Abstract
The placenta is a key organ in fetal growth and development because it controls maternal-to-fetal exchanges of nutrients and hormones. It also interferes with drug delivery to the fetus by expressing active membrane transporters and xenobiotic metabolism enzymes. Developing strategies to understand the role of the placenta in drug delivery is a challenge in toxicology. Despite common physiological functions, the placentas of different species are heterogeneous in their morphology and in their expression of membrane transporters and metabolizing proteins. These characteristics raise the difficulty of obtaining a good representative model of human placental transfer. To date, different in vitro, in vivo, and ex vivo tools have been used to elucidate transport and metabolism processes in the human placenta. This study recapitulates the typical features of human placenta and then presents the placental enzymes of xenobiotic metabolism, ATP-binding cassette transporters, solute carrier transporters, and their role in fetal exposure to xenobiotics. The study also compares the characteristics of different models of human placenta, in terms of membrane localization of transporters, and the expression of xenobiotic metabolism enzymes. The use of these models for toxicological studies, in particular xenobiotic transfer, is described, and the advantages and limits of each model are summarized.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.033571.
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ABBREVIATIONS:
- P450
- cytochrome P450
- ABC
- ATP-binding cassette
- MDR1, ABCB1
- multidrug resistance-associated proteins
- P-gp
- P-glycoprotein
- PSC833
- 6-{(2S,4R,6E)-4-methyl-2-(methylamino)-3-oxo-6-octenoic} cyclosporine D. GG918, N-{4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl}-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamine
- MRPs, ABCCs
- multidrug resistance proteins
- BCRP
- ABCG2, breast cancer resistance proteins
- PhIP
- 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
- SLC
- solute carrier
- OATP
- organic anion-transporting polypeptide
- OAT
- organic anion transporter
- OCT
- organic cation transporter
- OCTN
- organic cation/carnitine transporter
- SERT
- serotonin transporter
- NET
- norepinephrin transporter
- MCT
- monocarboxylate transporter
- ENT
- equilibrative nucleoside transporter
- FRα
- folate receptor alpha
- RFC-1
- reduced folate carrier 1
- PCFT/HCP1
- proton-coupled folate transporter/heme carrier protein 1
- hCG
- human chorionic gonadotropin
- IFN
- interferon
- IL
- interleukin
- ASCT
- amino acid transporter
- SNP
- single nucleotide polymorphism.
- Received March 26, 2010.
- Accepted July 6, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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