Yokel Robert A
College of Pharmacy and Graduate Center for Toxicology, University of Kentucky Medical Center, Pharmacy Building, Rose Street, Lexington, KY 40536-0082, USA.
Environ Health Perspect. 2002 Oct;110 Suppl 5(Suppl 5):699-704. doi: 10.1289/ehp.02110s5699.
My colleagues and I investigated the sites and mechanisms of aluminum (Al) and manganese (Mn) distribution through the blood-brain barrier (BBB). Microdialysis was used to sample non-protein-bound Al in the extracellular fluid (ECF) of blood (plasma) and brain. Brain ECF Al appearance after intravenous Al citrate injection was too rapid to attribute to diffusion or to transferrin-receptor-mediated endocytosis, suggesting another carrier-mediated process. The brain:blood ECF Al concentration ratio was 0.15 at constant blood and brain ECF Al concentrations, suggesting carrier-mediated brain Al efflux. Pharmacological manipulations suggested the efflux carrier might be a monocarboxylate transporter (MCT). However, the lack of Al (14)C-citrate uptake into rat erythrocytes suggested it is not a good substrate for isoform MCT1 or for the band 3 anion exchanger. Al (14)C-citrate uptake into murine-derived brain endothelial cells appeared to be carrier mediated, Na independent, pH independent, and energy dependent. Uptake was inhibited by substrate/inhibitors of the MCT and organic anion transporter families. Determination of (26)Al in rat brain at various times after intravenous (26)Al suggested a prolonged brain (26)Al half-life. It appears that Al transferrin and Al citrate cross the BBB by different mechanisms, that much of the Al entering brain ECF is rapidly effluxed, probably as Al citrate, but that some Al is retained for quite some time. Brain influx of the Mn(2+) ion and Mn citrate, determined with the in situ brain perfusion technique, was greater than that attributable to diffusion, suggesting carrier-mediated uptake. Mn citrate uptake was approximately 3-fold greater than the Mn(2+) ion, suggesting it is a primary Mn species entering the brain. After Mn(2+) ion, Mn citrate, or Mn transferrin injection into the brain, brain Mn efflux was not more rapid than that predicted from diffusion. The BBB permeation of Al and Mn is mediated by carriers that may help regulate their brain concentrations.
我和我的同事研究了铝（Al）和锰（Mn）通过血脑屏障（BBB）的分布位点及机制。采用微透析技术对血液（血浆）和脑的细胞外液（ECF）中未与蛋白质结合的铝进行采样。静脉注射柠檬酸铝后，脑ECF中铝的出现速度太快，无法归因于扩散或转铁蛋白受体介导的内吞作用，这表明存在另一种载体介导的过程。在血液和脑ECF中铝浓度恒定的情况下，脑与血液ECF中铝的浓度比为0.15，这表明存在载体介导的脑铝外流。药理学操作表明，外流载体可能是单羧酸转运体（MCT）。然而，大鼠红细胞对（14）C-柠檬酸铝缺乏摄取，这表明它不是MCT1亚型或带3阴离子交换蛋白的良好底物。小鼠来源的脑内皮细胞对（14）C-柠檬酸铝的摄取似乎是载体介导的，不依赖钠，不依赖pH，且依赖能量。摄取受到MCT和有机阴离子转运体家族的底物/抑制剂的抑制。静脉注射（26）Al后不同时间对大鼠脑内（26）Al的测定表明，脑内（26）Al的半衰期延长。看来铝转铁蛋白和柠檬酸铝通过不同机制穿过血脑屏障，进入脑ECF的大部分铝可能以柠檬酸铝的形式迅速外流，但仍有一些铝会保留相当长的时间。采用原位脑灌注技术测定，Mn（2+）离子和柠檬酸锰进入脑内的量大于扩散所致的量，这表明存在载体介导的摄取。柠檬酸锰的摄取量约为Mn（2+）离子的3倍，这表明它是进入脑内的主要锰形式。向脑内注射Mn（2+）离子、柠檬酸锰或锰转铁蛋白后，脑内锰的外流速度并不比扩散预测的速度快。铝和锰通过血脑屏障的渗透是由载体介导的，这些载体可能有助于调节它们在脑内的浓度。
