title: 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, 17α-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 trans-inhibition 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 concentration-dependent 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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA.
authors.forename: Shringi
authors.initials: S
authors.lastname: Sharma
authors.forename: Ewa C S
authors.initials: EC
authors.lastname: Ellis
authors.forename: Roberto
authors.initials: R
authors.lastname: Gramignoli
authors.forename: Kenneth
authors.initials: K
authors.lastname: Dorko
authors.forename: Veysel
authors.initials: V
authors.lastname: Tahan
authors.forename: Marc
authors.initials: M
authors.lastname: Hansel
authors.forename: Donald R
authors.initials: DR
authors.lastname: Mattison
authors.forename: Steve N
authors.initials: SN
authors.lastname: Caritis
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Hines
authors.forename: Raman
authors.initials: R
authors.lastname: Venkataramanan
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Strom
mesh_terms: D000077713:17 alpha-Hydroxyprogesterone Caproate; D000328:Adult; D000367:Age Factors; D000368:Aged; D001692:Biological Transport; D002478:Cells, Cultured; D003080:Cold Temperature; D016572:Cyclosporine / Q000494:pharmacology; D005260:Female; D005865:Gestational Age; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006908:Hydroxyprogesterones / Q000378:metabolism* / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D012333:RNA, Messenger / Q000378:metabolism; D012293:Rifampin / Q000494:pharmacology; D013656:Taurocholic Acid / Q000378:metabolism*; D014700:Verapamil / Q000494:pharmacology; D055815:Young Adult
chemical_list: C000715087:ABCC2 protein, human; D006908:Hydroxyprogesterones; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D012333:RNA, Messenger; D000077713:17 alpha-Hydroxyprogesterone Caproate; D013656:Taurocholic Acid; D016572:Cyclosporine; D014700:Verapamil; D012293:Rifampin