Beneficial effect of ursodeoxycholic acid on alterations induced by cholestasis of pregnancy in bile acid transport across the human placenta

doi:10.1016/S0168-8278(98)80234-1

Journal of Hepatology

Volume 28, Issue 5, May 1998, Pages 829-839

https://doi.org/10.1016/S0168-8278(98)80234-1 Get rights and content

Abstract

Background/Aims: 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.

Methods: 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.

Results: 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.

Conclusions: 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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In this study we explored the association between ICP and changes in mitochondrial activity, as defined by the profiling of the expression of all 13 mitochondrial-encoded genes, mtDNA relative abundance and OS status. ICP has potentially severe short and long term effect on the progeny [2,3,5–7] and it is characterized by intracellular accumulation of bile acids in the placenta [3,7] affecting mitochondria [7,11,20–23]. We determined that the expression of 4 protein-coding mitochondrial-encoded genes, MT-ND4L, MT-ND4, MT-ND5 and MT-CYTB, is correlated to ICP.
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Here we explored the hypothesis that elevated bile acid levels of ICP modify the placental mitochondrial activity.
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This preliminary study suggests that mitochondria in placenta respond to high oxidative stress to modify their gene expression which may play an important role in the pathophysiology of ICP.
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Beneficial effect of ursodeoxycholic acid on alterations induced by cholestasis of pregnancy in bile acid transport across the human placenta

Abstract

Exp Toxicol Pathol

Gastroenterology

Gastroenterology

Gastroenterol Clin North Am

Hepatology

Hepatology

Biochimie

Am J Obstet Gynecol

Eur J Obstet Gynecol Reprod Biol

Clin Chim Acta

J Chromatograph

Biochim Biophys Acta

Placenta

Anal Biochem

Biochim Biophys Acta

J Hepatol

Int Hepat Comm

Correlation between fetal and maternal serum bile acid concentrations

Pediatr Res

Relationship between bile acid transplacental gradients and transport across the fetal-facing plasma membrane of the human trophoblast

Pediatr Res

Effects of lithocholic acid exposure throughout pregnancy on late prenatal and early postnatal development in rats

Teratology