Overview of Drug Transporters in Human Placenta
Abstract
:1. Introduction
2. Literature Review Procedure
3. Physiological Functions of Drug Transporters
3.1. ABC Transporters
3.1.1. ABCB (Multidrug Resistance: MDR) Family
3.1.2. ABCC (Multidrug-Resistance-Associated Protein: MRP) Family
3.1.3. ABCG2 (Breast Cancer Resistant Protein: BCRP)
3.2. SLC Transporters
3.2.1. SLCO (Organic Anion Transporting Polypeptide: OATP) Family
3.2.2. SLC22A Family
3.2.3. SLC29A (Equilibrative Nucleotide Transporter: ENT) Family
3.2.4. SLC47A (Multidrug and Toxin Extrusion: MATE) Family
4. Morphology of the Human Placental Barrier
5. Drug Transporters Reported in Human Placenta
Superfamily | Family | Transporter Name | HGNC Name | Physiological Substrates | Drug Substrates | Localization in Placenta | Period (Trimester) | Cell Lines | References | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Sy | Cy | FE | 1st | 2nd | 3rd | Unknown | BeWo | JEG3 | JAR | HTR | |||||||
ABC | ABCB | MDR1 | ABCB1 | hydrophobic compounds | vinblastine, vincristine, digoxin, saquinavir | + | + | + | R, P | R, P | R, P | + | + | + | + | [15,32,33,34,35,36,37,38,39,40] | |
MDR3 | ABCB4 | bile acids | vinblastine, digoxin | + | NA | NA | R | NA | R | + | + | + | NA | [11,15,33,37] | |||
ABCC | MRP1 | ABCC1 | bile acids, folic acid, LTC4, E217bG, | maraviroc, pravastatin | + | ND | + | R | NA | R, P | + | + | + | + | [37,41,42,43,44,45,46] | ||
MRP2 | ABCC2 | organic anion | talinolol | + | NA | NA | R | R, P | R, P | + | +(P) | + | NA | [15,42,44,45,47,48,49,50,51] | |||
MRP3 | ABCC3 | cholate | methotrexate (HEK293) | + | ND | + | R | NA | R, P | + | + | + | NA | [15,42,44,45,48,52] | |||
MRP4 | ABCC4 | estradiol, cAMP, cGMP, | adefovir (kidney) | + | NA | NA | NA | NA | R, P | + | + | + | NA | [15,48,53] | |||
MRP5 | ABCC5 | cAMP, cGMP | doxorubicin (nonsmallcell lungcancer cell-lines) | + | ND | + | R | NA | R, P | + | NA | NA | NA | [44,45,54] | |||
MRP6 | ABCC6 | LTC4 | etoposide, doxorubicin, BQ−123 ** | NA | NA | NA | NA | NA | NA | R | NA | NA | NA | NA | [18,55,56] | ||
MRP8 | ABCC11 | cGMP, cAMP | maraviroc | NA | NA | NA | NA | NA | R | + | + | + | NA | [15,57,58,59,60] | |||
ABCG | BCRP | ABCG2 | organic anion | pravastatin, nitrofurantoin | + | + | + | R, P | R, P | R, P | +(P) | +(P) | + | NA | [15,35,37,38,40,50,51,61,62,63,64] | ||
SLC | SLCO | OATP1A2 | SLCO1A2 | unconjugated bilirubin, steroids, thyroid hormones | maraviroc | + | + | ND | R, P | NA | R, P | + | + | + | NA | [11,15,41,65] | |
OATP1B1 | SLCO1B1 | estradiol, taurocholate, leukotrienes, steroids, thyroid hormones | rifampicin (kidney), pravastatin (HEK293) | NA | NA | NA | R | NA | ND | ND | ND | ND | NA | [11,15,66,67] | |||
OATP2B1 | SLCO2B1 | estrone 3-sulfate | fexofenadine | + | + | NA | NA | NA | R | + | + | + | NA | [11,15,68,69] | |||
OATP3A1 | SLCO3A1 | vasopressin, PG, thyroid hormones | simvastatin (HEK293) | NA | NA | NA | R | NA | R | NA | NA | NA | NA | [11,68,70] | |||
OATP4A1 | SLCO4A1 | taurocholate, PG | ** | + | ND | ND | R, P | NA | R, P | NA | NA | NA | NA | [11,65,71] | |||
SLC22A | OCT1 | SLC22A1 | choline, dopamine | metformin (HEK293), pazopanib(hepatocytes), ranitidine (HEK293) | NA | NA | NA | NA | NA | R | + | + | NA | NA | [24,27,28,72,73,74,75,76] | ||
OCT2 | SLC22A2 | histamine, dopamine, | metformin (HEK293) | NA | NA | NA | NA | NA | R | ND | ± | NA | NA | [24,27,72,76,77] | |||
OCT3 | SLC22A3 | organic cations | metformin (HEK293) | + * | + * | + | R, P | R, P | R, P | ND | ND | NA | NA | [26,27,72,76,77,78,79] | |||
OCTN1 | SLC22A4 | carnitine, organic cations | sulpiride ** | NA | NA | NA | NA | NA | R | + | + | NA | NA | [27,80] | |||
OCTN2 | SLC22A5 | carnitine, organic cations | etoposide (HEK293), quinidine, verapamil, and valproate (HEK293) | + | ND | + * | NA | NA | R, P | + | + | NA | NA | [27,81,82,83,84] | |||
OAT1 | SLC22A6 | alpha -ketoglutarate, PGE2, PGF2a, cGMP, cAMP | adefovir (kidney) | NA | NA | NA | NA | NA | NA | R | NA | NA | NA | NA | [85] | ||
OAT4 | SLC22A11 | estrone 3-sulfate, | olmesartan | + | + | ND | R, P | R, P | R, P | + | + | NA | NA | [51,68,86,87,88,89,90] | |||
OAT10 | SLC22A13 | urate, organic cations | cyclosporine ** | + | ND | ND | NA | R, P | R, P | + | NA | NA | NA | [88,91,92] | |||
SLC29A | ENT1 | SLC29A1 | adenosine, inosine | entecavir, abacavir | + | ND | + | R | NA | R, P | + | NA | NA | NA | [93,94,95,96,97] | ||
ENT2 | SLC29A2 | adenosine, inosine | entecavir | + | ND | ND | R | NA | R, P | + | NA | NA | NA | [93,94,96,97] | |||
ENT4 | SLC29A4 | dopamine, histamine, adenosine | atenolol (HEK293) | NA | NA | NA | NA | NA | R | NA | NA | NA | NA | [73,98] | |||
