S-adenosylhomocysteine Hydrolase, Intracellular Adenosine, and AICAR

This issue with methotrexate elevating extracellular adenosine (and intracellular adenosine) is really complicated, and no one has a complete handle on it. It's confusing. The main issue is that both methotrexate (an antifolate) and folate repletion, by either folic acid or reduced folates, elevate extracellular adenosine concentrations. But methotrexate produces this elevation by mechanisms that are, at least to some extent, the opposite of the mechanisms by which folate elevates the extracellular adenosine concentration. If exogenous purines and pyrimidines are ever going to be used in an effective way, in some adjunctive role, to treat traumatic brain injuries or neurodegenerative diseases (or liver disease for that matter), an understanding of these confusing aspects of purine metabolism will be helpful.

There are lots of possible mechanisms by which AICAR or phosphate sequestration or both (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1896274) (along with the combined interactions of those factors with glucose and adenine nucleotide metabolism as a whole) could be involved in this, but I'm going to focus on AICAR and on the activities of S-adenosylhomocysteine hydrolase (SAHH) and 5'-nucleotidase. I'm thinking about the way 5'-nucleotidase activity fits into this because of some articles I was looking at. This one shows that 5'-nucleotidase activity, in the monocytes from the blood of some people taking methotrexate, was decreased in those who were showing evidence of liver toxicity from methotrexate:

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1753961

But that effect emerged only after 6 weeks, and many more articles show that the methotrexate-induced increases in extracellular adenosine ultimately depend on ecto-5'-nucleotidase (CD73) activity (on an increase in the flux of substrates through CD73). Here's one that gets at the core of the usual explanation for the way methotrexate elevates extracellular adenosine:

http://www.jimmunol.org/cgi/content/full/167/5/2911
(pubmed: http://www.ncbi.nlm.nih.gov/pubmed/11509639?dopt=Abstract)

The usual explanation is that AICAR (ZMP) accumulates and inhibits AMP deaminase, thereby causing AMP to accumulate (by preventing its conversion into IMP). The AMP then is thought to serve as a substrate for its ecto-5'-nucleotidase-mediated conversion into adenosine, thereby elevating extracellular adenosine and producing anti-inflammatory effects by activating plasma membrane adenosine (in the above article, A2b adenosine) receptors.

But given that the inhibition of SAHH may be the predominant mechanism by which AICAR (http://cat.inist.fr/?aModele=afficheN&cpsidt=3336180) mediates the effects of methotrexate, it's possible that the inhibition of SAHH occurs, allows the inwardly-directed transmembrane adenosine gradient to intensify (as in folate depletion and Hcy elevation), and also occurs in the face of limited AICAR-mediated inhibition of AMP deaminase activity. That would allow the ecto-5'-nucleotidase-mediated conversion of AMP into extracellular adenosine, and the higher levels of extracellular adenosine could both activate adenosine receptors and contribute to a supposed methotrexate-mediated increase in the influx of adenosine. Adenosine also can inhibit SAHH by binding to allosteric site(s) on SAHH. In any case, this would explain some of the discrepancies in the research. I'll have to finish this topic and organize the rest of the papers at some other time.