Expression and function of ABCB1 and ABCG2 in human placental tissue.
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.
Kolwankar
Dhanashri
D
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, 308 Harvard St. SE, Minneapolis, MN 55455, USA.
Glover
Douglas D
DD
Ware
Joseph A
JA
Tracy
Timothy S
TS
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000502:physiology*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000502:physiology*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008861:Microsomes / Q000378:metabolism; D008942:Mitoxantrone / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000502:physiology*; D010920:Placenta / Q000378:metabolism* / Q000648:ultrastructure; D011247:Pregnancy; D012907:Smoking / Q000378:metabolism; D014747:Vinblastine / Q000378:metabolism
C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D014747:Vinblastine; D008942:Mitoxantrone; D019363:Cytochrome P-450 CYP1A1