SLC47A | MATE1 | SLC47A1 | creatine, thiamine | metformin (HEK293), cimetidine (HEK293) | NA | NA | NA | R | NA | R | NA | NA | NA | NA | [76,99,100] | ||
MATE2 | SLC47A2 | creatine, thiamine | metformin (HEK293), aciclovir (HEK293) | NA | NA | NA | R | NA | R | NA | NA | NA | NA | [76,99,101] |
5.1. ABC Transporters
5.1.1. ABCB (MDR) Family
5.1.2. ABCC (MRP) Family
5.1.3. ABCG2 (BCRP)
5.2. SLC Transporters
5.2.1. SLC21A (OATP) Family
5.2.2. SLC22A Family
5.2.3. SLC29A (ENT) Family
5.2.4. SLC47A (MATE) Family
6. Regulation of Placental Drug Transporters
7. Experimental Models for Human Placental Drug Transport
7.1. Cell Lines
7.2. Placental Explants
7.3. Placental Membrane
7.4. Placenta-on-a-Chip
7.5. Ex Vivo Placenta Perfusion Model
7.6. Functional Assays on Placental Drug Transporters
8. Discussion
9. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Juan-Carlos, P.-D.M.; Perla-Lidia, P.-P.; Stephanie-Talia, M.-M.; Mónica-Griselda, A.-M.; Luz-María, T.-E. ABC transporter superfamily. An updated overview, relevance in cancer multidrug resistance and perspectives with personalized medicine. Mol. Biol. Rep. 2021, 48, 1883–1901. [Google Scholar] [CrossRef] [PubMed]
- Schumann, T.; König, J.; Henke, C.; Willmes, D.M.; Bornstein, S.R.; Jordan, J.; Fromm, M.F.; Birkenfeld, A.L. Solute Carrier Transporters as Potential Targets for the Treatment of Metabolic Disease. Pharmacol. Rev. 2020, 72, 343–379. [Google Scholar] [CrossRef]
- Blanco-Castañeda, R.; Galaviz-Hernández, C.; Souto, P.C.D.S.; Lima, V.V.; Giachini, F.R.; Escudero, C.; Damiano, A.E.; Barragán-Zúñiga, L.J.; Martínez-Aguilar, G.; Sosa-Macías, M. The role of xenobiotic-metabolizing enzymes in the placenta: A growing research field. Expert Rev. Clin. Pharmacol. 2020, 13, 247–263. [Google Scholar] [CrossRef] [PubMed]
- Dilworth, M.; Sibley, C. Review: Transport across the placenta of mice and women. Placenta 2012, 34, S34–S39. [Google Scholar] [CrossRef] [PubMed]
- Schmidt, A.; Prieto, D.M.M.; Pastuschek, J.; Fröhlich, K.; Markert, U.R. Only humans have human placentas: Molecular differences between mice and humans. J. Reprod. Immunol. 2015, 108, 65–71. [Google Scholar] [CrossRef] [PubMed]
- Dean, M.; Rzhetsky, A.; Allikmets, R. The Human ATP-Binding Cassette (ABC) Transporter Superfamily. Genome Res. 2001, 11, 1156–1166. [Google Scholar] [CrossRef] [PubMed]
- Mai, Y.; Dou, L.; Yao, Z.; Madla, C.M.; Gavins, F.K.H.; Taherali, F.; Yin, H.; Orlu, M.; Murdan, S.; Basit, A.W. Quantification of P-Glycoprotein in the Gastrointestinal Tract of Humans and Rodents: Methodology, Gut Region, Sex, and Species Matter. Mol. Pharm. 2021, 18, 1895–1904. [Google Scholar] [CrossRef]
- Fu, D. Where Is It and How Does It Get There—Intracellular Localization and Traffic of P-glycoprotein. Front. Oncol. 2013, 3. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bruckmueller, H.; Martin, P.; Kähler, M.; Haenisch, S.; Ostrowski, M.; Drozdzik, M.; Siegmund, W.; Cascorbi, I.; Oswald, S. Clinically Relevant Multidrug Transporters Are Regulated by microRNAs along the Human Intestine. Mol. Pharm. 2017, 14, 2245–2253. [Google Scholar] [CrossRef] [Green Version]
- Deleuze, J.; Jacquemin, E.; Dubuisson, C.; Cresteil, D.; Dumont, M.; Erlinger, S.; Bernard, O.; Hadchouel, M. Defect of multidrug-resistance 3 gene expression in a subtype of progressive familial intrahepatic cholestasis. Hepatology 1996, 23, 904–908. [Google Scholar] [CrossRef]
- Patel, P.; Weerasekera, N.; Hitchins, M.; Boyd, C.; Johnston, D.; Williamson, C. Semi Quantitative Expression Analysis of MDR3, FIC1, BSEP, OATP-A, OATP-C,OATP-D, OATP-E and NTCP Gene Transcripts in 1st and 3rd Trimester Human Placenta. Placenta 2003, 24, 39–44. [Google Scholar] [CrossRef]
- Sultana, R.; Butterfield, D.A. Oxidatively Modified GST and MRP1 in Alzheimer’s Disease Brain: Implications for Accumulation of Reactive Lipid Peroxidation Products. Neurochem. Res. 2004, 29, 2215–2220. [Google Scholar] [CrossRef] [PubMed]
- Mookerjee, A.; Basu, J.M.; Majumder, S.; Chatterjee, S.; Panda, G.S.; Dutta, P.; Pal, S.; Mukherjee, P.; Efferth, T.; Roy, S.; et al. A novel copper complex induces ROS generation in doxorubicin resistant Ehrlich ascitis carcinoma cells and increases activity of antioxidant enzymes in vital organs in vivo. BMC Cancer 2006, 6, 267. [Google Scholar] [CrossRef] [Green Version]
- Keitel, V.; Kartenbeck, J.; Nies, A.T.; Spring, H.; Brom, M.; Keppler, D. Impaired protein maturation of the conjugate export pump multidrug resistance protein 2 as a consequence of a deletion mutation in dubin-johnson syndrome. Hepatology 2000, 32, 1317–1328. [Google Scholar] [CrossRef] [PubMed]
