Note On Pyridoxine

The therapeutic range for vitamin B6 (pyridoxine) is fairly small, and dosages above about 125 mg/d have the potential, over the long term, to cause peripheral neuropathy. What I mean is that pyridoxine, taken at dosages higher than about 125 or *maybe* 150-200 mg/d, is quite likely to cause peripheral neuropathy in the long term. Some people set the limit at 150-200, but I'd guess it's closer to 125-150 mg/d, with a conservative dosage being 100 mg/d. The activity of erythrocyte aspartate aminotransferase, a PLP-dependent enzyme, is saturated at around 100-150 mg/d anyway. I have some references on those issues (red cell aspartate aminotransferase and dose-dependent development of peripheral neuropathy) in my old folic acid paper. There are many articles that discuss peripheral neuropathy in relation to pyridoxine. The mechanism isn't known, and there's probably no way to prevent it. I read one article that found some reactive metabolite of pyridoxine that can accumulate and that could cause peripheral neuropathy, and I've never seen research that shows any real way by which the effect could be prevented.

Aside from peripheral neuropathy, there's the potential for porphyrias at higher dosages. If a person had not addressed any megaloblastic issues in his or her bone marrow, pyridoxine could increase the activity of delta-aminolevulinic acid synthetase in preapoptotic cells or cells that would be "destined" to die off from the absence of cobalamin or reduced folates or who knows what else. The cells would then release their porphyrins into the blood, etc. Or they would survive for awhile and release them gradually, causing bad effects. Pyridoxine can also reduce porphyrin accumulation in some cases, because there can be ineffective erythropoiesis due to pyridoxine depletion (and that can cause the reticulocytes to die off). There are also hepatic porphyrias, in which the porphyrins are produced by the liver and released into the blood. I'm not up for going through articles on it now, but here are some of the articles showing the complexity of the picture: (http://scholar.google.com/scholar?q=porphyria+pyridoxine&hl=en&lr=). It's complicated, and the effect depends on the particular step that's being disrupted in heme biosynthesis. One way someone might avoid some of this type of risk would be to only increase the dose slowly and begin with a lower dose. The full effect of a dosage increase on porphyrin accumulation might not be apparent for a few days.

Even though some articles make statements suggesting that pyridoxine supplementation has no erythropoietic effects in people who don't have genetic disorders (such as X-linked, pyridoxine-responsive sideroblastic anemia), this is not true. This article shows the almost explosive quality of the accumulation of free erythrocyte protoporphyrin in a person taking pyridoxine in the context of an existing disease state (prostate cancer) [Lee et al., 1966: (http://www.ncbi.nlm.nih.gov/pubmed/5931587)]. If the erythrocytes are not maturing properly or have damage to their DNA due to some disease state or folate or cobalamin deficiencies, the porphyrin production can be almost uncontrolled and could conceivably cause life-threatening problems. Any vascular disease or liver disease or condition associated with oxidative stress (porphyrias tend to be associated with oxidative stress, vague as that is) could increase the risk of porphyrin accumulation in response to something like pyridoxine, and it would be worth discussing that type of thing with one's doctor.

I've never seen a report of porphyrias in response to supplementation with folates or cobalamin. That would be the rationale for beginning by addressing the folate- and cobalamin-dependent one-carbon metabolism. Porphyrias could conceivably occur if a person were severely cobalamin deficient and took folates, but, for whatever reasons, it doesn't seem to occur very frequently, if at all. Even though both folate and cobalamin depletion produce "ineffective erythropoiesis," pyridoxine specifically activates porphyrin biosynthesis at the rate-limiting step (ALAS) and is sort of unique in its capacity to produce porphyrias. Some porphyrias can occur in iron deficiency, but iron excess can also produce different types of porphyrias, etc.

Another issue is the fact that histidine decarboxylase is PLP-dependent, and pyridoxine could conceivably increase histamine release from mast cells, etc. This probably is not really the way it works in normal people, because histidine decarboxylase activity is regulated by many different factors in different cell types. But if a person has asthma or some allergic disease or mastocytosis/mast cell "leukemia," pyridoxine could conceivably worsen the condition. This article, however, shows that high-dose pyridoxine actually lowers brain histamine (which could be either mast-cell-derived or neuron-derived) levels, as long as there isn't histidine supplementation [Lee et al., 1988: (http://www.ncbi.nlm.nih.gov/pubmed/3362950)]. The effects of pyridoxine on that type of thing, on neurotransmitter and glutamate/aspartate metabolism in the brain, is really complex. PLP is also a cofactor for glycogen phosphorylase and would influence carbohydrate metabolism in a multitude of ways. Here's an article that shows the extreme complexity of the effects of pyridoxine on the brain, with biphasic effects on neurotransmitters at different doses [Schaeffer et al., 1998: (http://jn.nutrition.org/cgi/content/full/128/10/1829) (http://www.ncbi.nlm.nih.gov/pubmed/9772157?dopt=Abstract)].

This article shows that low serum levels of PLP (pyridoxal-5'-phosphate) are associated with a higher risk of deep vein thrombosis, and many other articles have shown that adequate pyridoxine status is vasculoprotective [Cattaneo et al., 2001: (http://circ.ahajournals.org/cgi/content/full/104/20/2442) (http://www.ncbi.nlm.nih.gov/pubmed/11705822?dopt=Abstract)]. There are lots of articles showing antithrombotic effects of pyridoxine, but the mechanism isn't all that clear. PLP is a cofactor for various enzymes involved in the transsulfuration (and transamination--homocysteine can be broken down by transamination) of homocysteine, but pyridoxine only lowers homocysteine a little, if at all. Here are some other good articles, out of countless others, showing that low B6 levels are associated, independently of homocysteine, with increased risks of stroke, peripheral arterial disease (PAD), etc. [Robinson et al., 1998: (http://circ.ahajournals.org/cgi/content/full/97/5/437)]; [Kelly et al., 2003: (http://stroke.ahajournals.org/cgi/content/full/strokeaha;34/6/e51)]. This article shows that poor B6 status is associated with high C-reactive protein (CRP) levels [Friso et al., 2001: (http://circ.ahajournals.org/cgi/content/full/103/23/2788)]. The CRP level is thought to be a "marker" of pro-inflammatory processes in the body, etc.