High Doses of Ursodeoxycholic Acid Up-Regulate the Expression of Placental Breast Cancer Resistance Protein in Patients Affected by Intrahepatic Cholestasis of Pregnancy

Azzaroli, Francesco; Raspanti, M.E.; Simoni, Patrizia; Montagnani, Marco; Lisotti, Andrea; Cecinato, Paolo; Arena, Rosario; Simonazzi, Giuliana; Farina, Antonio; Rizzo, Nicola; Mazzella, Giuseppe

doi:10.1371/journal.pone.0064101

Cited by 11 publications

(7 citation statements)

References 25 publications

(24 reference statements)

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“…However, no involvement of FXR was observed. Azzaroli et al (2013) reported that UDCA is not an effective ligand for nuclear receptor FXR, which is in line with our current data . This could be due to several reasons: (1) UDCA is a weak agonist to FXR that may explain the noninvolvement of FXR in this study and (2) could be due to the organ specific FXR mRNA expression, low level of mRNA for FXR in the heart but high expression in the kidney and adrenal gland.…”

Section: Discussionsupporting

confidence: 88%

Ursodeoxycholic acid protects cardiomyocytes against cobalt chloride induced hypoxia by regulating transcriptional mediator of cells stress hypoxia inducible factor 1α and p53 protein

Hanafi

Kadir

et al. 2017

Cell Biochemistry & Function

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In hepatocytes, ursodeoxycholic acid (UDCA) activates cell signalling pathways such as p53, intracellular calcium ([Ca ] ), and sphingosine-1-phosphate (S1P)-receptor via Gα -coupled-receptor. Recently, UDCA has been shown to protect the heart against hypoxia-reoxygenation injury. However, it is not clear whether UDCA cardioprotection against hypoxia acts through a transcriptional mediator of cells stress, HIF-1α and p53. Therefore, in here, we aimed to investigate whether UDCA could protect cardiomyocytes (CMs) against hypoxia by regulating expression of HIF-1α, p53, [Ca ] , and S1P-Gα -coupled-receptor. Cardiomyocytes were isolated from newborn rats (0-2 days), and hypoxia was induced by using cobalt chloride (CoCl ). Cardiomyocytes were treated with UDCA and cotreated with either FTY720 (S1P-receptor agonist) or pertussis toxin (PTX; Gα inhibitor). Cells were subjected for proliferation assay, beating frequency, QuantiGene Plex assay, western blot, immunofluorescence, and calcium imaging. Our findings showed that UDCA counteracted the effects of CoCl on cell viability, beating frequency, HIF-1α, and p53 protein expression. We found that these cardioprotection effects of UDCA were similar to FTY720, S1P agonist. Furthermore, we observed that UDCA protects CMs against CoCl -induced [Ca ] dynamic alteration. Pharmacological inhibition of the Gα -sensitive receptor did not abolish the cardioprotection of UDCA against CoCl detrimental effects, except for cell viability and [Ca ] . Pertussis toxin is partially effective in inhibiting UDCA protection against CoCl effects on CM cell viability. Interestingly, PTX fully inhibits UDCA cardioprotection on CoCl -induced [Ca ] dynamic changes. We conclude that UDCA cardioprotection against CoCl -induced hypoxia is similar to FTY720, and its actions are not fully mediated by the Gα -coupled protein sensitive pathways. Ursodeoxycholic acid is the most hydrophilic bile acid and is currently used to treat liver diseases. Recently, UDCA is shown to have a cardioprotection effects; however, the mechanism of UDCA cardioprotection is still poorly understood. The current data generated were the first to show that UDCA is able to inhibit the activation of HIF-1α and p53 protein during CoCl -induced hypoxia in cardiomyocytes. This study provides an insight of UDCA mechanism in protecting cardiomyocytes against hypoxia.

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Section: Discussionsupporting

confidence: 88%

Ursodeoxycholic acid protects cardiomyocytes against cobalt chloride induced hypoxia by regulating transcriptional mediator of cells stress hypoxia inducible factor 1α and p53 protein

Hanafi

Kadir

et al. 2017

Cell Biochemistry & Function

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“…The abundance of this protein was further increased in the placenta of ICP patients treated with standard doses of UDCA. Enhanced expression of placental ABCG2 has been found previously in ICP patients treated with high doses of UDCA [28]. The fact that mRNA was not enhanced in the UDCA treated group suggests that mechanisms other than transcription were involved.…”

Section: Concentration (Mm)supporting

confidence: 53%

“…To determine whether the beneficial effect of UDCA involved an enhancement of the placental barrier for bile acids and PMS, changes in the expression of OATP1B3, main responsible for bile acid transport into the placenta [26], as well as the export pumps which have been suggested to play a role in the hepatobiliary function of the placenta [13,16,27,28] were investigated. Relative SLCO1B3 mRNA levels determined by quantitative PCR in control, ICP and ICP+UDCA placentas were similar, as shown in Table 4.…”

Section: Effect Of Icp and Udca Treatment On The Placental Barrier Fomentioning

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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“…A higher concentration (10 μM) of PhIP decreased expression of BCRP while the mRNA levels were upregulated both at lower (1 μM) and higher concentrations (10 μM) (233). Ursodiol (ursodeoxycholic acid, the drug of choice for intrahepatic cholestasis in pregnancy) was shown to cause an increase in the expression of BCRP at the mRNA and protein level thus causing an efflux of bile acids from the fetal side (234). Recently, Jebbink et al studied the relation between placental transport of bile acids and ABCG2 expression in preeclamptic pregnancies complicated by hemolysis elevated liver enzymes and low platelets and found that the lower levels of bile acids in the fetal compartment compared to maternal levels is not related with the placental ABCG2 expression levels (235).…”

Section: Abc Transporters In the Placentamentioning

confidence: 99%

Placental ABC Transporters: Biological Impact and Pharmaceutical Significance

et al. 2016

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The human placenta fulfills a variety of essential functions during prenatal life. Several ABC transporters are expressed in the human placenta, where they play a role in the transport of endogenous compounds and may protect the fetus from exogenous compounds such as therapeutic agents, drugs of abuse, and other xenobiotics. To date, considerable progress has been made toward understanding ABC transporters in the placenta. Recent studies on the expression and functional activities are discussed. This review discusses the placental expression and functional roles of several members of ABC transporter subfamilies B, C, and G including MDR1/P-glycoprotein, the MRPs, and BCRP, respectively. Since placental ABC transporters modulate fetal exposure to various compounds, an understanding of their functional and regulatory mechanisms will lead to more optimal medication use when necessary in pregnancy.

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High Doses of Ursodeoxycholic Acid Up-Regulate the Expression of Placental Breast Cancer Resistance Protein in Patients Affected by Intrahepatic Cholestasis of Pregnancy

Cited by 11 publications

References 25 publications

Ursodeoxycholic acid protects cardiomyocytes against cobalt chloride induced hypoxia by regulating transcriptional mediator of cells stress hypoxia inducible factor 1α and p53 protein

Ursodeoxycholic acid protects cardiomyocytes against cobalt chloride induced hypoxia by regulating transcriptional mediator of cells stress hypoxia inducible factor 1α and p53 protein

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

Placental ABC Transporters: Biological Impact and Pharmaceutical Significance

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