- Serrano, M.A.; Macias, R.; Briz, O.; Monte, M.J.; Blazquez, A.; Williamson, C.; Kubitz, R.; Marin, J. Expression in Human Trophoblast and Choriocarcinoma Cell Lines, BeWo, Jeg-3 and JAr of Genes Involved in the Hepatobiliary-like Excretory Function of the Placenta. Placenta 2007, 28, 107–117. [Google Scholar] [CrossRef]
- Reid, G.; Wielinga, P.; Zelcer, N.; van der Heijden, I.; Kuil, A.; de Haas, M.; Wijnholds, J.; Borst, P. The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs. Proc. Natl. Acad. Sci. USA 2003, 100, 9244–9249. [Google Scholar] [CrossRef] [Green Version]
- Jedlitschky, G.; Burchell, B.; Keppler, D. The Multidrug Resistance Protein 5 Functions as an ATP-dependent Export Pump for Cyclic Nucleotides. J. Biol. Chem. 2000, 275, 30069–30074. [Google Scholar] [CrossRef] [Green Version]
- Bergen, A.A.; Plomp, A.S.; Schuurman, E.J.; Terry, S.F.; Breuning, M.H.; Dauwerse, H.G.; Swart, J.; Kool, M.; Van Soest, S.; Baas, F.; et al. Mutations in ABCC6 cause pseudoxanthoma elasticum. Nat. Genet. 2000, 25, 228–231. [Google Scholar] [CrossRef] [PubMed]
- Matsuo, H.; Takada, T.; Ichida, K.; Nakamura, T.; Nakayama, A.; Ikebuchi, Y.; Ito, K.; Kusanagi, Y.; Chiba, T.; Tadokoro, S.; et al. Common Defects of ABCG2, a High-Capacity Urate Exporter, Cause Gout: A Function-Based Genetic Analysis in a Japanese Population. Sci. Transl. Med. 2009, 1, 5ra11. [Google Scholar] [CrossRef]
- Fredriksson, R.; Nordström, K.J.; Stephansson, O.; Hägglund, M.G.; Schiöth, H.B. The solute carrier (SLC) complement of the human genome: Phylogenetic classification reveals four major families. FEBS Lett. 2008, 582, 3811–3816. [Google Scholar] [CrossRef] [Green Version]
- Colas, C.; Ung, P.M.-U.; Schlessinger, A. SLC transporters: Structure, function, and drug discovery. MedChemComm 2016, 7, 1069–1081. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pan, Q.; Zhang, X.; Zhang, L.; Cheng, Y.; Zhao, N.; Li, F.; Zhou, X.; Chen, S.; Li, J.; Xu, S.; et al. Solute Carrier Organic Anion Transporter Family Member 3A1 Is a Bile Acid Efflux Transporter in Cholestasis. Gastroenterology 2018, 155, 1578–1592.e16. [Google Scholar] [CrossRef]
- Roth, M.; Obaidat, A.; Hagenbuch, B. OATPs, OATs and OCTs: The organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. Br. J. Pharmacol. 2012, 165, 1260–1287. [Google Scholar] [CrossRef] [Green Version]
- Wessler, I.; Roth, E.; Deutsch, C.; Brockerhoff, P.; Bittinger, F.; Kirkpatrick, C.J.; Kilbinger, H. Release of non-neuronal acetylcholine from the isolated human placenta is mediated by organic cation transporters. Br. J. Pharmacol. 2001, 134, 951–956. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Reznichenko, A.; Sinkeler, S.J.; Snieder, H.; Born, J.V.D.; De Borst, M.; Damman, J.; Van Dijk, M.C.R.F.; Van Goor, H.; Hepkema, B.G.; Hillebrands, J.-L.; et al. SLC22A2 is associated with tubular creatinine secretion and bias of estimated GFR in renal transplantation. Physiol. Genom. 2013, 45, 201–209. [Google Scholar] [CrossRef] [Green Version]
- Kliman, H.J.; Quaratella, S.B.; Setaro, A.C.; Siegman, E.C.; Subha, Z.T.; Tal, R.; Milano, K.M.; Steck, T.L. Pathway of Maternal Serotonin to the Human Embryo and Fetus. Endocrinology 2018, 159, 1609–1629. [Google Scholar] [CrossRef]
- Hasegawa, N.; Furugen, A.; Ono, K.; Koishikawa, M.; Miyazawa, Y.; Nishimura, A.; Umazume, T.; Narumi, K.; Kobayashi, M.; Iseki, K. Cellular uptake properties of lamotrigine in human placental cell lines: Investigation of involvement of organic cation transporters (SLC22A1–5). Drug Metab. Pharmacokinet. 2020, 35, 266–273. [Google Scholar] [CrossRef] [PubMed]
- Rizwan, A.N.; Burckhardt, G. Organic Anion Transporters of the SLC22 Family: Biopharmaceutical, Physiological, and Pathological Roles. Pharm. Res. 2007, 24, 450–470. [Google Scholar] [CrossRef]
- Higashino, T.; Morimoto, K.; Nakaoka, H.; Toyoda, Y.; Kawamura, Y.; Shimizu, S.; Nakamura, T.; Hosomichi, K.; Nakayama, A.; Ooyama, K.; et al. Dysfunctional missense variant of OAT10/SLC22A13 decreases gout risk and serum uric acid levels. Ann. Rheum. Dis. 2019, 79, 164–166. [Google Scholar] [CrossRef] [Green Version]
- Boswell-Casteel, R.C.; Hays, F.A. Equilibrative nucleoside transporters—A review. Nucleosides Nucleotides Nucleic Acids 2016, 36, 7–30. [Google Scholar] [CrossRef]
- Nies, A.T.; Damme, K.; Kruck, S.; Schaeffeler, E.; Schwab, M. Structure and function of multidrug and toxin extrusion proteins (MATEs) and their relevance to drug therapy and personalized medicine. Arch. Toxicol. 2016, 90, 1555–1584. [Google Scholar] [CrossRef]
- Coles, L.D.; Lee, I.J.; Voulalas, P.J.; Eddington, N.D. Estradiol and Progesterone-Mediated Regulation of P-gp in P-gp Overexpressing Cells (NCI-ADR-RES) and Placental Cells (JAR). Mol. Pharm. 2009, 6, 1816–1825. [Google Scholar] [CrossRef]
