ABCG2/BCRP decreases the transfer of a food-born chemical carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in perfused term human placenta.
We have studied the role of ATP binding cassette (ABC) transporters in fetal exposure to carcinogens using 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) a known substrate for ABC transporters as a model compound. In perfusion of human term placenta, transfer of (14)C-PhIP (2 microM) through the placenta resulted in fetal-to-maternal concentration ratio (FM ratio) of 0.72+/-0.09 at 6 h. The specific ABCG2 inhibitor KO143 increased the transfer of (14)C-PhIP from maternal to fetal circulation (FM ratio 0.90+/-0.08 at 6 h, p<0.05) while the ABCC1/ABCC2 inhibitor probenecid had no effect (FM ratio at 6 h 0.75+/-0.10, p=0.84). There was a negative correlation between the expression of ABCG2 protein in perfused tissue and the FM ratio of (14)C-PhIP (R=-0.81, p<0.01) at the end of the perfusion. The expression of ABCC2 protein did not correlate with FM ratio of PhIP (R: -0.11, p=0.76). In addition, PhIP induced the expression of ABC transporters in BeWo cells at mRNA level. In conclusion, our data indicates that ABCG2 decreases placental transfer of (14)C-PhIP in perfused human placenta. Also, PhIP may modify ABC transporter expression in choriocarcinoma cells.
Myllynen
Päivi
P
Department of Pharmacology and Toxicology, University of Oulu, PO Box 5000, 90014, Oulu, Finland. paivi.myllynen@oulu.fi
Kummu
Maria
M
Kangas
Tiina
T
Ilves
Mika
M
Immonen
Elina
E
Rysä
Jaana
J
Pirilä
Rauna
R
Lastumäki
Anni
A
Vähäkangas
Kirsi H
KH
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D002273:Carcinogens / Q000378:metabolism* / Q000633:toxicity; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000502:physiology; D005260:Female; D005502:Food / Q000633:toxicity; D006801:Humans; D007093:Imidazoles / Q000378:metabolism* / Q000633:toxicity; D008431:Maternal-Fetal Exchange / Q000502:physiology; D000089762:Multidrug Resistance-Associated Protein 2; D009363:Neoplasm Proteins / Q000502:physiology*; D010477:Perfusion / Q000379:methods*; D010920:Placenta / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy
C000715087:ABCC2 protein, human; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D002273:Carcinogens; D007093:Imidazoles; D000089762:Multidrug Resistance-Associated Protein 2; D009363:Neoplasm Proteins; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine