Abstract
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.
Highlights
Adenosine triphosphate binding cassette (ABC) transporters transfer lipid-soluble molecules across cellular interfaces either directly or after enzymatic metabolism
ABC genes and their related metabolic enzymes identified in this study together with their estimated transcript numbers are shown in Supplementary Tables S1 and S2 respectively
Results are described in detail for eight ABC transporter transcripts that have evidence of efflux function in the tissues s tudied[18,19,20,21]
Summary
Adenosine triphosphate binding cassette (ABC) transporters transfer lipid-soluble molecules across cellular interfaces either directly or after enzymatic metabolism. The aim of the present study was to use Illumina RNA-Sequencing (RNA-Seq) of E19 placenta and fetal, early postnatal (P5) and adult brain and choroid plexus to determine the level of transcriptomic expression of these transporters and their related enzymes in these tissues. We tested their regulatory response to paracetamol exposure. In functional studies the concentration and transfer ratios of paracetamol (and its metabolites) were measured across placental and brain barriers at two different drug doses (3.75 or 15 mg/kg) and durations of administration (acute or 5 days). These experiments were carried out to to investigate if varying exposure to paracetamol could influence the effectiveness of brain and placenta barriers to this drug in vivo
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