Department of Biochemistry & Pharmacology, University of Melbourne, Parkville, VIC, 3010, Australia.
Department of Neuroscience, Monash University, Melbourne, VIC, 3004, Australia.
Sci Rep. 2021 Oct 6;11(1):19878. doi: 10.1038/s41598-021-99139-6.
Adenosine triphosphate binding cassette (ABC) transporters transfer lipid-soluble molecules across cellular interfaces either directly or after enzymatic metabolism. RNAseq analysis identified transcripts for ABC transporters and enzymes in rat E19, P5 and adult brain and choroid plexus and E19 placenta. Their functional capacity to efflux small molecules was studied by quantitative analysis of paracetamol (acetaminophen) and its metabolites using liquid scintillation counting, autoradiography and ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). Animals were treated acutely (30 min) and chronically (5 days, twice daily) with paracetamol (15 mg/kg) to investigate ability of brain and placenta barriers to regulate ABC transport functionality during extended treatment. Results indicated that transcripts of many efflux-associated ABC transporters were higher in adult brain and choroid plexus than at earlier ages. Chronic treatment upregulated certain transcripts only in adult brain and altered concentrations of paracetamol metabolites in circulation of pregnant dams. Combination of changes to metabolites and transport system transcripts may explain observed changes in paracetamol entry into adult and fetal brains. Analysis of lower paracetamol dosing (3.75 mg/kg) indicated dose-dependent changes in paracetamol metabolism. Transcripts of ABC transporters and enzymes at key barriers responsible for molecular transport into the developing brain showed alterations in paracetamol pharmacokinetics in pregnancy following different treatment regimens.
三磷酸腺苷结合盒（ABC）转运蛋白通过直接或酶代谢后将脂溶性分子转运穿过细胞界面。RNAseq 分析鉴定了大鼠 E19、P5 和成年脑、脉络丛和 E19 胎盘的 ABC 转运蛋白和酶的转录本。通过使用液体闪烁计数、放射自显影和超高效液相色谱-串联质谱（UPLC-MS/MS）定量分析对乙酰氨基酚（扑热息痛）及其代谢物，研究了它们外排小分子的功能能力。动物被急性（30 分钟）和慢性（5 天，每天两次）用对乙酰氨基酚（15mg/kg）处理，以研究脑和胎盘屏障在延长治疗期间调节 ABC 转运功能的能力。结果表明，许多外排相关 ABC 转运蛋白的转录本在成年脑和脉络丛中的表达高于早期。慢性治疗仅在成年脑中上调某些转录本，并改变了妊娠母体循环中对乙酰氨基酚代谢物的浓度。代谢物和转运系统转录本的组合变化可能解释了观察到的对乙酰氨基酚进入成年和胎儿大脑的变化。对较低剂量对乙酰氨基酚（3.75mg/kg）的分析表明，对乙酰氨基酚代谢存在剂量依赖性变化。负责分子进入发育中大脑的关键屏障的 ABC 转运蛋白和酶的转录本显示，在不同治疗方案下，妊娠期间对乙酰氨基酚药代动力学发生了变化。
