title: Toxicokinetics of the food-toxin IQ in human placental perfusion is not affected by ABCG2 or xenobiotic metabolism.
abstract: 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.
authors.affiliation: Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
authors.forename: E
authors.initials: E
authors.lastname: Immonen
authors.forename: M
authors.initials: M
authors.lastname: Kummu
authors.forename: A
authors.initials: A
authors.lastname: Petsalo
authors.forename: T
authors.initials: T
authors.lastname: Pihlaja
authors.forename: L
authors.initials: L
authors.lastname: Mathiesen
authors.forename: J K S
authors.initials: JK
authors.lastname: Nielsen
authors.forename: L E
authors.initials: LE
authors.lastname: Knudsen
authors.forename: K
authors.initials: K
authors.lastname: Vähäkangas
authors.forename: P
authors.initials: P
authors.lastname: Myllynen
mesh_terms: 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*
chemical_list: 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