This article [Alexander et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18381567)] discusses the results of a trial using 250 mg/day of oral pyridoxal 5'-phosphate (PLP, the coenzymated form of vitamin B6) to improve postsurgical outcomes following coronary bypass surgeries. There's a whole series of articles in which different authors argue that PLP acts as a pan-P2-purinergic receptor antagonist (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=P2+pyridoxal+purinergic+OR+purinoceptor) and blocks calcium influx into cells by that mechanism. It may be that that does occur, but there are many, many other effects of PLP. It's a cofactor for a large number of enzymes. I forget the number, but it's over 100. It looks like PLP can be more potent than pyridoxine (B6), the usual form of vitamin B6 that's used [Mason and Emerson, 1973: (http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1588335&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/4691061)]. That's similar to this article [Lee et al., 1966: (http://www.ncbi.nlm.nih.gov/pubmed/5931587)], which shows pronounced hematological effects of B6 in a person in a disease state [Natuzzi et al., 1999: (http://www.ncbi.nlm.nih.gov/pubmed/10682911)] [see discussion here: ((http://hardcorephysiologyfun.blogspot.com/2009/01/note-on-pyridoxine.html)]. The inhibition of calcium influx by P2 receptor antagonism could conceivably reduce platelet aggregation and account for some of the supposed protective effects [and for the decrease in the risk of deep vein thrombosis among people with higher serum PLP concentrations (http://hardcorephysiologyfun.blogspot.com/2009/01/note-on-pyridoxine.html)], but I would wonder if that type of effect wouldn't become maximal after a certain point. The effect of additional PLP on glutamate-oxaloacetate transaminase (aspartate aminotransferase) could also enhance mitochondrial functioning in the short term and account for some of the effects. Also, there's research showing that PLP can inhibit mitochondrial dicarboxylic acid transporters, such as for 2-oxoglutarate, etc. (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=pyridoxal+phosphate+%22oxoglutarate+carrier%22+OR+%22dicarboxylate+carrier%22+OR+%22dicarboxylate+transport%22). The article by Alexander et al. (2008) cited some articles showing protective effects of PLP, when given to people, after surgeries, for short periods of time.
I just am not sure why they're assuming that it's acting as a P2 antagonist in vivo. What are the EC50 (i.e. for inhibition of some effect that is reliably elicited by P2 receptor activation in vivo) or Ki values for the inhibition of P2 receptors by PLP, and what are the serum PLP values following oral PLP? For some cofactors and physiological substrates, it can be difficult to draw facile conclusions about EC50 values, based on known Ki values. It's often possible to predict meaningful inhibition in vivo, if one knows that the concentration of the ligand is likely to be near, in vivo and in the vicinity of the receptor in question, the Ki for receptor inhibition by that ligand. The Kd/EC50 (the coupling efficiency index, which is a way of looking at receptor-effector coupling) (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=%22Kd%2FEC50%22+coupling+efficiency) values tend to be somewhat predictable for drug agonists, and people sometimes assume that the EC50 is about the same as the Ki or Kd for a ligand (even for physiological ligands, such as GABA). The IC50 usually refers to some specific effect in an isolated system, such as the inhibition of ligand binding to a receptor. The EC50 refers to the concentration at which 50 percent of either an inhibitory or agonistic effect occurs in some system at large, such as in a cell or in vivo. Some people use the terms more loosely, but, for the purposes of some analyses, they're not the same thing. Some researchers look at selectivity indices, such as the IC50 (for cytotoxicity)/EC50(for antiviral effects in vitro or in vivo), etc. In any case, the Kd/EC50 values and Kd values themselves can be very strange for physiological ligands, particularly for something like PLP (which is metabolized and bound almost *everywhere* in the body). This article describes some of the pitfalls in drawing hasty conclusions about druglike effects of physiological ligands/substrates, such as GABA [Edgar et al., 1992: (http://www.ncbi.nlm.nih.gov/pubmed/1319548)]. It's not that one can't draw crude conclusions, but one has to be careful in drawing those conclusions. Vitamin B6 just has really big effects on lots of different functions and enzymes.
In my opinion, the main problem would be using PLP in the long term at such high dosages. Even though these trials look to be fairly short in duration, I've come to think that, in the long term, the therapeutic dosage range for B6 [note in the article by Mason and Emerson (1973) that PLP can be four or more times as potent as B6] is lower than most people might think. I don't know what the right dosage is, but, in my opinion, a long-term dosage range might be 25-75 mg/day. In past postings, I've discussed vitamin B6 in relation to glutamate-oxaloacetate transaminase (GOT) and glutamate/glutamine/2-oxoglutarate metabolism, and my current thinking is that that enzyme and maybe glutamate decarboxylase and glycogen phosphorylase (also PLP-dependent enzymes) contribute in important ways to a lot of the so-called therapeutic effects of B6 and PLP and also to their toxic effects. The effects of B6 or PLP supplementation on alkaline phosphatase activity are also likely to be important for some of the toxic effects at higher dosages (effects that would primarily emerge in the long term, in my opinion, but who's to say what the long term is). These are just my opinions, and they're not very specific statements. For example, increases in GOT activity could, in my opinion, accelerate the turnover and oxidation of tricarboxylic acid cycle substrates and cause problems. It's hard to think outside the box, when it comes to something like B6. I used to think that the absence of reports of peripheral neuropathy at doses below 100 mg/day (and the extreme rarity of reports at doses between 125 and 200 mg/day or so) meant that 100 mg/day would be a safe long-term dosage. I'm not sure I think that anymore. It doesn't make a lot of sense to think that, in part because I don't see any reason to think that toxic metabolites of B6 accumulate at those dosages. I think it produces a lot of different effects that change as one increases the dosage (and the effects of increasing PLP levels on some enzymes are larger than on others, etc.), but I don't think it's possible to clearly define what's a therapeutic effect and what isn't. For example, B6 supplementation tends to increase glycogenolysis (http://scholar.google.com/scholar?q=pyridoxine+glycogenolysis+OR+glycogenolytic&hl=en&lr=), and that could be beneficial, under some conditions, and also could become pathological, in conjunction with other effects of B6. The glycogenolytic effects are unlikely to be solely due to increases in catecholamine biosynthesis and release (i.e. by the PLP-dependent enzyme dopa decarboxylase), in my opinion, and I say that partly because fairly low dosages of B6 are used to treat McArdle's disease, a genetic disorder that impairs glycogenolysis (PLP is a cofactor for glycogen phosphorylase) (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=pyridoxine+McArdle%27s). (Myophosphorylase is the muscle-specific isoform of glycogen phosphorylase) When they say there's low muscle B6 or PLP in McArdle's disease, it's not because the disorder specifically affects B6 metabolism. It's almost certainly because there's an acceleration of B6 turnover, due to all the rhabdomyolysis and other metabolic stresses that occur in people who have the disorder. People who have McArdle's disease have a variety of different mutations that cause loss of function in myophosphorylase. In any case, the point is that saturating all or some or most of the PLP-dependent enzymes is not necessarily going to be beneficial, in my opinion, in the long term. There are no biochemical rules that say that PLP-dependent enzymes "should" be saturated or nearly saturated with their PLP cofactors or that the enzymes' saturation will produce saturation of "health potential" or whatever. I guess no one refers to anything in those terms, but I just wanted to make that point.
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