These are some articles [Iglesias et al., 2001: (http://cat.inist.fr/?aModele=afficheN&cpsidt=13399682); Jia et al., 2006: (http://wjg.wjgnet.com/downpdf.asp?url=/1007-9327/12/1373)(http://www.ncbi.nlm.nih.gov/pubmed/16552804); Schuster et al., 2009: (http://www.ncbi.nlm.nih.gov/pubmed/19324476); Hong et al., 1992: (http://www.ncbi.nlm.nih.gov/pubmed/1546897)] that show the capacity of glutamine (GLN) to protect against various types of liver damage in animals. GLN reduced the amount of damage produced by acetaminophen-induced liver failure in rats (Hong et al., 1992), for example. The mortality rate in the group that had received GLN was 15% (4/26 rats), but the mortality rate in the control group was 46% (13/28). Hong et al. (1992) focused, to some extent, on the role that the preservation of hepatic glutathione (GSH) concentrations are thought to play in the resistance to acetaminophen-induced liver failure, and they discussed some of the research in which GLN availability, in some cell types, had been shown to be rate-limiting, for all practical purposes, for GSH biosynthesis. There is, actually, more of a rationale for the use of GLN as a precursor of GSH in something like acetaminophen-induced liver failure, as noted by the authors, than there is for the use of GLN as a GSH precursor in other contexts. As discussed by Hong et al. (1992), acetaminophen can reduce the overall GSH pool ([GSH] + [GSSG]) and doesn't just disturb the intracellular redox state, as reflected in the [GSSG]/[GSH] ratio. The authors cited research that had shown a [GSSG]/[GSH] ratio of less than .01 in the livers of animals that had been subjected to acetaminophen-induced liver failure, and, even in the presence of that ratio, the absolute levels of reduced GSH (GSH is the reduced state) levels were drastically depleted. But, in many cases, the assumption has been that it's enough to simply replenish the overall GSH+GSSG levels, and that's not necessarily going to be beneficial in many other contexts. But my point was that the hepatoprotective effects were not necessarily a result of the GLN-induced increases in hepatic GSH availability. But I've seen other research that supports the authors' assertion that GLN availability can be limiting for GSH biosynthesis under some conditions. I'd add that there's a lot of research showing that orally or parenterally-administered nucleotides can protect against experimental liver injuries in animals, and I tend to think that nucleotide monophosphates or diphosphates or triphosphates (or triacetyluridine), along with reduced folates, such as L-methylfolate or levoleucovorin, and some amount of methylcobalamin, would be more effective than trimethylglycine (betaine) or phosphatidylcholine or many of the other approaches to liver damage, but that's only my opinion. I've discussed that in past postings. Experimental liver damage is almost used as a kind of generic method, in animals, for evaluating mitochondrial toxicity or any number of other processes, and the research tends to be relevant to many other disease states that involve organs other than the liver.
Those articles, along with other articles, are relevant to an understanding of the way GLN behaves in cells that are largely nonmitotic or postmitotic, such as the brain. GLN is known to be utilized as a precursor of tricarboxylic acid (TCA) cycle intermediates and for other purposes by Kupffer cells and hepatic stellate cells in the liver, especially following a liver injury, and those cells are mitotic (again, especially after an injury). But my point is that it's possible to make crude comparisons between the effects of GLN on the liver and the effects of GLN on the brain. In contrast, the effects of GLN on proliferating lymphocytes can vary throughout the cell cycle, etc.