- Ushigome, F.; Takanaga, H.; Matsuo, H.; Yanai, S.; Tsukimori, K.; Nakano, H.; Uchiumi, T.; Nakamura, T.; Kuwano, M.; Ohtani, H.; et al. Human placental transport of vinblastine, vincristine, digoxin and progesterone: Contribution of P-glycoprotein. Eur. J. Pharmacol. 2000, 408, 1–10. [Google Scholar] [CrossRef]
- Sun, M.; Kingdom, J.; Baczyk, D.; Lye, S.; Matthews, S.; Gibb, W. Expression of the Multidrug Resistance P-Glycoprotein, (ABCB1 glycoprotein) in the Human Placenta Decreases with Advancing Gestation. Placenta 2006, 27, 602–609. [Google Scholar] [CrossRef]
- Gil, S.; Saura, R.; Forestier, F.; Farinotti, R. P-glycoprotein expression of the human placenta during pregnancy. Placenta 2005, 26, 268–270. [Google Scholar] [CrossRef] [PubMed]
- Mathias, A.A.; Hitti, J.; Unadkat, J.D. P-glycoprotein and breast cancer resistance protein expression in human placentae of various gestational ages. Am. J. Physiol. Integr. Comp. Physiol. 2005, 289, R963–R969. [Google Scholar] [CrossRef]
- Evseenko, D.A.; Paxton, J.; Keelan, J. ABC drug transporter expression and functional activity in trophoblast-like cell lines and differentiating primary trophoblast. Am. J. Physiol. Integr. Comp. Physiol. 2006, 290, R1357–R1365. [Google Scholar] [CrossRef] [PubMed]
- Lye, P.; Bloise, E.; Dunk, C.; Javam, M.; Gibb, W.; Lye, S.; Matthews, S. Effect of oxygen on multidrug resistance in the first trimester human placenta. Placenta 2013, 34, 817–823. [Google Scholar] [CrossRef] [PubMed]
- Dunk, C.E.; Pappas, J.J.; Lye, P.; Kibschull, M.; Javam, M.; Bloise, E.; Lye, S.J.; Szyf, M.; Matthews, S.G. P-Glycoprotein (P-gp)/ABCB1 plays a functional role in extravillous trophoblast (EVT) invasion and is decreased in the pre-eclamptic placenta. J. Cell. Mol. Med. 2018, 22, 5378–5393. [Google Scholar] [CrossRef]
- Kallol, S.; Moser-Haessig, R.; Ontsouka, C.E.; Albrecht, C. Comparative expression patterns of selected membrane transporters in differentiated BeWo and human primary trophoblast cells. Placenta 2018, 72–73, 48–52. [Google Scholar] [CrossRef]
- Tupova, L.; Hirschmugl, B.; Sucha, S.; Pilarova, V.; Székely, V.; Bakos, É.; Novakova, L.; Özvegy-Laczka, C.; Wadsack, C.; Ceckova, M. Interplay of drug transporters P-glycoprotein (MDR1), MRP1, OATP1A2 and OATP1B3 in passage of maraviroc across human placenta. Biomed. Pharmacother. 2020, 129, 110506. [Google Scholar] [CrossRef] [PubMed]
- St-Pierre, M.V.; Serrano, M.A.; Macias, R.; Dubs, U.; Hoechli, M.; Lauper, U.; Meier, P.J.; Marin, J. Expression of members of the multidrug resistance protein family in human term placenta. Am. J. Physiol. Integr. Comp. Physiol. 2000, 279, R1495–R1503. [Google Scholar] [CrossRef] [PubMed]
- Aye, I.; Paxton, J.; Evseenko, D.; Keelan, J. Expression, Localisation and Activity of ATP Binding Cassette (ABC) Family of Drug Transporters in Human Amnion Membranes. Placenta 2007, 28, 868–877. [Google Scholar] [CrossRef]
- Pascolo, L.; Fernetti, C.; Pirulli, D.; Crovella, S.; Amoroso, A.; Tiribelli, C. Effects of maturation on RNA transcription and protein expression of four MRP genes in human placenta and in BeWo cells. Biochem. Biophys. Res. Commun. 2003, 303, 259–265. [Google Scholar] [CrossRef]
- Zu Schwabedissen, H.E.M.; Grube, M.; Heydrich, B.; Linnemann, K.; Fusch, C.; Kroemer, H.K.; Jedlitschky, G. Expression, Localization, and Function of MRP5 (ABCC5), a Transporter for Cyclic Nucleotides, in Human Placenta and Cultured Human Trophoblasts: Effects of Gestational Age and Cellular Differentiation. Am. J. Pathol. 2005, 166, 39–48. [Google Scholar] [CrossRef]
- Granitzer, S.; Ellinger, I.; Khan, R.; Gelles, K.; Widhalm, R.; Hengstschläger, M.; Zeisler, H.; Desoye, G.; Tupova, L.; Ceckova, M.; et al. In vitro function and in situ localization of Multidrug Resistance-associated Protein (MRP)1 (ABCC1) suggest a protective role against methyl mercury-induced oxidative stress in the human placenta. Arch. Toxicol. 2020, 94, 3799–3817. [Google Scholar] [CrossRef]
- May, K.; Minarikova, V.; Linnemann, K.; Zygmunt, M.; Kroemer, H.K.; Fusch, C.; Siegmund, W. Role of the Multidrug Transporter Proteins ABCB1 and ABCC2 in the Diaplacental Transport of Talinolol in the Term Human Placenta. Drug Metab. Dispos. 2008, 36, 740–744. [Google Scholar] [CrossRef] [Green Version]
- Azzaroli, F.; Mennone, A.; Feletti, V.; Simoni, P.; Baglivo, E.; Montagnani, M.; Rizzo, N.; Pelusi, G.; DE Aloysio, D.; Lodato, F.; et al. Clinical trial: Modulation of human placental multidrug resistance proteins in cholestasis of pregnancy by ursodeoxycholic acid. Aliment. Pharmacol. Ther. 2007, 26, 1139–1146. [Google Scholar] [CrossRef]
