Hepatobiliary Disposition of 17-OHPC and Taurocholate in Fetal Human Hepatocytes: A Comparison with Adult Human Hepatocytes

Abstract

Little information is available in the literature regarding the expression and activity of transporters in fetal human liver or cultured cells. A synthetic progesterone structural analog, 17a-hydroxyprogesterone caproate (17-OHPC), is used in the prevention of spontaneous abortion in women with a history of recurrent miscarriage (habitual abortion). 17-OHPC has been reported to traverse the placental barrier and gain access to fetal circulation. In this study, the role of transporters in the disposition of 17-OHPC in fetal and adult human hepatocytes was examined. Progesterone metabolites have been reported to induce transinhibition of bile acid transporter, ABCB11. Thus, we investigated the effect of 17-OHPC or its metabolites on [ 3 H]taurocholic acid transport in sandwich-cultured human fetal and adult hepatocytes. 17-OHPC was taken up rapidly into the cells and transported out partially by an active efflux process that was significantly inhibited by cold temperature, cyclosporine, verapamil, and rifampin. The active efflux mechanism was observed in both adult and fetal hepatocyte cultures. 17-OHPC produced a concentrationdependent inhibition of taurocholate efflux into canaliculi in sandwich-cultured adult and fetal human hepatocytes. However, given the high concentrations required to cause inhibition of these transport processes, no adverse effects would be anticipated from therapeutic levels of 17-OHPC. We also evaluated the expression of various hepatic transporters (ABCB1, ABCB4, SLCO1B1, SLCO1B3, SLCO2B1, ABCB11, SLC10A1, ABCC2, ABCC3, ABCC4, and ABCG2) in fetal and adult hepatocytes. With the exception of ABCB4, all transporters examined were expressed, albeit at lower mRNA levels in fetal hepatocytes compared with adults.

Proteomic Analysis of the Developmental Trajectory of Human Hepatic Membrane Transporter Proteins in the First Three Months of Life

“…With exploration of the relationship between age and protein expression, four developmental patterns emerged. We describe these patterns, but they should be interpreted with care, as after correction for multiple testing, the effect of (Mooij et al, 2014), and low expression in fetal (n = 30) versus pediatric and adult samples (n = 30 each) (Burgess et al, 2015), and again lower mRNA expression in 3 fetuses than 3 adults (Sharma et al, 2013).…”

Malaria Infection Alters the Expression of Hepatobiliary and Placental Drug Transporters in Pregnant Mice

“…This suggests that drug transporter regulatory mechanisms occur in fetal tissues and that these tissues are also subject to inflammation-mediated changes in gene expression. Although expression of Abcb1a and Abcb1b is much lower in fetal liver than that of adult levels (Sharma et al, 2013), levels are thought to increase rapidly postgestation (Lee et al, 2011); therefore inflammationmediated alterations in gene expression could impact ontogenic changes and potential function in fetal and neonatal livers.…”

The Hepatobiliary Disposition of Timosaponin B2 Is Highly Dependent on Influx/Efflux Transporters but Not Metabolism

“…Temperature-dependent accumulation was determined by incubating the hepatocytes with warm (37°C) and cold (4°C) dosing solution, dmd.aspetjournals.org as previously described elsewhere (Sharma et al, 2013). In brief, hepatocytes were incubated in warm (37°C) and cold (4°C) media with 1 ml of dosing solution (HBSS containing 10 mM TB-2).…”