Export of Urate and Methotrexate (and Probably Folates) by MRP4

This is a really interesting article and shows that urate and methotrexate are both exported from cells by multidrug resistance protein-4 (MRP4). Even though the authors are saying they bind to different allosteric sites on MRP4, purines and reduced folates/MTX do show some structural similarities, and this type of thing could be a mechanism explaining the strange effects of folate repletion on purine metabolism and purinergic signalling. Here's the article:

http://ajprenal.physiology.org/cgi/content/full/288/2/F327 (Remon Van Aubel et al., 2005)
(pubmed: http://www.ncbi.nlm.nih.gov/pubmed/15454390?dopt=Abstract)

This is the renal MRP4 (one of the organic anion transporters), and its very high Km for urate export (~1.5 mM) may be a result of its high level of expression in the proximal tubules of the kidneys. I can't believe the intracellular urate concentrations in the liver or other extrarenal tissues are in the millimolar range in humans. Maybe they are, but I've never seen any data on the intracellular levels in humans.

Such large intracellular urate concentrations would have significant implications for hypouricemia-associated disease states like multiple sclerosis or Parkinson's disease. The intracellular levels could decrease during the known, ischemia-associated elevations in CSF urate, for example. Exogenously-induced elevations in serum urate or in endogenously-produced urate, from purines salvaged intracellularly, could buffer intracellular urate levels via some contribution to urate export from some equilibrative transporter (in a manner similar to the equilibrative transporters for other purines). The MRP's are not equilibrative, but I'm talking about other processes.

This type of thing with the MRP's could conceivably lead to either conservation of or loss of intracellular folates in association with changes in the purine pool, by the complex interdependencies, shown in that article, of the cGMP, cAMP, ATP, and urate levels.

These intracellular urate concentrations are much higher than I thought they'd be, but most of them are for non-human species. The serum urate concentrations are 100 times higher in humans than the serum urate concentrations are for almost all other species of mammals, and I would think that would somehow be reflected in a human-specific difference in the intracellular urate levels. I have yet to see any article mention the intracellular urate levels in humans, either during ischemia or under normal conditions.