- Zu Schwabedissen, H.E.M.; Jedlitschky, G.; Gratz, M.; Haenisch, S.; Linnemann, K.; Fusch, C.; Cascorbi, I.; Kroemer, H.K. Variable expression of MRP2 (ABCC2) in human placenta: Influence of gestational age and cellular differentiation. Drug Metab. Dispos. 2005, 33, 896–904. [Google Scholar] [CrossRef] [PubMed]
- Mason, C.W.; Buhimschi, I.; Buhimschi, C.S.; Dong, Y.; Weiner, C.P.; Swaan, P.W. ATP-Binding Cassette Transporter Expression in Human Placenta as a Function of Pregnancy Condition. Drug Metab. Dispos. 2011, 39, 1000–1007. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Huuskonen, P.; Myllynen, P.; Storvik, M.; Pasanen, M. The effects of aflatoxin B1 on transporters and steroid metabolizing enzymes in JEG-3 cells. Toxicol. Lett. 2013, 218, 200–206. [Google Scholar] [CrossRef] [PubMed]
- Chen, Z.S.; Belinsky, M.G.; Kruh, G.D.; Zeng, H.; Rea, P.A. Transport of methotrexate (MTX) and folates by multidrug resistance protein (MRP) 3 and MRP1: Effect of polyglutamylation on MTX transport. Cancer Res. 2001, 61, 7225–7232. [Google Scholar]
- Imaoka, T.; Kusuhara, H.; Adachi, M.; Schuetz, J.D.; Takeuchi, K.; Sugiyama, Y. Functional Involvement of Multidrug Resistance-Associated Protein 4 (MRP4/ABCC4) in the Renal Elimination of the Antiviral Drugs Adefovir and Tenofovir. Mol. Pharmacol. 2006, 71, 619–627. [Google Scholar] [CrossRef] [Green Version]
- Yoshida, M.; Suzuki, T.; Komiya, T.; Hatashita, E.; Nishio, K.; Kazuhiko, N.; Fukuoka, M. Induction of MRP5 and SMRP mRNA by adriamycin exposure and its overexpression in human lung cancer cells resistant to adriamycin. Int. J. Cancer 2001, 94, 432–437. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Belinsky, M.G.; Chen, Z.-S.; Shchaveleva, I.; Zeng, H.; Kruh, G.D. Characterization of the drug resistance and transport properties of multidrug resistance protein 6 (MRP6, ABCC6). Cancer Res. 2002, 62, 6172–6177. [Google Scholar] [PubMed]
- Madon, J.; Hagenbuch, B.; Landmann, L.; Meier, P.J.; Stieger, B. Transport Function and Hepatocellular Localization of mrp6 in Rat Liver. Mol. Pharmacol. 2000, 57, 634–641. [Google Scholar] [CrossRef] [PubMed]
- Yabuuchi, H.; Shimizu, H.; Takayanagi, S.-I.; Ishikawa, T. Multiple Splicing Variants of Two New Human ATP-Binding Cassette Transporters, ABCC11 and ABCC12. Biochem. Biophys. Res. Commun. 2001, 288, 933–939. [Google Scholar] [CrossRef] [PubMed]
- Tammur, J.; Prades, C.; Arnould, I.; Rzhetsky, A.; Hutchinson, A.; Adachi, M.; Schuetz, J.D.; Swoboda, K.; Ptácek, L.J.; Rosier, M.; et al. Two new genes from the human ATP-binding cassette transporter superfamily, ABCC11 and ABCC12, tandemly duplicated on chromosome 16q12. Gene 2001, 273, 89–96. [Google Scholar] [CrossRef]
- Joshi, A.A.; Vaidya, S.S.; St-Pierre, M.V.; Mikheev, A.M.; Desino, K.E.; Nyandege, A.N.; Audus, K.L.; Unadkat, J.D.; Gerk, P.M. Placental ABC Transporters: Biological Impact and Pharmaceutical Significance. Pharm. Res. 2016, 33, 2847–2878. [Google Scholar] [CrossRef] [PubMed]
- Vinot, C.; Gavard, L.; Tréluyer, J.M.; Manceau, S.; Courbon, E.; Scherrmann, J.M.; Decleves, X.; Duro, D.; Peytavin, G.; Mandelbrot, L.; et al. Placental Transfer of Maraviroc in anEx VivoHuman Cotyledon Perfusion Model and Influence of ABC Transporter Expression. Antimicrob. Agents Chemother. 2013, 57, 1415–1420. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Feinshtein, V.; Holcberg, G.; Amash, A.; Erez, N.; Rubin, M.; Sheiner, E.; Polachek, H.; Ben-Zvi, Z. Nitrofurantoin transport by placental choriocarcinoma JAr cells: Involvement of BCRP, OATP2B1 and other MDR transporters. Arch. Gynecol. Obstet. 2009, 281, 1037–1044. [Google Scholar] [CrossRef] [PubMed]
- Afrouzian, M.; Al-Lahham, R.; Patrikeeva, S.; Xu, M.; Fokina, V.; Fischer, W.G.; Abdel-Rahman, S.Z.; Costantine, M.; Ahmed, M.S.; Nanovskaya, T. Role of the efflux transporters BCRP and MRP1 in human placental bio-disposition of pravastatin. Biochem. Pharmacol. 2018, 156, 467–478. [Google Scholar] [CrossRef] [PubMed]
- Ceckova, M.; Libra, A.; Pavek, P.; Nachtigal, P.; Brabec, M.; Fuchs, R.; Staud, F. Expression and functional activity of breast cancer resistance protein (BCRP, ABCG2) transporter in the human choriocarcinoma cell line BEWO. Clin. Exp. Pharmacol. Physiol. 2006, 33, 58–65. [Google Scholar] [CrossRef] [PubMed]
- Lye, P.; Bloise, E.; Nadeem, L.; Gibb, W.; Lye, S.J.; Matthews, S.G. Glucocorticoids modulate multidrug resistance transporters in the first trimester human placenta. J. Cell. Mol. Med. 2018, 22, 3652–3660. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Loubière, L.; Vasilopoulou, E.; Bulmer, J.; Taylor, P.; Stieger, B.; Verrey, F.; McCabe, C.; Franklyn, J.; Kilby, M.; Chan, S.-Y. Expression of thyroid hormone transporters in the human placenta and changes associated with intrauterine growth restriction. Placenta 2010, 31, 295–304. [Google Scholar] [CrossRef] [Green Version]
