Aluminum transport out of brain extracellular fluid is proton dependent and inhibited by mersalyl acid, suggesting mediation by the monocarboxylate transporter (MCT1).
Blood brain barrier transport of aluminum citrate was assessed in rats by microdialysis of the jugular vein as well as the right and left frontal cortices. Previous studies (Allen et al., 1995. Evidence for energy-dependent transport of aluminum out of brain extracellular fluid. Toxicology 92, 193-202; Ackley and Yokel, 1997. Aluminum citrate is transported from brain into blood via the monocarboxylic acid transporter located at the blood-brain barrier. Toxicology 120, 89-97), and the current study, demonstrated that the steady-state brain-to-blood ratio of the unbound extracellular aluminum immediately surrounding the microdialysis probe is less than 1, suggesting the presence of a process other than diffusion across the blood brain barrier. It was speculated that a monocarboxylate transporter at the blood brain barrier was maintaining this ratio at less than 1 (Ackley and Yokel, 1997). Monocarboxylate transporters are proton co-transporters. Decreasing extracellular pH (increasing proton availability) increases monocarboxylate transport. After alkalinizing the dialysate perfusing a brain microdialysis probe (to pH = 10.2), the steady-state aluminum brain-to-blood ratio increased from 0.35 to 0.80. The addition of the proton ionophore, p-(trifluoromethoxy)phenylhydrazone (FCCP) (1 mM), to brain dialysate increased this ratio from 0.21 to 0.61. These increased ratios suggest that a proton-dependent process is removing Al from brain extracellular fluid. The monocarboxylate transporter is the only known proton-dependent transporter at the blood-brain barrier. There are two known isoforms of this transporter in the rodent, MCT1 and MCT2. Organomercurial thiol reagents, such as mersalyl acid, inhibit MCT1 but not MCT2. Mersalyl acid (50 mM) addition to brain dialysate increased the steady-state aluminum brain-to-blood ratio from 0.19 to 0.87, suggesting that MCT1 is at least partially mediating the efflux of aluminum from brain extracellular fluid.
Ackley
D C
DC
College of Pharmacy, University of Kentucky Medical Center, Lexington 40536-0082, USA.
Yokel
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RA
D000535:Aluminum / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005110:Extracellular Space / Q000378:metabolism; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008634:Mersalyl / Q000494:pharmacology*; D017551:Microdialysis; D027501:Monocarboxylic Acid Transporters; D011522:Protons; D051381:Rats; D017207:Rats, Sprague-Dawley
D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D027501:Monocarboxylic Acid Transporters; D011522:Protons; C091633:Slc16a7 protein, rat; D008634:Mersalyl; D000535:Aluminum