Issues With Exogenous Nucleotides and S-adenosylhomocysteine Hydrolase

One potential safety concern with the use of exogenous nucleotides, such as in the treatment of brain injuries or for neuroprotective or other purposes, is the potential for the derangement of nucleotide metabolism in general or for inhibition of S-adenosylhomocysteine hydrolase by purines or intermediates in de novo purine formation. Additionally, deoxyadenosine triphosphate inhibits ribonucleotide diphosphate reductase ("ribonucleotide reductase"), an enzyme system that converts ribonucleotide diphosphates into deoxyribonucleotide diphosphates.

There's not much to be done to regulate ribonucleotide reductase activity. Iron deficiency has been shown to reduce ribonucleotide reductase activity, and selenium supplementation could either enhance or inhibit it. Selenium, incidentally, has a narrow therapeutic window, and doses of 300-400 micrograms per day, a dose that could produce some undesirable inhibition of ribonucleotide reductase activity, can also decrease insulinlike growth factor-I (IGF-I) levels and may decrease thyroid hormone levels (by some exotic mechanism involving changes in thyroid peroxidase levels or selenium-dependent deiodinase enzymes). Doses of selenium in the range of 100-150 mcg/day, though, are more reasonable. Hypoxia also decreases ribonucleotide reductase activity, and this could derange purine metabolism in a tissue-specific manner. I don't have time to post all the references on this, but it's easy to find articles on all these topics.

I don't have time to go into the pharmacological analysis in relation to exogenous nucleotides, but one study found that the adenosine concentration in the portal circulation, following oral ATP in rodents, was transiently elevated 1,000-fold by, I think, 7.5 mg/kg ATP. So the liver would probably be most sensitive to S-adenosylhomocysteine hydrolase inhibition by oral AMP or ATP, but another study found that only adenosine concentrations above 1 millimolar (100 times the normal levels in most tissues) would inhibit S-adenosylhomocysteine hydrolase and induce cytotoxic, apoptotic, or cytostatic effects by that mechanism. Even if a 1 mM adenosine concentration were reached in the portal vein following oral AMP or ATP, this would not be a long-lasting effect. Nonetheless, some lymphocyte populations are very sensitive to purine-induced (mainly adenosine-induced) apoptosis, and it's important to be aware of these potential effects. For example, the interstitial adenosine concentration in sites outside the liver could gradually increase. Adenosine is metabolized extremely rapidly, however, and this 1,000-fold elevation would be confined to the portal circulation and would not occur in the systemic circulation. The liver would take up most of this, for better or worse. The intracellular adenosine concentration in hepatocytes could nonetheless be elevated to a point that would favor S-adenosylhomocysteine hydrolase formation (this is what I mean by "inhibition" by adenosine, but the effect by dAdo is different--there's also more than one adenosine binding site on S-adenosylhomocysteine hydrolase).

Additionally, AICAR may accumulate in response to exogenous deoxynucleosides (http://lib.bioinfo.pl/pmid:3109390), AICAR itself can inhibit S-adenosylhomocysteine hydrolase at somewhat physiologically-achievable concentrations (http://www.ncbi.nlm.nih.gov/pubmed/10411156), and uracil misincorporation into DNA may also increase in response to exogenous deoxynucleosides (http://www.ncbi.nlm.nih.gov/pubmed/15183762?dopt=Abstract). Some of these effects could probably be prevented with systematic folic acid supplementation, given that folic acid reduces uracil misincorporation and tends to reduce AICAR levels. These are deoxynucleosides, though, and their synthesis is fairly strictly regulated by ribonucleotide reductase. A more likely sort of effect of exogenous nucleotides could be something to do with competition for transporters that transport one or more nucleotides into and out of cells or mitochondria, etc.

It's important to consider these things in the broader context, however, given that ischemia and anoxia can elevate interstitial adenosine concentrations 100-fold and derange purine metabolism and purinergic signalling. Thus, to the extent that exogenous purines could reduce ischemia by reducing inducible nitric oxide synthase activity, such as by reducing PARP activity through ATP elevation or other mechanisms, a transient derangement of purinergic signalling, in response to exogenous purines, could be a small price to pay for longer-term amelioration of chronic, ongoing ischemia-reperfusion injuries, etc.