Institute of Biomedicine, Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
Placenta. 2010 Jul;31(7):641-8. doi: 10.1016/j.placenta.2010.05.002. Epub 2010 Jun 8.
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.
代谢酶和转运体影响异源化合物（如药物和致癌物）在人胎盘内的毒代动力学。杂环胺 2-氨基-3-甲基咪唑[4,5-f]喹啉（IQ）是一种食源性致癌物，可被细胞色素 P450（CYP）酶代谢激活，特别是 CYP1A1/2。IQ 也是 ABCG2 转运体的底物。在芬兰和丹麦进行的 4-6 小时离体人胎盘灌注研究中，评估了（14）C-IQ 的胎盘转移。在芬兰，胎盘单独用（14）C-IQ 灌注（0.5μM，n=6），或与 GF120918（ABCG2 抑制剂，1μM，n=6）或 Ko143（ABCG2 特异性抑制剂，2μM，n=4）联合灌注，以研究 ABCG2 抑制在转移中的作用，而在丹麦仅用（14）C-IQ 进行灌注。灌注过程中分析了关键参数（从胎儿到母体循环的漏出、pH 值、血气、葡萄糖消耗、hCG 激素的产生和安替比林的转运）。通过液体闪烁计数测定母侧和胎儿侧的（14）C-IQ。在芬兰，还通过 LC/TOF-MS 测定最终灌注液中的 IQ 及其代谢物。从灌注组织中分析 ABCG2 表达和 EROD 活性（CYP1A1/2）。（14）C-IQ 很容易从母体侧转移到胎盘的胎儿侧，这在两个实验室中都是如此。在不吸烟母亲的胎盘组织中，未发现明显的 EROD 活性或 IQ 代谢物。GF120918（IQ 的 FM 比为 0.95）或 Ko143（IQ 的 FM 比为 0.94）抑制 ABCG2 并不影响（14）C-IQ 转移（仅 IQ 灌注的 IQ 的 FM 比为 0.97），这表明胎盘 ABCG2 对保护胎儿免受 IQ 的影响没有显著作用。
