Abstract
The placenta plays an important role in modulating xenobiotic passage from mother to fetus. Studies in mice have demonstrated that placental ABCB1 and ABCG2 can affect the transfer of drugs across the placental barrier, suggesting a role for these transporters in protecting the fetus from environmental toxicants or drugs ingested by the mother during pregnancy. To assess the role of these transporters in the human placenta, studies were conducted to evaluate the expression and functional activity of placental ABCB1 and ABCG2. The effect of maternal smoking on these placental transporters was also assessed. Uptake rates of [3H]vinblastine and [3H]mitoxantrone were used to measure ABCB1 and ABCG2 activity, respectively, and CYP1A1 activity was assessed using ethoxyresorufin O-deethylation as a positive control for smoking-related enzyme induction. ABCB1 and ABCG2 expression levels were measured by immunoblotting techniques. ATP-dependent uptake of [3H]vinblastine in vesicles was osmotically sensitive, suggesting intravesicular accumulation, and was inhibited by verapamil, an ABCB1 inhibitor. ATP-dependent uptake of [3H]mitoxantrone was inhibited by fumitremorgin C, an ABCG2 inhibitor, but not by verapamil, suggesting that the uptake of [3H]mitoxantrone was primarily mediated by ABCG2. Although CYP1A1 activity was greatly induced in smokers, no statistical differences (p > 0.05) were noted in ABCB1 and ABCG2 activity or expression between smokers and nonsmokers. In summary, both ABCB1 and ABCG2 are expressed at high levels in human placenta and are functionally active, suggesting a protective role with respect to fetal exposure to xenobiotics ingested by the mother.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.104.002261.
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ABBREVIATIONS: P-gp, P-glycoprotein; CNS, central nervous system; mdr, multidrug resistance; PAH, polycyclic aromatic hydrocarbon; CYP1A1, cytochrome P450 1A1; 3-MC, 3-methylcholanthrene; ABC superfamily, ATP-binding cassette superfamily; ABCP, ABC transporter in placenta; BCRP, breast cancer resistance protein; MXR, mitoxantrone resistance gene; DMSO, dimethyl sulfoxide; DTT, dithiothreitol; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin.
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↵1 Current address: Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, IN.
- Received September 14, 2004.
- Accepted January 5, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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