- Litjens, C.H.C.; Heuvel, J.J.M.W.v.D.; Russel, F.G.M.; Aarnoutse, R.E.; Brake, L.H.M.T.; Koenderink, J.B. Rifampicin Transport by OATP1B1 Variants. Antimicrob. Agents Chemother. 2020, 64. [Google Scholar] [CrossRef]
- Kameyama, Y.; Yamashita, K.; Kobayashi, K.; Hosokawa, M.; Chiba, K. Functional characterization of SLCO1B1 (OATP-C) variants, SLCO1B1*5, SLCO1B1*15 and SLCO1B1*15+C1007G, by using transient expression systems of HeLa and HEK293 cells. Pharm. Genom. 2005, 15, 513–522. [Google Scholar] [CrossRef]
- Ugele, B.; St-Pierre, M.V.; Pihusch, M.; Bahn, A.; Hantschmann, P. Characterization and identification of steroid sulfate transporters of human placenta. Am. J. Physiol. Metab. 2003, 284, E390–E398. [Google Scholar] [CrossRef]
- Pinto, L.; Bapat, P.; Moreira, F.D.L.; Lubetsky, A.; Cavalli, R.D.C.; Berger, H.; Lanchote, V.L.; Koren, G. Chiral Transplacental Pharmacokinetics of Fexofenadine: Impact of P-Glycoprotein Inhibitor Fluoxetine Using the Human Placental Perfusion Model. Pharm. Res. 2021, 38, 647–655. [Google Scholar] [CrossRef] [PubMed]
- Atilano-Roque, A.; Joy, M.S. Characterization of simvastatin acid uptake by organic anion transporting polypeptide 3A1 (OATP3A1) and influence of drug-drug interaction. Toxicol. Vitr. 2017, 45, 158–165. [Google Scholar] [CrossRef]
- Lofthouse, E.M.; Torrens, C.; Manousopoulou, A.; Nahar, M.; Cleal, J.K.; O’Kelly, M.I.; Sengers, B.G.; Garbis, S.D.; Lewis, R.M. Ursodeoxycholic acid inhibits uptake and vasoconstrictor effects of taurocholate in human placenta. FASEB J. 2019, 33, 8211–8220. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bottalico, B.; Larsson, I.; Brodszki, J.; Hernandez-Andrade, E.; Casslén, B.; Marsál, K.; Hansson, S. Norepinephrine Transporter (NET), Serotonin Transporter (SERT), Vesicular Monoamine Transporter (VMAT2) and Organic Cation Transporters (OCT1, 2 and EMT) in Human Placenta from Pre-eclamptic and Normotensive Pregnancies. Placenta 2004, 25, 518–529. [Google Scholar] [CrossRef] [PubMed]
- Lee, N.; Hebert, M.F.; Prasad, B.; Easterling, T.R.; Kelly, E.J.; Unadkat, J.D.; Wang, J. Effect of Gestational Age on mRNA and Protein Expression of Polyspecific Organic Cation Transporters during Pregnancy. Drug Metab. Dispos. 2013, 41, 2225–2232. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ellawatty, W.E.A.; Masuo, Y.; Fujita, K.-I.; Yamazaki, E.; Ishida, H.; Arakawa, H.; Nakamichi, N.; Abdelwahed, R.; Sasaki, Y.; Kato, Y. Organic Cation Transporter 1 Is Responsible for Hepatocellular Uptake of the Tyrosine Kinase Inhibitor Pazopanib. Drug Metab. Dispos. 2017, 46, 33–40. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Meyer, M.J.; Seitz, T.; Brockmöller, J.; Tzvetkov, M.V. Effects of genetic polymorphisms on the OCT1 and OCT2-mediated uptake of ranitidine. PLoS ONE 2017, 12, e0189521. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Brake, L.H.M.T.; Heuvel, J.J.M.W.V.D.; Buaben, A.O.; van Crevel, R.; Bilos, A.; Russel, F.G.; Aarnoutse, R.E.; Koenderink, J.B. Moxifloxacin Is a Potent In Vitro Inhibitor of OCT- and MATE-Mediated Transport of Metformin and Ethambutol. Antimicrob. Agents Chemother. 2016, 60, 7105–7114. [Google Scholar] [CrossRef] [Green Version]
- Kimura, N.; Okuda, M.; Inui, K.-I. Metformin Transport by Renal Basolateral Organic Cation Transporter hOCT2. Pharm. Res. 2005, 22, 255–259. [Google Scholar] [CrossRef] [PubMed]
- Sata, R.; Ohtani, H.; Tsujimoto, M.; Murakami, H.; Koyabu, N.; Nakamura, T.; Uchiumi, T.; Kuwano, M.; Nagata, H.; Tsukimori, K.; et al. Functional Analysis of Organic Cation Transporter 3 Expressed in Human Placenta. J. Pharmacol. Exp. Ther. 2005, 315, 888–895. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Karahoda, R.; Horackova, H.; Kastner, P.; Matthios, A.; Cerveny, L.; Kucera, R.; Kacerovsky, M.; Tebbens, J.D.; Bonnin, A.; Abad, C.; et al. Serotonin homeostasis in the materno-foetal interface at term: Role of transporters (SERT/SLC6A4 and OCT3/SLC22A3) and monoamine oxidase A (MAO-A) in uptake and degradation of serotonin by human and rat term placenta. Acta Physiol. 2020, 229, e13478. [Google Scholar] [CrossRef] [PubMed]
- Watanabe, K.; Sawano, T.; Jinriki, T.; Sato, J. Studies on Intestinal Absorption of Sulpiride (3): Intestinal Absorption of Sulpiride in Rats. Biol. Pharm. Bull. 2004, 27, 77–81. [Google Scholar] [CrossRef] [Green Version]
- Grube, M.; zu Schwabedissen, H.M.; Draber, K.; Präger, D.; Möritz, K.-U.; Linnemann, K.; Fusch, C.; Jedlitschky, G.; Kroemer, H.K. Expression, localization, and function of the carnitine transporter OCTN2 (SLC22A5) in human placenta. Drug Metab. Dispos. 2004, 33, 31–37. [Google Scholar] [CrossRef] [Green Version]
