TY - JOUR
T1 - Toxicokinetics of the food-toxin IQ in human placental perfusion is not affected by ABCG2 or xenobiotic metabolism
AU - Immonen, E
AU - Kummu, M
AU - Petsalo, A
AU - Pihlaja, T
AU - Mathiesen, L
AU - Nielsen, Jeanette Kolstrup Søgaard
AU - Knudsen, Lisbeth E.
AU - Vähäkangas, K
AU - Myllynen, P
N1 - Copyright © 2010 Elsevier Ltd. All rights reserved.
PY - 2010/7
Y1 - 2010/7
N2 - 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 14C-IQ was evaluated in 4-6 h ex vivo human placental perfusions in Finland and Denmark. In Finland placentas were perfused with 14C-IQ alone (0.5 μM, n = 6) or in combination with GF120918 (inhibitor of ABCG2, 1 μM, n = 6) or Ko143 (specific inhibitor of ABCG2, 2 μM, n = 4) to study the role of ABCG2 inhibition in transfer while in Denmark perfusions were performed with 14C-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. 14C-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. 14C-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 14C-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.
AB - 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 14C-IQ was evaluated in 4-6 h ex vivo human placental perfusions in Finland and Denmark. In Finland placentas were perfused with 14C-IQ alone (0.5 μM, n = 6) or in combination with GF120918 (inhibitor of ABCG2, 1 μM, n = 6) or Ko143 (specific inhibitor of ABCG2, 2 μM, n = 4) to study the role of ABCG2 inhibition in transfer while in Denmark perfusions were performed with 14C-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. 14C-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. 14C-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 14C-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.
U2 - 10.1016/j.placenta.2010.05.002
DO - 10.1016/j.placenta.2010.05.002
M3 - Journal article
C2 - 20570348
SN - 0143-4004
VL - 31
SP - 641
EP - 648
JO - Placenta
JF - Placenta
ER -