scholarly journals Effects of Antiviral Drugs on Organic Anion Transport in Human Placental BeWo Cells

2015 ◽  
Vol 59 (12) ◽  
pp. 7666-7670 ◽  
Author(s):  
Tomohiro Nabekura ◽  
Tatsuya Kawasaki ◽  
Yuki Kamiya ◽  
Yuichi Uwai
Keyword(s):  
Cellular Uptake ◽  
Organic Anion ◽  
Anion Transport ◽  
Antiviral Drugs ◽  
Organic Anion Transport ◽  
Drug Transfer ◽  
Bewo Cells ◽  
Anion Transporters ◽  
Maximum Uptake Rate ◽  
Hiv Drugs

ABSTRACTPlacental drug transfer is important for achieving better pharmacotherapy in pregnant women and in fetuses. In the present study, we examined the effects of anti-hepatitis C virus (HCV) and anti-HIV drugs on organic anion transport in human placental BeWo cells. The cellular uptake of two fluorescence organic anions, 8-(2-[fluoresceinyl]aminoethylthio)adenosine-3′,5′-cyclic monophosphate (8-FcAMP) and fluorescein, was temperature and concentration dependent. The Michaelis constant (Km) and the maximum uptake rate (Vmax) for 8-FcAMP transport in BeWo cells were estimated to be 6.45 ± 0.75 μM and 25.55 ± 5.93 pmol/mg protein/10 min, respectively. TheKmandVmaxvalues for fluorescein uptake were estimated to be 31.2 ± 11.8 μM and 510.9 ± 90.6 pmol/mg protein/10 min, respectively. Several known substrates of organic anion transporters in human placenta, including atorvastatin, glibenclamide, estrone-3-sulfate, and rifampin, inhibited cellular uptake of 8-FcAMP and fluorescein in BeWo cells. Transport of 8-FcAMP and fluorescein was inhibited by the antiviral drugs boceprevir, telaprevir, elvitegravir, and maraviroc. These findings suggest that some antiviral drugs are sufficiently potent to influence placental drug transfer and cause drug-drug interactions.

scholarly journals Characterization of an organic anion transport system in a placental cell line

2003 ◽  
Vol 285 (5) ◽  
pp. E1103-E1109 ◽  
Author(s):  
Fanfan Zhou ◽  
Kunihiko Tanaka ◽  
Michael J. Soares ◽  
Guofeng You
Keyword(s):  
Cell Line ◽  
Transport System ◽  
Apical Membrane ◽  
Organic Anion ◽  
Phosphodiesterase Inhibitor ◽  
Anion Transport ◽  
Organic Anion Transport ◽  
Estrone Sulfate ◽  
Anion Transporters ◽  
Anion Transport System

Transporters within the placenta play a crucial role in the distribution of nutrients and xenobiotics across the maternal-fetal interface. An organic anion transport system was identified on the apical membrane of the rat placenta cell line HRP-1, a model for the placenta barrier. The apical uptake of 3H-labeled organic anion estrone sulfate in HRP-1 cells was saturable ( Km = 4.67 μM), temperature and Na+ dependent, Li+ tolerant, and pH sensitive. The substrate specificity of the transport system includes various steroid sulfates, such as β-estradiol 3,17-disulfate, 17β-estradiol 3-sulfate, and dehydroepiandrosterone 3-sulfate (DHEAS) but does not include taurocholate, p-aminohippuric acid (PAH), and tetraethylammonium. Preincubation of HRP-1 cells with 8-bromo-cAMP (a cAMP analog) and forskolin (an adenylyl cyclase activator) acutely stimulated the apical transport activity. This stimulation was further enhanced in the presence of IBMX (a phosphodiesterase inhibitor). Together these data show that the apical membrane of HRP-1 cells expresses an organic anion transport system that is regulated by cellular cAMP levels. This transport system appears to be different from the known taurocholate-transporting organic anion-transporting polypeptides and PAH-transporting organic anion transporters, both of which also mediate the transport of estrone sulfate and DHEAS.

