"Reducing Sugars"

Here's one short-term "toxicological" evaluation of ribose:

http://www.jissn.com/content/5/1/13/abstract

The decline in fasting plasma glucose is pretty significant in that study, and ribose has consistently produced those hypoglycemic effects in other studies. They should really have done a dose-response study to see if the hypoglycemic effects stop increasing. It looks like the effect was still increasing at the end of the 14-day period. Admittedly, that's an absurdly-large dose, but there's also the trend toward a decrease in the white blood cell count. I'm sure the safety profile is good overall, and that study above shows it. But it would be nice to know more about the mechanisms at work. Here are the citations for three of the series of strange articles showing apoptotic effects of ribose on monocytes or fibroblasts and referring to the concept of ribose and deoxyribose as "reducing sugars":

http://www.ncbi.nlm.nih.gov/pubmed/8024552

http://www.ncbi.nlm.nih.gov/pubmed/9480824

http://www.ncbi.nlm.nih.gov/pubmed/3931087

It's obvious that deoxyribose is more toxic, and there's much more research on the effects of deoxyribose in relation to obscure topics in monocyte differentiation, angiogenesis, etc. Those three studies have a crazed quality, though, and they use concentrations of ribose that are usually 17 times the highest level of plasma ribose achieved in a human, during "intensive ribose infusions." There can be studies like that, where the researchers just show all these extreme, toxic effects, using grossly-supraphysiological concentrations of some substance. One wonders what the point is, because the research doesn't say anything about what the mechanism would be. I think that research probably shouldn't be dismissed, though, given the decrease in the WBC count in that first study I linked to.

Another reason this concept of "reducing sugars" (it seems like outdated terminology to me) is interesting and may have some mechanistic underpinnings to it is that xylitol acts as more of an "enzymatically-mediated" reducing sugar, as discussed in this article:

http://www.jbc.org/cgi/content/abstract/246/24/7623

The results in that article make more sense to me than the results in the previous three articles and show that xylitol increases the cytosolic NADH/NAD+ ratio, thereby increasing the availability of cytosolic "reducing equivalents." The three articles I cited previously, using the 20-50 mM, supraphysiological ribose concentrations, must mean that very large concentrations of ribose are acting as nonenzymatic reducing agents? Is that what they mean?

It's still worth paying attention to those articles, though, because they may be showing an extreme version the consequences of an increase in glycolysis in the absence of a concomitant increase in oxidative ATP production (oxidative phosphorylation occurs in the mitochondria), as in the article on xylitol as a reducing sugar. That article (the JBC citation) found that the elevated cytosolic NADH/NAD+ ratio had led to inhibition of the (mitochondrial) tricarboxylic acid cycle and, as one would expect, increased the cytosolic lactate/pyruvate ratio. This is similar to the effect, of augmenting cerebral blood flow, that an elevation in the lactate/pyruvate ratio can have, under normal circumstances, on cerebral blood flow, as described in this article:

http://www.pnas.org/content/103/6/1964.full

An increase in the lactate/pyruvate ratio is one marker for mitochondrial disorders (http://www.springerlink.com/content/w0jj2620067n77j0/), because there's deficient oxidative phosphorylation in the presence of glycolysis. With ribose and xylitol, the increase in lactate production is not really bad in and of itself, given that things like exercise increase the lactate/pyruvate ratio transiently. I don't think ribose or xylitol produces effects that are analogous to the effects of so-called "exercise mimetics," such as AICAR, given that ribose, particularly in concert with nucleotides, would not be expected to inhibit mitochondrial function by binding directly to the respiratory chain, as occurs in the case of AICAR, or to decrease the ATP/AMP ratio and lead to an AMPK-activation-induced elevation of glycolysis and so-called "exercise mimesis," or whatever one wants to call it. The problems might occur in cells that have poor oxidative capacities to begin with (such as in red blood cells), cells in which large doses of ribose could potentially artificially elevate glycolysis in the absence of the NADPH levels that would normally be expected to accompany, as a result of activation of the oxidative pentose phosphate pathway, a high level of available, intracellular ribose. That's speculative, but it's worth considering these things.

The article on xylitol is actually really interesting and thoughtful, in part because it shows that xylitol doesn't increase the ATP/ADP ratio and induces some adenine nucleotide depletion. The adenine nucleotide depletion, as I mentioned in previous postings, has been consistently been shown to occur with fructose and xylitol but not consistently with ribose. But xylitol substituted for ribose in a patient with myoadenylate deaminase deficiency, and the person had to switch to ribose because of xylitol-induced hyperuricemia. The sort of minimal effect of xylitol on ATP production is consistent with the effects of ribose by itself, but there's a large amount of research showing that ribose + purine nucleotides (or pyrimidines in some cases) does increase ATP levels (when either ribose or nucleotides fails to by itself). I'm thinking that that approach might be good for neuroprotection in the context of neurodegenerative diseases, but some of these effects of ribose still seem mysterious. One would want to have a better handle on understanding the hypoglycemic effects and enzymatically-mediated "reducing" effects before one got ahead of oneself. These are some articles that show that or discuss it:

http://www.ncbi.nlm.nih.gov/pubmed/9794092

(note that that above article, one that is great except for the orotate issue, and other articles use orotate with the aim of replenishing uridine in cardiac myocytes following ischemia, but orotate is generally toxic and reliably produces fatty liver disease by many mechanisms)

http://www.ncbi.nlm.nih.gov/pubmed/11841784

http://www.actabp.pl/pdf/4_2000/1171-1178s.pdf