Lowes Simon, Sykes Destiny, Breen Christopher M, Ragone Leigh J, Miller David S
Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
J Pharmacol Exp Ther. 2005 Oct;315(1):136-43. doi: 10.1124/jpet.105.087056. Epub 2005 Jun 15.
Initial rates of uptake of the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D; 20 microM) were measured in intact lateral choroid plexus from rat. Although inhibition of uptake by millimolar concentrations of estrone sulfate (ES) and unlabeled 2,4-D was maximal at 85%, inhibition by p-aminohippurate (PAH) saturated at about 50%. Inhibition by ES plus PAH was no greater than by ES or 2,4-D alone. Thus, inhibition studies indicated three distinct components of uptake; two mediated and one not. The sodium-dependent component of 2,4-D uptake coincided with the PAH-sensitive component, indicating uptake mediated by organic anion transporter subtype (Oat) 3. Consistent with this, efflux of 2,4-D from preloaded tissue was accelerated by all Oat3 substrates tested, and 2,4-D increased the efflux of the Oat3 substrate, PAH. Consistent with the inhibition data, kinetic analysis showed three components of 2,4-D uptake: a nonmediated component (linear kinetics), a high-affinity component, and a low-affinity component. The high-affinity component appeared to coincide with the PAH-sensitive and sodium-dependent component characterized in inhibition studies. The PAH-insensitive, low-affinity component was inhibited by ES, dehydroepiandrosterone sulfate, and taurocholate but not by 5-hydroxyindole acetic acid. Thus, the first step in transport of 2,4-D from cerebrospinal fluid to blood involves two transporters: Oat3 and a PAH-insensitive, sodium-independent transporter. Based on inhibitor profile, the latter may be Oatp3.
测定了大鼠完整侧脑室脉络丛对除草剂2,4-二氯苯氧乙酸（2,4-D；20微摩尔）的初始摄取速率。尽管毫摩尔浓度的硫酸雌酮（ES）和未标记的2,4-D对摄取的抑制作用最大可达85%，但对氨基马尿酸（PAH）的抑制作用在约50%时达到饱和。ES加PAH的抑制作用并不比单独使用ES或2,4-D时更强。因此，抑制研究表明摄取有三个不同的成分；两个是介导的，一个是非介导的。2,4-D摄取的钠依赖性成分与PAH敏感成分一致，表明是由有机阴离子转运体亚型（Oat）3介导的摄取。与此一致的是，所有测试的Oat3底物都加速了预加载组织中2,4-D的流出，并且2,4-D增加了Oat3底物PAH的流出。与抑制数据一致，动力学分析显示2,4-D摄取有三个成分：一个非介导成分（线性动力学）、一个高亲和力成分和一个低亲和力成分。高亲和力成分似乎与抑制研究中表征的PAH敏感和钠依赖性成分一致。PAH不敏感的低亲和力成分受到ES、硫酸脱氢表雄酮和牛磺胆酸盐的抑制，但不受5-羟吲哚乙酸的抑制。因此，2,4-D从脑脊液向血液转运的第一步涉及两种转运体：Oat3和一种PAH不敏感、钠非依赖性转运体。根据抑制剂谱，后者可能是Oatp3。
