Toxicokinetics of the food-toxin IQ in human placental perfusion is not affected by ABCG2 or xenobiotic metabolism.
Metabolizing enzymes and transporters affect toxicokinetics of foreign compounds (e.g. drugs and carcinogens) in human placenta. The heterocyclic amine, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) is a food-borne carcinogen being metabolically activated by cytochrome P450 (CYP) enzymes, especially by CYP1A1/2. IQ is also a substrate for ABCG2 transporter. Placental transfer of (14)C-IQ was evaluated in 4-6 h ex vivo human placental perfusions in Finland and Denmark. In Finland placentas were perfused with (14)C-IQ alone (0.5 microM, n = 6) or in combination with GF120918 (inhibitor of ABCG2, 1 microM, n = 6) or Ko143 (specific inhibitor of ABCG2, 2 microM, n = 4) to study the role of ABCG2 inhibition in transfer while in Denmark perfusions were performed with (14)C-IQ alone. Critical parameters (leak from fetal to maternal circulation, pH values, blood gases, glucose consumption, the production of hCG hormone and transport of antipyrine) were analyzed during the perfusions. (14)C-IQ on maternal and fetal sides was determined by liquid scintillation counting. In Finland IQ and its metabolites in final perfusates were determined also by LC/TOF-MS. ABCG2 expression and EROD activity (CYP1A1/2) were analyzed from perfused tissues. (14)C-IQ was easily transferred through the placenta from maternal to fetal side in both laboratories. Neither significant EROD activity nor IQ metabolites were found in placentas from non-smoking mothers. Inhibition of ABCG2 by GF120918 (FM-ratio of IQ 0.95) or Ko143 (FM-ratio of IQ 0.94) did not affect (14)C-IQ transfer (FM-ratio of IQ in IQ only perfusions 0.97), which indicates that placental ABCG2 does not have a significant role in protecting fetus from IQ.
Immonen
E
E
Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
Kummu
M
M
Petsalo
A
A
Pihlaja
T
T
Mathiesen
L
L
Nielsen
J K S
JK
Knudsen
L E
LE
Vähäkangas
K
K
Myllynen
P
P
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000166:Acridines / Q000494:pharmacology; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D002273:Carcinogens / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D054659:Diketopiperazines; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings; D006801:Humans; D008431:Maternal-Fetal Exchange / Q000502:physiology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010477:Perfusion; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011804:Quinolines / Q000493:pharmacokinetics*; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D015262:Xenobiotics / Q000378:metabolism*
C541506:3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino(1',2'-1,6)pyrido(3,4-b)indol-3-yl)propionic acid tert-butyl ester; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000166:Acridines; D002273:Carcinogens; D054659:Diketopiperazines; D006576:Heterocyclic Compounds, 4 or More Rings; D009363:Neoplasm Proteins; D011804:Quinolines; D044005:Tetrahydroisoquinolines; D015262:Xenobiotics; C029216:2-amino-3-methylimidazo(4,5-f)quinoline; D019363:Cytochrome P-450 CYP1A1; D000241:Adenosine; C083501:Elacridar