- Chang, T.-T.; Shyu, M.-K.; Huang, M.-C.; Hsu, C.-C.; Yeh, S.-Y.; Chen, M.-R.; Lin, C.-J.; Chun-Jung, L. Hypoxia-Mediated Down-Regulation of OCTN2 and PPARα Expression in Human Placentas and in BeWo Cells. Mol. Pharm. 2010, 8, 117–125. [Google Scholar] [CrossRef]
- Hu, C.; Lancaster, C.S.; Zuo, Z.; Hu, S.; Chen, Z.; Rubnitz, J.E.; Baker, S.; Sparreboom, A. Inhibition of OCTN2-Mediated Transport of Carnitine by Etoposide. Mol. Cancer Ther. 2012, 11, 921–929. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ohashi, R.; Tamai, I.; Yabuuchi, H.; Nezu, J.I.; Oku, A.; Sai, Y.; Shimane, M.; Tsuji, A. Na(+)-dependent carnitine transport by organic cation transporter (OCTN2): Its pharmacological and toxicological relevance. J. Pharmacol. Exp. Ther. 1999, 291, 778–784. [Google Scholar]
- Hosoyamada, M.; Sekine, T.; Kanai, Y.; Endou, H. Molecular cloning and functional expression of a multispecific organic anion transporter from human kidney. Am. J. Physiol. Physiol. 1999, 276, F122–F128. [Google Scholar] [CrossRef]
- Lofthouse, E.; Brooks, S.E.; Cleal, J.; Hanson, M.; Poore, K.; O’Kelly, I.M.; Lewis, R.M. Glutamate cycling may drive organic anion transport on the basal membrane of human placental syncytiotrophoblast. J. Physiol. 2015, 593, 4549–4559. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cha, S.H.; Sekine, T.; Kusuhara, H.; Yu, E.; Kim, J.Y.; Kim, D.K.; Sugiyama, Y.; Kanai, Y.; Endou, H. Molecular Cloning and Characterization of Multispecific Organic Anion Transporter 4 Expressed in the Placenta. J. Biol. Chem. 2000, 275, 4507–4512. [Google Scholar] [CrossRef] [Green Version]
- Uehara, I.; Kimura, T.; Tanigaki, S.; Fukutomi, T.; Sakai, K.; Shinohara, Y.; Ichida, K.; Iwashita, M.; Sakurai, H. Paracellular route is the major urate transport pathway across the blood-placental barrier. Physiol. Rep. 2014, 2, e12013. [Google Scholar] [CrossRef] [PubMed]
- Tomi, M.; Miyata, Y.; Noguchi, S.; Nishimura, S.; Nakashima, E. Role of protein kinase A in regulating steroid sulfate uptake for estrogen production in human placental choriocarcinoma cells. Placenta 2014, 35, 658–660. [Google Scholar] [CrossRef] [PubMed]
- Noguchi, S.; Nishimura, T.; Fujibayashi, A.; Maruyama, T.; Tomi, M.; Nakashima, E. Organic Anion Transporter 4-Mediated Transport of Olmesartan at Basal Plasma Membrane of Human Placental Barrier. J. Pharm. Sci. 2015, 104, 3128–3135. [Google Scholar] [CrossRef] [Green Version]
- Burckhardt, G. Drug transport by Organic Anion Transporters (OATs). Pharmacol. Ther. 2012, 136, 106–130. [Google Scholar] [CrossRef] [PubMed]
- Bahn, A.; Hagos, Y.; Reuter, S.; Balen, D.; Brzica, H.; Krick, W.; Burckhardt, B.C.; Sabolić, I.; Burckhardt, G. Identification of a New Urate and High Affinity Nicotinate Transporter, hOAT10 (SLC22A13). J. Biol. Chem. 2008, 283, 16332–16341. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nishimura, T.; Sano, Y.; Takahashi, Y.; Noguchi, S.; Uchida, Y.; Takagi, A.; Tanaka, T.; Katakura, S.; Nakashima, E.; Tachikawa, M.; et al. Quantification of ENT1 and ENT2 Proteins at the Placental Barrier and Contribution of These Transporters to Ribavirin Uptake. J. Pharm. Sci. 2019, 108, 3917–3922. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cerveny, L.; Ptackova, Z.; Ceckova, M.; Karahoda, R.; Karbanova, S.; Jiraskova, L.; Greenwood, S.L.; Glazier, J.D.; Staud, F. Equilibrative Nucleoside Transporter 1 (ENT1, SLC29A1) Facilitates Transfer of the Antiretroviral Drug Abacavir across the Placenta. Drug Metab. Dispos. 2018, 46, 1817–1826. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pfeifer, E.; Parrott, J.; Lee, G.T.; Domalakes, E.; Zhou, H.; He, L.; Mason, C.W. Regulation of human placental drug transporters in HCV infection and their influence on direct acting antiviral medications. Placenta 2018, 69, 32–39. [Google Scholar] [CrossRef] [PubMed]
- Govindarajan, R.; Bakken, A.H.; Hudkins, K.L.; Lai, Y.; Casado, F.J.; Anglada, M.P.; Tse, C.-M.; Hayashi, J.; Unadkat, J.D. In situ hybridization and immunolocalization of concentrative and equilibrative nucleoside transporters in the human intestine, liver, kidneys, and placenta. Am. J. Physiol. Integr. Comp. Physiol. 2007, 293, R1809–R1822. [Google Scholar] [CrossRef] [Green Version]
- Errasti-Murugarren, E.; Díaz, P.; Godoy, V.; Riquelme, G.; Pastor-Anglada, M. Expression and Distribution of Nucleoside Transporter Proteins in the Human Syncytiotrophoblast. Mol. Pharmacol. 2011, 80, 809–817. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mimura, Y.; Yasujima, T.; Ohta, K.; Inoue, K.; Yuasa, H. Functional Identification of Plasma Membrane Monoamine Transporter (PMAT/SLC29A4) as an Atenolol Transporter Sensitive to Flavonoids Contained in Apple Juice. J. Pharm. Sci. 2017, 106, 2592–2598. [Google Scholar] [CrossRef] [Green Version]