Interaction of Human Organic Anion Transporters 2 and 4 with Organic Anion Transport Inhibitors

2002 ◽  
Vol 301 (3) ◽  
pp. 797-802 ◽  
Author(s):  
Atsushi Enomoto ◽  
Michio Takeda ◽  
Minoru Shimoda ◽  
Shinichi Narikawa ◽  
Yukari Kobayashi ◽  
...  
Keyword(s):  
Organic Anion ◽  
Anion Transport ◽  
Organic Anion Transporters ◽  
Organic Anion Transport ◽  
Anion Transporters ◽  
Transport Inhibitors

Characterization of organic anion transport inhibitors using cells stably expressing human organic anion transporters

2001 ◽  
Vol 419 (2-3) ◽  
pp. 113-120 ◽  
Author(s):  
Michio Takeda ◽  
Shinichi Narikawa ◽  
Makoto Hosoyamada ◽  
Seok Ho Cha ◽  
Takashi Sekine ◽  
...  
Keyword(s):  
Organic Anion ◽  
Anion Transport ◽  
Organic Anion Transporters ◽  
Organic Anion Transport ◽  
Anion Transporters ◽  
Transport Inhibitors

scholarly journals Characteristics of bile salt uptake into skate hepatocytes

1994 ◽  
Vol 299 (3) ◽  
pp. 665-670 ◽  
Author(s):  
G Fricker ◽  
V Dubost ◽  
K Finsterwald ◽  
J L Boyer
Keyword(s):  
Substrate Specificity ◽  
Bile Salt ◽  
Transport System ◽  
Bile Salts ◽  
Organic Anion ◽  
Anion Transport ◽  
Organic Anion Transport ◽  
Salt Uptake ◽  
Anion Transport System ◽  
Alpha 7

The substrate specificity for the transporter that mediates the hepatic uptake of organic anions in freshly isolated hepatocytes of the elasmobranch little skate (Raja erinacea) was determined for bile salts and bile alcohols. The Na(+)-independent transport system exhibits a substrate specificity, which is different from the specificity of Na(+)-dependent bile salt transport in mammals. Unconjugated and conjugated di- and tri-hydroxylated bile salts inhibit uptake of cholyltaurine and cholate competitively. Inhibition is significantly greater with unconjugated as opposed to glycine- or taurine-conjugated bile salts. However, the number of hydroxyl groups in the steroid moiety of the bile salts has only minor influences on the inhibition by the unconjugated bile salts. Since the transport system seems to represent an archaic organic-anion transport system, other anions, such as dicarboxylates, amino acids and sulphate, were also tested, but had no inhibitory effect on bile salt uptake. To clarify whether bile alcohols, the physiological solutes in skate bile, share this transport system, cholyltaurine transport was studied after addition of 5 beta-cholestane-3 beta,5 alpha,6 beta-triol, 5 alpha-cholestan-3 beta-ol and 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha-triol. These bile alcohols inhibit cholyltaurine uptake non-competitively. In contrast, uptake of 5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol, which is Na(+)-independent, is not inhibited by cholyltaurine. The findings further characterize a Na(+)-independent organic-anion transport system in skate liver cells, which is not shared by bile alcohols and has preference for unconjugated lipophilic bile salts.

scholarly journals Hepatocanalicular organic-anion transport is regulated by protein kinase C

1991 ◽  
Vol 278 (3) ◽  
pp. 637-641 ◽  
Author(s):  
H Roelofsen ◽  
R Ottenhoff ◽  
R P J Oude Elferink ◽  
P L M Jansen
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Organic Anion ◽  
Phosphodiesterase Inhibitor ◽  
Second Messenger ◽  
Anion Transport ◽  
Organic Anion Transport ◽  
Kinase C ◽  
Transport Assay ◽  
Messenger System

In order to investigate the regulation of canalicular organic-anion transport, we used a hepatocyte transport assay in which canalicular secretion of a model organic anion, dinitrophenyl-glutathione (GS-DNP), was measured in the presence of stimulators and inhibitors of the Ca2+/protein kinase C (PKC) second-messenger system and of the cyclic AMP (cAMP) second-messenger system. Vasopressin (24 nM) and the phorbol ester phorbol 12-myristate 13-acetate (1 microgram/ml), both stimulators of PKC, stimulated GS-DNP efflux by 65 +/- 36% and 55 +/- 28% respectively, whereas staurosporine (10 microM), an inhibitor of PKC, inhibited efflux by 53 +/- 13%. Glucagon and forskolin, both stimulators of the cAMP second-messenger system, as well as the cAMP analogue dibutyryl cAMP and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine, did not significantly influence the GS-DNP efflux. It can be concluded that canalicular organic-anion transport in hepatocytes is either directly or indirectly regulated by PKC.

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