More specifically, the traditional model of the intercellular compartmentation of glutamine and glutamate metabolism in periportal and perivenous hepatocytes [Souba, 1991: (http://www.ncbi.nlm.nih.gov/pubmed/1892702)] is reminiscent of the traditional model of the glutamine-glutamate cycle in the brain, but neither one of those traditional models is especially helpful in allowing one to understand the effects of exogenous GLN on the brain (or liver). In each case, the traditional model is an oversimplification of the reality, in vivo, and can even become problematic, particularly if one is trying to understand the effects of exogenous (supplemental) GLN in any kind of disease state, as noted by Souba (1991). According to the traditional model, GLN is transported into periportal hepatocytes and deamidated into glutamate by glutaminase, a mitochondrial enzyme that is abundantly-expressed in periportal hepatocytes and that is presented as being expressed to a negligible extent in perivenous hepatocytes (Souba, 1991). Periportal hepatocytes also display more abundant (or, supposedly, exclusive) expression of urea cycle enzymes and utilize glutaminase-derived ammonia in the urea cycle. Perivenous hepatocytes are much less numerous than periportal hepatocytes [Haussinger, 1990: (http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1131284&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/2185740)] and supposedly are the primary or exclusive subtype of hepatocytes that express glutamine synthetase (Souba, 1991). That type of model would seem to suggest that exogenous GLN would be utilized only or primarily by periportal hepatocytes, but that's unlikely to really be the case. For example, Watford and Smith (1990) [Watford and Smith, 1990: (http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1131276&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/1970242)] found that perivenous hepatocytes did, in fact, display glutaminase activity, even though the glutaminase activity in periportal hepatocytes was 2.33 times the activity in perivenous hepatocytes. Those authors cited research that had shown that perivenous hepatocytes evidently comprise the only subtype of hepatocytes that expresses GLN synthetase. But the perivenous hepatocytes wouldn't even necessarily have to express glutaminase in order to be influenced by exogenous GLN, however. Many articles have shown that increases in the intracellular GLN concentration, up to 650 uM or so [Smith et al., 1984: (http://www.ncbi.nlm.nih.gov/pubmed/6146632)], at least, are accompanied by decreases in GLN synthetase activity, and Sandrasagra et al. (1988) [Sandrasagra et al., 1988: (http://www.ncbi.nlm.nih.gov/pubmed/2903721)] cited a lot of those articles, including some that have shown an inverse relationship between intracellular GLN concentrations and GLN synthetase activity. But the point is that some of the research has shown that GLN can fairly directly and rapidly, such as within 1.5 hours (Sandrasagra et al., 1988), decrease GLN synthetase activity. The mechanism still isn't known, but it could be that it's an allosteric effect or that the GLN-mediated increase in the proteasomal degradation of GLN synthetase requires the formation of glutaminyl-tRNA, etc. But some of the articles have shown changes in the Vmax in response to GLN, and it's unlikely that the ubiquitination of the GLN synthetase protein, by proteasomal enzymes directed to GLN synthetase by exogenous GLN (via unknown mechanisms), would be responsible for a GLN-induced decrease in the Vmax (Smith et al., 1984) of GLN synthetase, although anything's possible. So exogenous GLN could decrease GLN synthetase activity in perivenous hepatocytes, and that could reduce ATP consumption. Also, 2-oxoglutarate or alanine or aspartate or other substrates, derived from the metabolism of GLN in periportal hepatocytes, could enter perivenous hepatocytes, etc. The point is that the model of the "cycle" in the liver has the potential to be misleading and make it seem as if cells in the liver are limited, in a "strict" way, in their capacities to utilize or respond to exogenous GLN. One can look at research on the GLN-GLT-GABA cycle in the brain and get the same type of misleading sense that GLN can only be used by neurons and that it's going to build up in astrocytes and cause encephalopathy or something. It's ammonia that causes most of those effects, in my opinion, in the context of hepatic encephalopathy. Ammonia causes excessive calcium influx and inhibits multiple mitochondrial enzymes, and the resulting ATP depletion basically cripples the volume regulatory functions of astrocytes and causes astrocytic swelling that is partially a consequence of a cell-energy-metabolism-failure-induced impairment in the export of GLN from astrocytes. But the fundamental problem is not that GLN per se is causing osmoregulatory disturbances. The problem is mitochondrial dysfunction in astrocytes, in my opinion. The beneficial effects of GLN synthetase inhibitors in hepatic encephalopathy could, incidentally, be partly a result of decreases in ATP consumption and not just a result of decreases in GLN formation and in GLN-dependent astrocytic swelling.