- Ahmadimoghaddam, D.; Zemankova, L.; Nachtigal, P.; Dolezelova, E.; Neumanova, Z.; Červený, L.; Ceckova, M.; Kacerovsky, M.; Micuda, S.; Staud, F. Organic Cation Transporter 3 (OCT3/SLC22A3) and Multidrug and Toxin Extrusion 1 (MATE1/SLC47A1) Transporter in the Placenta and Fetal Tissues: Expression Profile and Fetus Protective Role at Different Stages of Gestation1. Biol. Reprod. 2013, 88, 55. [Google Scholar] [CrossRef]
- Ohta, K.-Y.; Inoue, K.; Yasujima, T.; Ishimaru, M.; Yuasa, H. Functional Characteristics of Two Human MATE Transporters: Kinetics of Cimetidine Transport and Profiles of Iinhibition by Various Compounds. J. Pharm. Pharm. Sci. 2009, 12, 388–396. [Google Scholar] [CrossRef] [Green Version]
- Tanihara, Y.; Masuda, S.; Sato, T.; Katsura, T.; Ogawa, O.; Inui, K.-I. Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H+-organic cation antiporters. Biochem. Pharmacol. 2007, 74, 359–371. [Google Scholar] [CrossRef] [Green Version]
- Liu, Y.; Fan, X.; Wang, R.; Lu, X.; Dang, Y.-L.; Wang, H.; Lin, H.-Y.; Zhu, C.; Ge, H.; Cross, J.C.; et al. Single-cell RNA-seq reveals the diversity of trophoblast subtypes and patterns of differentiation in the human placenta. Cell Res. 2018, 28, 819–832. [Google Scholar] [CrossRef] [Green Version]
- Li, H.; Huang, Q.; Liu, Y.; Garmire, L.X. Single cell transcriptome research in human placenta. Reproduction 2020, 160, R155–R167. [Google Scholar] [CrossRef]
- Staud, F.; Ceckova, M. Regulation of drug transporter expression and function in the placenta. Expert Opin. Drug Metab. Toxicol. 2015, 11, 533–555. [Google Scholar] [CrossRef]
- Liu, F.; Soares, M.J.; Audus, K.L. Permeability properties of monolayers of the human trophoblast cell line BeWo. Am. J. Physiol. Physiol. 1997, 273, C1596–C1604. [Google Scholar] [CrossRef] [PubMed]
- Pastuschek, J.; Nonn, O.; Gutiérrez-Samudio, R.N.; Murrieta-Coxca, J.M.; Müller, J.; Sanft, J.; Huppertz, B.; Markert, U.R.; Groten, T.; Morales-Prieto, D.M. Molecular characteristics of established trophoblast-derived cell lines. Placenta 2021, 108, 122–133. [Google Scholar] [CrossRef] [PubMed]
- Baumann, M.U.; Schneider, H.; Malek, A.; Palta, V.; Surbek, D.V.; Sager, R.; Zamudio, S.; Illsley, N.P. Regulation of Human Trophoblast GLUT1 Glucose Transporter by Insulin-Like Growth Factor I (IGF-I). PLoS ONE 2014, 9, e106037. [Google Scholar] [CrossRef] [PubMed]
- Göhner, C.; Svensson-Arvelund, J.; Pfarrer, C.; Häger, J.-D.; Faas, M.; Ernerudh, J.; Cline, J.M.; Dixon, D.; Buse, E.; Markert, U.R. The Placenta in Toxicology. Part IV. Toxicol. Pathol. 2013, 42, 345–351. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Booth, A.G.; Olaniyan, R.O.; Vanderpuye, O.A. An improved method for the preparation of human placental syncytiotrophoblast microvilli. Placenta 1980, 1, 327–336. [Google Scholar] [CrossRef]
- Kelley, L.K.; Smith, C.H.; King, B.F. Isolation and partial characterization of the basal cell membrane of human placental trophoblast. Biochim. Biophys. Acta (BBA) Biomembr. 1983, 734, 91–98. [Google Scholar] [CrossRef]
- Pu, Y.; Gingrich, J.; Veiga-Lopez, A. A 3-dimensional microfluidic platform for modeling human extravillous trophoblast invasion and toxicological screening. Lab. Chip 2020, 21, 546–557. [Google Scholar] [CrossRef] [PubMed]
- Kreuder, A.-E.; Bolaños-Rosales, A.; Palmer, C.; Thomas, A.; Geiger, M.-A.; Lam, T.; Amler, A.-K.; Markert, U.R.; Lauster, R.; Kloke, L. Inspired by the human placenta: A novel 3D bioprinted membrane system to create barrier models. Sci. Rep. 2020, 10, 15606. [Google Scholar] [CrossRef] [PubMed]
- Blundell, C.; Yi, Y.-S.; Ma, L.; Tess, E.R.; Farrell, M.J.; Georgescu, A.; Aleksunes, L.; Huh, D. Placental Drug Transport-on-a-Chip: A Microengineered In Vitro Model of Transporter-Mediated Drug Efflux in the Human Placental Barrier. Adv. Healthc. Mater. 2017, 7, 1700786. [Google Scholar] [CrossRef] [PubMed]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Yamashita, M.; Markert, U.R. Overview of Drug Transporters in Human Placenta. Int. J. Mol. Sci. 2021, 22, 13149. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222313149
Yamashita M, Markert UR. Overview of Drug Transporters in Human Placenta. International Journal of Molecular Sciences. 2021; 22(23):13149. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222313149
Chicago/Turabian StyleYamashita, Michiko, and Udo R. Markert. 2021. "Overview of Drug Transporters in Human Placenta" International Journal of Molecular Sciences 22, no. 23: 13149. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222313149