Beneficial effect of ursodeoxycholic acid on alterations induced by cholestasis of pregnancy in bile acid transport across the human placenta.
ABSTRACT The existence of impairment in bile acid transport across the placenta during intrahepatic cholestasis of pregnancy and the effect of ursodeoxycholic acid treatment (1 g/day) were investigated.
Kinetic parameters were calculated from experiments carried out on membrane vesicles obtained from basal (TPMb, fetal-facing) and apical (TPMa, maternal-facing) trophoblast plasma membranes. Bile acid uptake was measured using varying concentrations of [14C]-glycocholate and a rapid filtration technique.
The maximal velocity of transport (Vmax), the apparent affinity constant (Kt) and the efficiency (Ef) of transport (Vmax/Kt) of the anion:bile acid exchanger located at the TPMb were reduced in intrahepatic cholestasis of pregnancy. Ursodeoxycholic acid induced a reversal of Vmax, Kt and Ef to normal values. Owing to the 3-fold increase in Vmax, with no change in Kt, intrahepatic cholestasis of pregnancy induced an enhancement in Ef of ATP-independent bile acid transport across TPMa. Both Vmax and Ef were restored to normal values by ursodeoxycholic acid. Finally, in ATP-dependent bile acid transport across TPMa, a reduction in the Ef due to an increase in Vmax together with a more pronounced increase in Kt was found. This impairment was also reversed by ursodeoxycholic acid.
These results suggest that placenta bile acid transport systems are impaired in intrahepatic cholestasis of pregnancy. Moreover, together with the confirmed beneficial effect for intrahepatic cholestasis of pregnancy patients, such as the relief of pruritus and the improvement in biochemical markers of cholestasis, ursodeoxycholic acid treatment restores the ability of the placenta to carry out vectorial bile acid transfer.
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ABSTRACT: Abstract Objective: Corticotropin-releasing hormone (CRH) is one of the most potent vasodilatory factors in the human feto-placental circulation. The expression of CRH was significantly down-regulated in patients with intrahepatic cholestasis of pregnancy (ICP). Methods: One hundred pregnant women diagnosed with ICP at 34-34(+6) weeks of gestation agreed to participate in this prospective nested case-control study. Thirty ICP patients were finally recruited in this study, with 16 cases in the ursodeoxycholic acid (UDCA) group (UDCA 750 mg/d) and 14 cases in the control group (Transmetil 1000mg/d or Essentiale 1368mg/d). Maternal serum samples were obtained in diagnosis and at 37-37(+6) weeks of gestation. Placental tissues were obtained from participants after delivery. ELISA, enzymatic colorimetric and Western blotting were used to evaluate the concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bile acid (TBA) and CRH in maternal serum and expression of CRH in placenta tissues. Results: UDCA group yield more reduction on maternal serum ALT, AST and TBA levels in ICP patients (all p<0.01). Maternal serum CRH concentrations in the UDCA group after treatment (122.10±44.20) pg/ml was significantly higher than pretreatment (95.45±26.47) pg/ml (p<0.01). After treatment, maternal serum CRH concentrations of the UDCA group (122.10±44.20) pg/ml was significantly higher than in the control group (80.71±41.10) pg/ml (p<0.01). Placental CRH expression in the UDCA group (2.79±1.72) was significantly higher than in the control group (0.69 ± 0.36) (p<0.01). Conclusions: Maternal serum and placental CRH expression in ICP patients were up-regulated after treatment of UDCA. The up-regulation of CRH expression after UDCA treatment may play an important role in the therapeutic mechanism of ICP. All patients recruited in this study had severe cholestatsis (TBA ≥40µmol/L). Further studies are warranted in different gestational weeks and TBA levels to provide more evidence for the correlation between UDCA treatment and CRH expression in ICP patients.Current Medical Research and Opinion 03/2014; DOI:10.1185/03007995.2014.907560 · 2.37 Impact Factor
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ABSTRACT: Objective. To determine the correlation between maternal bile acid (BA) level and fetal pulmonary surfactant in rats and study the effects of BA on fetal lung in rat model of intrahepatic cholestasis of pregnancy. Methods. Forty pregnant rats were treated with (A) 5.5 mg/kg BA, (B) 1.4 mg/kg BA, and (C) 1 ml physiological saline. Levels of total bile acid (TBA), ALT, AST, TBIL, DBIL, and SP-A were determined and the lungs of fetal rats were analyzed for pathological changes. Results. Groups A and B intervened with BA showed significant higher level of TBA in both maternal and fetal serum, more mortality rate of fetal rats, more concentration of SP-A in fetal serum, and wider alveolus mesenchyme of fetal rats than the control Group C. Higher level of BA associated with increased fetal risk and lower numerical density of mitochondria in type II alveolar epithelial cells. The levels of TBA in maternal serum were found to have significant positive correlation with those in fetal serum and SP-A level but negatively with the area of alveolus and the numerical density of lamellar body. Conclusions. The TBA level in maternal serum showed significant association with lung pathological changes in fetal rats.International Journal of Endocrinology 03/2014; 2014:308274. DOI:10.1155/2014/308274 · 1.52 Impact Factor
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ABSTRACT: 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 intrauterine and perinatal complications. High levels of sulphated progesterone metabolites (PMS) have been suggested to be involved in the multifactorial etiopathogenesis of ICP. The aim of this study was to further investigate 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.Methods Using 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 RT-QPCR and immunofluorescence.ResultsIn ICP, markedly increased levels of bile acids (tauroconjugates >glycoconjugates >>unconjugated), progesterone and PMS in placenta and maternal serum were accompanied by enhanced levels 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 levels. 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.ConclusionsUDCA administration partially reduces ICP-induced bile acid accumulation in mothers and foetuses despite the lack of effect on levels of progesterone and PMS in maternal serum. Up-regulation of placental ABCG2 may play an important role in protecting the foetus from high levels of bile acids and PMS during ICP.British Journal of Clinical Pharmacology 08/2014; DOI:10.1111/bcp.12480 · 3.69 Impact Factor