Anyway, this posting is getting too long. I also found multiple articles that show that even intravenous GLN infusions tend to not elevate intracellular GLN concentrations in the liver or skeletal muscles, and the articles show the extremely high rate of turnover of GLN. Souba (1991), cited above, cited reference 6, on p. 291, as an example of research that had shown no increase in intracellular GLN in the liver in response to an infusion of GLN under pathological conditions, and that's relevant to the research that supposedly shows no entry of GLN into the brains of humans with traumatic brain injuries (see past postings). It's very likely that GLN did enter the brain in those people. Although Souba (1991) argued that it had been the slow rate of glutamine uptake that had been a limiting factor in the utilization of GLN, that's basically like saying that the rate of increase of intracellular GLN, in response to uptake + synthesis from glutamate or, by transamination, from aspartate, etc., had been less than the rate of decrease, either by glutaminase activity or export or deamidation by that family of non-glutaminase enzymes in the cytosol, etc. That's very similar to the situation at the blood-brain and blood-CSF barriers. The rate of efflux of GLN from the brain is 3-20 times (or something like that) higher than the rate of influx of GLN, but that doesn't mean that no GLN is being transported into the brain (and into astrocytes and neurons) (!). It says absolutely nothing about the amount of GLN that's passing through the interstitial fluid (ISF) in the CNS (to look at the ISF GLN concentration, in view of the research as a whole), especially given the drastic increases in the oxidation of GLN carbons in the TCA cycle, following ischemia, and the countless articles showing no elevations of intracellular GLN or even plasma GLN in response to parenteral or oral GLN. Watford and Smith (1990) discussed the concept that the intercellular cycling of GLN and ammonia in the liver is essentially a futile cycle (or, similarly, in the brain, although the discussions of the GLN-GLT cycle in the brain generally focus on GLT as a substrate of GLN synthetase and only focus on ammonia, as a substrate, in the context of hepatic encephalopathy and other pathological states), although the cycling is clearly not only an ATP-consuming system. But a lot of ATP is consumed. Anyway, the point is that there's a lot of research showing that GLN decreases GLN synthetase activity across small changes in extracellular GLN, and there's also research showing that GLN lessens the glucocorticoid-induced increases in GLN synthetase activity [Hickson et al., 1996: (http://www.ncbi.nlm.nih.gov/pubmed/8945950)]. Another relevant point is that Hickson et al. (1996) cited articles, on p. R1165, in which researchers had found that the glucocorticoid-induced increases in GLN synthetase expression had correlated positively with the degree of muscle atrophy or denervation of the skeletal muscles, in animal experiments. That's important and is another line of indirect evidence that the pathological effects of elevations in GLN synthetase activity are, at least partially, a consequence of increases in ATP consumption, as a result of increases in GLN synthetase activity. But a lot of articles discuss GLN formation as if it's favorable to energy metabolism. In fact, astrocytes oxidize GLN carbons very readily, just as neurons do, and the GLN-GLT cycle can appear to be "robust" or "harmonious" and can actually be consuming large amounts of ATP with very little to show for it, at least in terms of the amelioration of disease states. The articles that have shown the resistance of intracellular and extracellular GLN concentrations to infusions of large amounts of GLN also suggest, in view of the other research that has shown GLN-mediated decreases in GLN synthetase activity, that a lot of the research showing no apparent effect of lower-intensity exercise on GLN metabolism might be sort of missing the point. If one only looks at the plasma GLN level and finds no change, one could erroneously conclude that exercise produced no significant effect on GLN metabolism. One could even do an MRS study and show no change in the intracellular GLN levels, but the point is that there could be a major change in ATP consumption by GLN synthetase, even though lower-intensity, endurance exercise has sometimes been shown to decrease GLN synthetase activity or expression in skeletal muscle myocytes. Hickson et al. (1996) cited some of the other paradoxes. The main point I'd make is that there needs to be more research that looks at the GLN-GLT cycle in the brain in the context of GLN supplementation, given the vast and increasing amounts of clinical research on the effects of GLN supplementation.
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