanaemia in ICP patients.• The beneficial effect of ursodeoxycholic acid (UDCA) treatment includes a reduction of maternal hypercholanaemia, which is not dependent on the correction of progesterone metabolites accumulation.• In spite of marked increases in maternal serum concentrations of sulphated progesterone metabolites and bile acids in ICP patients, the concentrations of these compounds in foetal serum remain normal or are only moderately elevated, respectively. The latter can be corrected by treatment with UDCA.• The ABCG2 export pump located at the apical membrane of trophoblast cells plays an important role in the placental barrier for sulphated progesterone metabolites and bile acids. ABCG2 up-regulation during ICP, and further by UDCA treatment, ...

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